WO2020106304A1 - Topical formulations - Google Patents

Abstract

Provided herein are gelled topical formulations for the treatment of skin diseases comprising: a) a MEK inhibitor; b) one or more organic solvents in an amount of about 70% to about 99% by weight; and c) a gelling agent; wherein the one or more organic solvents are selected from the group consisting of C2-6 alcohol, a C2-6 alkylene glycol, a di-(C2-6 alkylene) glycol, a polyethylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, DMSO, ethyl acetate, acetone, N-methyl pyrrolidone, benzyl alcohol, glycerin, and an oil; the gelling agent is hydroxypropyl cellulose having a molecular weight ranging from about 40,000 Dato about 2,500,000 Da; and wherein the gelled topical formulation has a viscosity of from 1 to 25,000 cps; and DMSO, when present, is combined with at least one other of said organic solvents such that DMSO is present in an amount of less than 50% by weight.

Description

TOPICAL FORMULATIONS

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priorty to U. S. Provisional Application No. 62/769,993, filed November 20, 2018, the content of which is incorporated herein in its entirety for all purposes.

BACKGROUND OF THE INVENTION

[0002] Neurofibromatosis type 1 (NF1) occurs in approximately 1 :3,500 births, and is one of the most common autosomal dominant single-gene disorders affecting neurological function in humans. Clinically, NF1 disease is characterized by the presence of benign peripheral nerve tumors, called neurofibromas, involving Schwann cells with biallelic mutations in the NF1 gene, as well as other tumor and non-tumor manifestations. See Jousma et al. Pediatr. Blood Cancer 62: 1709-1716, 2015. NF1 is associated with several dermal disorders, including dermal neurofibromas; plexiform neurofibromas; cafe au lait spots; and axillary and inguinal freckling. Dermal neurofibromas occur in over 95% of NF1 patients, and can appear anywhere on the body, causing itching, irritation, infection, physical pain, and disfigurement. Moreover, dermal neurofibromas are associated with social isolation and anxiety.

[0003] NF1 is caused by one or more germ line mutations in NF1, a gene that inactivates the RAS pathway. Because the NF1 gene encodes a Ras-GAP protein, NF1 loss results in high Ras-GTP. Therefore, NF1 research has focused intensively on testing inhibitors in the Ras signaling pathway, including the Ras-MAPK cascade. See Jousma et al. Pediatr. Blood Cancer 62: 1709-1716, 2015. Four distinct MAPK cascades have been identified and named according to their MAPK module. See Akinleye et al. Journal of Hematology & Oncology 6:27, 2013. MEK proteins belong to a family of enzymes that lie upstream to their specific MAPK targets in each of the four MAP kinase signaling pathways. Two of these MEK proteins, MEK1 and MEK2, are closely related and participate in this signaling pathway cascade. Inhibitors of MEK1 and MEK2 have been shown to effectively inhibit MEK signaling downstream of Ras, and thus provide a strong rationale for targeting MEK in the treatment of NF 1. See Rice et al. Medicinal Chemistry Letters 3:416-421, 2012. [0004] Currently available MEK inhibitors are designed to have oral bioavailability for systemic delivery, and are associated with significant side effects including decreased left ventricular ejection fraction, elevated creatine phosphokinase, pneumonitis, renal failure, diarrhea, infection, uticaria, and maculo-papular rash, all of which are dose limiting or require permanent discontinuation. Moreover, clinical trials have shown side effects with prolonged high-dose administration of MEK inhibitors. See Huang et al. J. Ocul. Pharmacol. Ther. 25:519— 530, 2009. For example, PD0325901 , a MEK inhibitor currently in clinical trials, has exhibited neurological side effects associated with ataxia, confusion, and syncope. In addition, a number of other side effects have been observed with systemic exposure to MEK inhibitors including: acneiform rash, CPK elevation, nausea, vomiting, diarrhea, abdominal pain, and fatigue. Thus, there is a need for therapies that inhibit MEK to treat NF1 associated dermal neurofibromas, which limit these serious side effects.

[0005] Benign cutaneous tumors of the vascular, keratinocytic, and melanocytic compartments often occur at birth or during childhood. These lesions, referred in this application as “birthmarks”, can cause cosmetic distress, disfigurement and social anxiety. In some cases, these lesions can predispose individuals to functional impairment or future malignancies. These birthmarks can be sporadic or arise as part of an underlying neurocutaneous syndrome.

[0006] Vascular birthmarks include, for example port wine stain/capillary malformation, angiomas, lobular capillary hemangiomas, arteriovascular malformation, lymphatic

malformation, vascular malformation, hemangiomas, and other angioma. Keratinocytic nevi refers to Keratinocytic epidermal nevi and nevi sebacei. Melanocytic nevi (commonly known as moles) include, for example congenital nevi, multiple lentigines (which can occur in syndromes such as LEOPARD), ephiledes (freckles), and nevus spiilus.

[0007] Neurocutaneous syndromes, also referred to as birthmarks, such as port-wine stains, are associated with congenital low-flow vascular malformations (capillary malformation) in the skin which, if left untreated, can hypertrophy and develop nodularity (Minkis, K. et al, Lasers Surg Med. (2009) 41 (6): pp423-426). Laser therapy is typically used for treatment of port-wine stains, but often without full resolution. Epidermal nevi are common cutaneous mosaic disorders, subdivided into keratinocytic and organoid nevi. Organoid nevi include nevus sebaceus (NS). Immunolabelling of NS is reportedly associated with increased phosphorylated ERK staining (Aslam, A, et al., Clinical and Experimental Dermatology (2014) 39: pp 1—6). Non-organoid keratinocytic epidermal nevus (KEN) is characterized by benign congenital hyperpigmented skin lesions. Epidermal nevi with localized epidermal thickening are present at birth or become visible during childhood. Other cutaneous disorders that also occur in childhood birthmarks include nevus cellular nevus, lobulary capillary hemangioma, congenital nevi, ephiledes (freckles), multiple lentigines (which can occur in multiple syndromes including LEOPARD syndrome), capillary angioma, nevus spilus, arterio-venous malformations, lymphatic malformations, and congenital melanocytic nevus. Lentigines can occur in childhood (in syndromes such as LEOPARD syndrome), which has mutations that activate RAS/MAPK pathway, as well as can be acquired in adults. In some cases birthmarks are not amenable to surgical excision and/or laser treatment. In some cases birthmarks, when untreated, can progress to lesions and/or proliferative skin conditions.

[0008] Modulation of ERK/MEK pathways may have a therapeutic effect on birthmarks. RAS mutations have been reported in mosaic RASopathies i.e. non-organoid KEN, and sebaceous nevus (Farschtschi S, et al., BMC Medical Genetics. (2015); 16: pp 6; and Sun, B.K. et. Al,

Journal of Investigative Dermatology, (2013); 3: pp824-827). Thus, inhibition ofRas signaling pathway, including the Ras-MAPK cascade, may be useful in treating birthmarks.

[0009] Four distinct MAPK cascades have been identified and named according to their MAPK module. See Akinleye et al. Journal of Hematology & Oncology 6:27, 2013. MEK proteins belong to a family of enzymes that lie upstream to their specific MAPK targets in each of the four MAP kinase signaling pathways. Two of these MEK proteins, MEK1 and MEK2, are closely related and participate in this signaling pathway cascade. Inhibitors of MEK 1 and MEK2 have been shown to effectively inhibit MEK signaling downstream of Ras (Rice et al. Medicinal Chemistry Letters 3:416-421, 2012), and thus provide a rationale for targeting MEK in the treatment of birthmarks.

[0010] Currently available MEK pathway inhibitors are designed to have oral bioavailability for systemic delivery, but are associated with one or more significant side effects including decreased left ventricular ejection fraction, elevated creatine phosphokinase, pneumonitis, renal failure, diarrhea, infection, uticaria, and maculo-papular rash, all of which are dose limiting or require permanent discontinuation. Moreover, clinical trials have shown one or more side effects with prolonged high-dose administration of MEK inhibitors. (Huang et al. J. Ocul. Pharmacol. Ther. 25:519-530, 2009). For example, PD0325901 , a clinically-tested MEK inhibitor, has exhibited one or more neurological side effects associated with ataxia, confusion, and syncope.

In addition, a number of other side effects have been observed with systemic exposure to MEK inhibitors including: acneiform rash, CPK elevation, nausea, vomiting, diarrhea, abdominal pain, and fatigue. Thus, there is a need for therapies that treat birthmarks and also limit one or more side effects associated with systemic exposure to MEK/ERK pathway inhibitors.

[0011] In view of the above, there is urgent need for the development of a topical formulation including MEK inhibitors that can be delivered topically to treat skin disorders such as MEK- inhibitor responsive dermal disorders or MEK-mediated dermal disorders, and birthmarks.

BRIEF SUMMARY OF THE INVENTION

[0012] In one aspect, the present invention provides a gelled topical formulation for the treatment of skin disorders. The gelled topical formulation includes:

a) a MEK inhibitor;

b) one or more organic solvents in an amount of about 70% to about 99% by weight; and c) a gelling agent;

wherein the one or more organic solvents are selected from the group consisting of C2-6 alcohol, a C2-e alkylene glycol, a di-(C2-6 alkylene) glycol, a polyethylene glycol, C1-3 alkyl-(OCH2CH2)i-5- OH, DMSO, ethyl acetate, acetone, N-methyl pyrrolidone, benzyl alcohol, glycerin, and an oil; the gelling agent is hydroxypropyl cellulose having a molecular weight ranging from about 40,000 Da to about 2,500,000 Da; and wherein the gelled topical formulation has a viscosity of from 1 to 25,000 cps; and DMSO, when present, is combined with at least one other of said organic solvents such that DMSO is present in an amount of less than 50% by weight.

[0013] In another aspect, the present invention provides a method of treating a skin disorder.

The method includes administering the gelled topical formulation including a MEK inhibitor, thereby treating the skin disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIGs. 1 and 2 show the skin permeation of gelled topical formulations containing Compound 2.003, using the protocol described in Example 4.

[0015] FIG. 3 shows a dose response of Compound 2.003 in suppression of p-ERK after application of gel topical formulations containing the compound, using the protocol described in Example 5.

[0016] FIG. 4 shows effective suppression of p-ERK in skin after the 7-day study in minipig, using the protocol described in Example 5.

[0017] FIG. 5 shows effective suppression of p-ERK in neurofibroma explants after application of the gel formulation containing Compound 2.003, using the protocol described in Example 6. FIG. 5A: human cutaneous neurofibroma and human tissue explant in media with gel applied to skin surface; FIG. 5B: sectioning of explant following treatment; and

FIG. 5C: Western blot showing biomarker suppression by Compound 2.003.

[0018] FIG. 6 shows the p-ERK suppression not observed in neurofibroma explants treated with the gel formulation of Example 1 only, using the protocol described in Example 6.

[0019] FIG. 7 shows a dose response of Compound 2.003 in suppression of p-ERK in neurofibroma explants after application of the gel formulation containing Compound 2.003, using the protocol described in Example 6.

[0020] FIG. 8 shows the penetration of the stratum comeum and the p-ERK suppression after application of the gel formulation containing Compound 2.003, using the protocol described in Example 6. FIG. 8A: Western blot data; and FIG. 8B: Concentration of Compound 2.003 in top and bottom of explant section.

[0021] FIG. 9 shows suppression of p-ERK in human nevus sebaceous explants after application of gel topical formulations containing vehicle only and Compound 2.003, using the protocol described in Example 7.

[0022] FIG. 10 shows a dose response of Compound 2.003 in suppression of p-ERK in human nevus sebaceous explants after application of gel topical formulations containing vehicle only and Compound No. 2.003, using the protocol described in Example 7. [0023] FIGs. 1 1 and 12 show synthesis Scheme 1-1 and Scheme 1-2 for the preparation of a compound of formula (la), respectively.

[0024] FIG. 13 shows synthesis Scheme 1-3 for the preparation of a compound of formula (lb).

[0025] FIGs. 14-18 show synthesies Schemes 11-1 to II-5 for the preparation of a compound of formula (II), respectively.

[0026] FIGs. 19-20 show synthesis Schemes III- 1 and III-2 for the preparation of a compound of formula (Ilia), respectively.

[0027] FIG. 21 shows synthesis Scheme IV-1 for the preparation of a compound of any one of formulae (IVa), (IVb), and (IVc).

[0028] FIG. 22 shows synthesis Scheme IV-2 for the preparation of a compound of any one of formulae (IVd-1), (IVd-2), (IVe-1) and (IVe-2).

[0029] FIG. 23 shows synthesis Scheme IV-3 for the the preparation of a compound of formula (IVa).

[0030] FIGs. 24-25 show synthesis Scheme V-l and V-2 for the preparation of a compound of formula (Va), repectively.

[0031] FIG. 26 shows synthesis Scheme V-3 for the preparation of a compound of

formula (Vb).

DETAILED DESCRIPTION OF THE INVENTION

I. GENERAL

[0032] Provided herein are gelled topical formulations including MEK inhibitors and methods of using these topical formulations for the treatment of skin diseases. The gelled topical formulations are administered topically, thereby treating the skin diseases. The skin diseases are MEK-inhibitor responsive dermal disorders or diseases, MEK-mediated dermal disorder or disease, or birthmarks. II. DEFINITION

[0033] The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0034] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the substituents that would result from writing the structure from right to left, e.g., -CH₂O- is meant to include -OCH₂-.

[0035] “Alkyl” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated (i.e., Ci-Ce means one to six carbons). Alkyl can include any number of carbons, such as C1 -C2, C1-C3, C1 -C4, C1 -C5, C1-C6, C₁ -C7, Ci -Cs, C₁ -C₉, C₁ -C₁₀, C₂-C₃, C₂- C4, C2-C5, C2-C6, C3-C4, C3-C5, C₃-C₆, C₄-C₅, C₄-C₆ and C₅-C₆. For example, C₁-C₆ alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc.

[0036] “Alkylene” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated (i.e., C₁ -C₆ means one to six carbons), and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For instance, a straight chain alkylene can be the bivalent radical of -(CH₂)_n-, where n is 1 , 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.

[0037] “Alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond and having the number of carbon atom indicated (i.e., C₂-C₆ means to two to six carbons). Alkenyl can include any number of carbons, such as C₂, C₂-C₃, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C3, C3-C4, C3-C5, C₃-C₆, C₄, C₄-C₅, C₄-C₅, C₅, C₅-C₆, and C₆. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1 , 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1 -butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl,

2-pentenyl, isopentenyl, 1,3-pentadienyl, 1 ,4-pentadienyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, 1 ,3-hexadienyl, 1 ,4-hexadienyl, 1 ,5-hexadienyl, 2,4-hexadienyl, or 1 ,3,5-hexatrienyl. [0038] “Alkynyl” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond and having the number of carbon atom indicated (i.e., C2-C₆ means to two to six carbons). Alkynyl can include any number of carbons, such as C₂, C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C3, C3-C4, C3-C5, C3-C6, C₄, C₄-C5, C₄-C₆, C5, C5-C₆, and C₆. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1 -pentynyl, 2-pentynyl, isopentynyl,

1.3-pentadiynyl, 1 ,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl,

1.4-hexadiynyl, 1 ,5-hexadiynyl, 2,4-hexadiynyl, or 1 ,3,5-hexatriynyl.

[0039] “Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C₃-C₆, C₄-C₆, C₅-C₆, C₃-C₈, C₄-C₈, C5-C8, C6-C8, C₃-C₉, C3-C₁₀, C3-C_{1 1}, and C3-C₁₂. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.

Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbomane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1 ,3- and 1 , 4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1 ,3-, 1 ,4- and 1,5 -isomers), norbomene, and norbomadiene. When cycloalkyl is a saturated monocyclic C₃-C₈ cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0040] “Cycloalkylalkyl” refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the cycloalkyl component and to the point of attachment. The alkyl component can include any number of carbons, such as C₁-C₆, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, C2-C3, C2-C4, C2-C5, C2-C6, C3-C4, C3-C5, C3-C6, C4-C5, C4-C6 and Cs-Ce. The cycloalkyl component is as defined above. Exemplary cycloalkyl-alkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. [0041] “Alkoxy” refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. Alkoxy groups can have any suitable number of carbon atoms, such as C1 -C6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc.

[0042] “Hydroxyalkyl” refers to an alkyl group, as defined above, where at least one of the hydrogen atoms is replaced with a hydroxy group. As for the alkyl group, a hydroxyalkyl group can have any suitable number of carbon atoms, such as Ci-Ce. Exemplary hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (where the hydroxy is in the 1 - or 2-position), hydroxypropyl (where the hydroxy is in the 1 -, 2- or 3-position), hydroxybutyl (where the hydroxy is in the 1 -, 2-, 3- or 4-position), hydroxypentyl (where the hydroxy is in the 1-, 2-, 3-, 4- or 5-position), hydroxyhexyl (where the hydroxy is in the 1-, 2-, 3-, 4-, 5- or 6-position), 1 ,2-dihydroxyethyl, and the like.

[0043] “Alkoxyalkyl” refers to a radical having an alkyl component and an alkoxy component, where the alkyl component links the alkoxy component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the alkoxy component and to the point of attachment. The alkyl component can include any number of carbons, such as C1 -C2, C₁ -C3, C1 -C4, C1 -C5, C1 -C6, C2-C3, C2-C₄, C2-C5, C2-C6, C3-C4, C3-C5, C3-C6, C4-C5, C4-C6 and C5-C6. The alkoxy component is as defined above. Examples of the alkoxy-alkyl group include, but are not limited to, 2-ethoxy-ethyl and methoxymethyl.

[0044] “Halogen” or“halo” refers to fluoro, chloro, bromo, or iodo.

[0045] “Haloalkyl” refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms. As for alkyl group, haloalkyl groups can have any suitable number of carbon atoms, such as C1-C6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, etc. In some instances, the term“perfluoro” can be used to define a compound or radical where all the hydrogens are replaced with fluorine. For example, perfluoromethyl refers to 1 ,1 ,1 -trifluoromethyl.

[0046] “Amino” as used herein, and unless otherwise specified, refers to -NH2. [0047] “Alkylamino” as used herein, and unless otherwise specified, refers to an -NHR radical where R is alkyl as defined herein, or an N-oxide derivative thereof. In some embodiments, alkylamino is C1-C6 alkylamino. In some embodiments, C1-C6 alkylamino is methylamino, ethylamino, n-, wo-propylamino, n-, iso-, tert-butylamino, or methylamino-N-oxide, and the like.

[0048] “Dialkylamino” as used herein, and unless otherwise specified, refers to an

— NR’R radical where R and R' are independently alkyl as defined herein, or an N-oxide derivative thereof. In some embodiments, dialkylamino is di-(Ci-C₆ alkyl)amino. In some embodiments, di-(Ci-C₆ alkyl)amino is dimethylamino, methyl-ethylamino, diethylamino, or dimethylamino-N-oxide, and the like.

[0049] “Aminoalkyl” as used herein, unless otherwise specified, refers to an alkyl group substituted with one or two NH2. In some embodiments, aminoalkyl is amino-Ci-Ce alkyl.

[0050] “Alkylaminoalkyl” as used herein, unless otherwise specified, refers to an alkyl group substituted with one or two -NH(alkyl) groups. In some embodiments, alkylaminoalkyl is C1-C6 alkylamino-Ci-Ce alkyl.

[0051] “Dialkylaminoalkyl” as used herein, unless otherwise specified, refers to an alkyl group substituted with one or two -N(alkyl)2 groups. In some embodiments, dialkylaminoalkyl is di-(Ci-C6 alkyl)amino-Ci-C6 alkyl.

[0052] “Hydroxyamino” as used herein, unless otherwise specified, refers to -NHOH.

[0053] “/V-alkylhydroxyamino” as used herein, unless otherwise specified, refers to the amine hydrogen of -NHOH is substituted with alkyl as defined herein. In some embodiments, N-alkyl hydroxyamino is A-C1-C6 alkyl-hydroxyamino. In some embodiments, N-Ci-Ce alkyl- hydroxyamino is /V-methylhydroxyamino, /V-ethylhydroxyamino, N-(n-, Ao-propyl)- hydroxyamino, or N-(n-, iso-, ter/-butyl)hydroxyamino, and the like.

[0054] “Heterocycloalkyl” refers to a saturated ring system having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(0)₂-. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 1 1, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1 , 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, quinuclidinyl, pyrazolidinyl, imidazolidinyl, piperazinyl (1 ,2-, 1 ,3- and 1 ,4-isomers), oxiranyl, oxetanyl, tetrahydrofuranyl, oxanyl (tetrahydropyranyl), oxepanyl, thiiranyl, thietanyl, thiolanyl (tetrahydrothiophenyl), thianyl (tetrahydrothiopyranyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, morpholinyl, thiomorpholinyl, dioxanyl, or dithianyl. The heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with C1-C6 alkyl or oxo (=0), among many others.

[0055] The heterocycloalkyl groups can be linked via any position on the ring. For example, aziridinyl can be 1 - or 2- aziridinyl, azetidinyl can be 1 - or 2- azetidinyl, pyrrolidinyl can be 1-,

2- or 3 -pyrrolidinyl, piperidinyl can be 1-, 2-, 3- or 4-piperidinyl, pyrazolidinyl can be 1-, 2-, 3-, or 4-pyrazolidinyl, imidazolidinyl can be 1-, 2-, 3- or 4-imidazolidinyl, piperazinyl can be 1 -, 2-,

3- or 4-piperazinyl, tetrahydrofuranyl can be 1 - or 2 -tetrahydrofuranyl, oxazolidinyl can be 2-, 3- , 4- or 5-oxazolidinyl, isoxazolidinyl can be 2-, 3-, 4- or 5 -isoxazolidinyl, thiazolidinyl can be 2-, 3-, 4- or 5 -thiazolidinyl, isothiazolidinyl can be 2-, 3-, 4- or 5- isothiazolidinyl, and morpholinyl can be 2-, 3- or 4-morpholinyl.

[0056] “N-linked heterocycloalkyl” or“nitrogen-linked heterocycloalkyl” refers to the heterocycloalkyl group linked via N-position on the ring. For example, N-linked aziridinyl is aziridin-l-yl, N-linked azetidinyl is azetidin-l -yl, N-linked pyrrolidinyl is pyrrolidin- 1 -yl, N- linked piperidinyl is piperidin-l-yl, N-linked pyrazolidinyl is pyrazolidin-l-yl or pyrazolidin-2- yl, N-linked imidazolidinyl can be imidazolidin-l-yl or imidazolidin-3-yl, N-linked piperazinyl is piperazin-l-yl or piperazin-4-yl, N-linked oxazolidinyl is oxazolidin-3-yl, N-linked isoxazolidiny is isoxazolidin-2-yl, N-linked thiazolidinyl is thiazolidin-3-yl, N-linked isothiazolidinyl is isothiazolidin-2-yl, and N-linked morpholinyl is 4-morpholinyl.

[0057] When heterocycloalkyl includes 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidinyl, piperidinyl,

tetrahydrofuranyl, oxanyl, tetrahydrothiophenyl, thianyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxzoalidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl and dithianyl. Heterocycloalkyl can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, with representative members including, but not limited to, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and morpholinyl.

[0058] “Alkylene glycol” refers to a compound having the formula of H-[0-alkylene]-OH, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkylene glycol is a C2-6 alkylene glycol. In some embodiments, the C2-6 alkylene glycol is propylene glycol (1.2- propanediol).

[0059] “Di-alkylene glycol” refers to a compound having the formula of [0-alkylene-OH]₂, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the di-alkylene glycol is a di-(C2-6 alkylene) glycol. In some embodiments, the di-(C2-6 alkylene) glycol is dipropylene glycol. Dipropylene glycol is a mixture of three isomers that are 4-oxa- 2,6-heptandiol, 2-(2-hydroxy-propoxy)-propan-l -ol, and 2-(2-hydroxy-l-methyl-ethoxy)-propan- l -ol.

[0060] “Polyethylene glycol refers to a polymer containing ethylene glycol monomer units of formula -O-CH2-CH2-. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., a methyl group. Also suitable are derivatives of polyethylene glycols having esterifiable carboxy groups. Polyethylene glycols useful in the present invention can be polymers of any chain length or molecular weight, and can include branching. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 9000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 5000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 900. In some embodiments, the average molecular weight of the polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to PEG200, PEG300, PEG400, PEG600, and PEG900. The number following the“PEG” in the name refers to the average molecular weight of the polymer. [0061] “Faty acid” refers to a carboxylic acid with a long aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, from 4 to 28.

[0062] “Saturated fatty acid” refers to a fatty acid having the formula of CH₃(CH₂)_PC(0)0H, with variations in subscript“p". In some embodiments, subscript p is an integer from 6 to 22 and the saturated fatty acid refers to a saturated fatty acid having 8-24 carbon atoms. The saturated fatty acid having 8-24 carbon atoms includes caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, and lignoceric acid. In some embodiments, the saturated fatty acid having 8-18 carbon atoms is caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, or stearic acid.

[0063] “Unsaturated fatty acid” refers to a carboxylic acid with a long aliphatic chain having one or more C=C double bonds. The C=C double bonds can give either cis or trans isomers. A cis configuration means that the two hydrogen atoms adjacent to the double bond lie on the same side of the chain. A trans configuration, by contrast, means that the adjacent two hydrogen atoms lie on opposite sides of the chain. Unsaturated fatty acid can include 10 to 24 carbons.

The unsaturated fatty acid includes mono-unsaturated fatty acids, di -unsaturated fatty acids, and poly-unsaturated fatty acids.

[0064] Mono-unsaturated faty acids include, but are not limited to, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, erucic acid, brassidic acid, and nervonic acid. In some embodiments, the unsaturated fatty acid group having 10-18 carbon atoms is caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, columbinic acid, pinolenic acid, or stearidonic acid.

[0065] Di -unsaturated fatty acids include, but are not limited to, linoleic acid, eicosadienoic acid, and docosadienoic acid. The di-unsaturated fatty acid having 18 carbon atoms is linoleic acid. [0066] Poly-unsaturated fatty acids include, but are not limited to, alpha-linolenic acid, gamma-linolenic acid, columbinic acid, pinolenic acid, eleostearic acid, beta-eleostearic acid, mead acid, dihomo-y-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. In some

embodiments, the poly-unsaturated fatty acid having 18 carbon atoms is alpha-linolenic acid, gamma-linolenic acid, columbinic acid, pinolenic acid, or stearidonic acid.

[0067] “Fatty alcohol” refers to a primary alcohol with a long aliphatic chain, which is either saturated or unsaturated. The fatty alcohol can also range from as few as 4-6 carbons to as many as 22-26 carbons. The fatty alcohol includes, but is not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol (unsaturated), heptadecyl alcohol, stearyl alcohol, oleyl alcohol

(unsaturated), nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol (unsaturated), and lignoceryl alcohol.

[0068] “Fatty ester” or“fatty acid ester” refers to a type of ester that results from the combination of a fatty acid with an alcohol.

[0069] “Glyceride” refers to a fatty ester when the alcohol component is glycerol. The glyceryl fatty esters (or glycerides) produced can be monoglycerides, diglycerides, or triglycerides. “Monoglyceride” is glyceride consisting of one fatty acid chain covalently bonded to a glycerol molecule through an ester linkage. “Diglyceride” is glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. “Triglyceride” is glyceride consisting of three fatty acid chains covalently bonded to a glycerol molecule through ester linkages.

[0070] “Adipate” refers to a diester of adipic acid;“sebacate” refers to a diester of sebacic acid;“laurate” refers to an ester of lauric acid;“myristate” refers to an ester of myristic acid”; “palmitate” refers an ester of palmitic acid; and“stearate” refers an ester of stearic acid”. In some embodiments, an adipate, a sebacate, a laurate, a myristate, a palmitate, or a stearate is a di- C -₆ alkyl ester of adipic acid, a di-Ci-₆ alkyl ester of sebacic acid, a Ci-₆ alkyl ester of palmitic acid, or a glycol monoester of stearic acid, respectively. [0071] “N-acylethanolamine” refers to a type of fatty acid amide formed when the acyl group of a fatty acid is linked to the nitrogen atom of ethanolamine.

[0072] “Protecting group” refers to a compound that renders a functional group unreactive to a particular set of reaction conditions, but that is then removable in a later synthetic step so as to restore the functional group to its original state. Such protecting groups are well known to one of ordinary skill in the art and include compounds that are disclosed in“Protective Groups in Organic Synthesis”, 4th edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, 2006, which is incorporated herein by reference in its entirety.

[0073] “Salt” refers to acid or base salts of the compounds of the present invention.

Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in

Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0074] Pharmaceutically acceptable salts of the acidic compounds of the present invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and

tris-(hydroxymethyl)-methyl-ammonium salts.

[0075] Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.

[0076] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. [0077] “Isomer” refers to compounds with the same chemical formula but which are structurally distinguishable. Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.

[0078] “Tautomer” refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one form to another.

[0079] “Solvate” refers to a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0080] “Hydrate” refers to a compound that is complexed to at least one water molecule. The compounds of the present invention can be complexed with from 1 to 10 water molecules.

[0081] “Substantially free of’ or“substantially in the absence of’ stereoisomers with respect to a composition refers to a composition that includes at least 85 or 90% by weight, in some embodiments 95%, 98 %, 99% or 100% by weight, of a designated stereoisomer of a compound in the composition. In some embodiments, in the methods and compounds provided herein, the compounds are substantially free of stereoisomers.

[0082] “Isolated” with respect to a composition refers to a composition that includes at least 85%, 90%, 95%, 98%, 99% to 100% by weight, of a specified compound, the remainder comprising other chemical species or stereoisomers.

[0083] “Composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and deleterious to the recipient thereof.

[0084] “Pharmaceutically acceptable excipient” refers to a substance that aids the

administration of an active agent to and absorption by a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0085] “Weight of the base formulation” refers to a total weight of a formulation without a

MEK inhibitor and a gelling agent.

[0086] “One or more organic solvents are present in an amount of 50% by weight of the base formulation” refers to the one or more organic solvents present in 50% by weight as compared to the total weight of the base formulation without a MEK inhibitor and a gelling agent. For example,“ethanol is present in an amount of about 45% by weight of the base formulation” refers to ethanol present in about 45% by weight as compared to the total weight of the base formulation without a MEK inhibitor and a gelling agent.

[0087] “MEK inhibitor is present in an amount of 0.5% by weight of the base formulation” refers the weight percentage of the MEK inhibitor as compared to the total weight of the formulation without the MEK inhibitor and a gelling agent.

[0088] “The gelling agent is present in an amount of 1.5% by weight of the base formulation” refers the weight percentage of the gelling agent as compared to the total weight of the formulation without a MEK inhibitor and the gelling agent. For example,“the hydoxypropyl cellulose is present in an amount of 1.5% by weight of the base formulation” refers the weight percentage of the hydoxypropyl cellulose as compared to the total weight of the base formulation without a MEK inhibitor and the hydoxypropyl cellulose.

[0089] “IC50” refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

[0090] “Inhibition”,“inhibits” and“inhibitor” refer to a compound that prohibits or a method of prohibiting, a specific action or function.

[0091] “Administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. [0092] “Treat”,“treating” and“treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.

[0093] “Patient” or“subject” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient is human.

[0094] “Therapeutically effective amount” refers to an amount of a compound or of a pharmaceutical composition useful for treating or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques {see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage

Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0095] The disclosure provides“soft” MEK inhibitors, compositions comprising“soft” MEK inhibitors, and methods of treating and/or preventing a dermal disorder {e.g. , a MEK-inhibitor responsive dermal disorder or a MEK mediated dermal disorder, e.g., a dermal rasopathy, e.g., a dermal disorder associated with neurofibromatosis type 1 (NF1), e.g., a dermal neurofibroma, a subdermal neurofibroma, or a superficial plexiform neurofibroma) with MEK inhibitors e.g., “soft” MEK inhibitors. For example, the methods described herein provide administration, e.g., local or non-systemic, e.g., topical, intradermal, or intralesional administration, of MEK inhibitors, e.g.,“soft” MEK inhibitors, e.g.,“soft” MEK inhibitors described herein, whereby the side effects exhibited with systemic exposure, e.g. , known side effects exhibited with MEK inhibitors designed for systemic delivery, are significantly reduced.

[0096] In some embodiments,“soft MEK inhibitor” is a compound which inhibits MEK1 and/or 2 and is characterized by a predictable and controllable metabolism/degradation to non toxic and biologically less active or inactive (i.e. does not inhibit, or inhibits to a lesser degree, MEK1 and/or 2) products after they have achieved their therapeutic role in the skin.

[0097] “Hard MEK inhibitor” refers to a MEK inhibitor known in the art. In some embodiments, a hard MEK inhibitor is designed for oral bioavailability. This is necessary to deliver therapeutically effective levels of MEK inhibitor to peripheral lesions with systemic delivery. Hard MEK inhibitor include, for example, PD0325901 ; PD184161 ; SMK-17;

AS703026 (Pimasertib, MSC1936369); RO-4987655; Selumetinib (AZD6244, ARRY142886); Binimetinib (MEK162, ARRY-162, ARRY-438162); Refametinib; Cobimetinib (GDC-0973, XL518); GDC-0623; AZD8330 (ARRY -424704); CI-1040 (PD184352); PD198306; PD318088; Trametinib; RO-4987655; GDC-0623; TAK-733; WX-554; CH5126766 (also as R05126766); G-573; Arry 300; SHR 7390; MSC2015103B (also known as AS-703988); CS 3006; and LY 2228820 (also know as Ralimetinib).

[0098] While not wishing to be bound by theory, it is believed that soft MEK inhibitors, e.g., such as the“soft” MEK inhibitors described herein, are more metabolically labile than known “hard” MEK inhibitors. Due to their inherent metabolic instability, e.g., for degradation upon reaching the systemic circulation,“soft” MEK inhibitors, e.g., such as the“soft” MEK inhibitors described herein, are dermally active but have low systemic exposure upon local or non-systemic administration, e.g., topical, intradermal, or intralesional administration, because they rapidly degrade upon exposure to plasma or blood or hepatic metabolic enzymes. Unlike“soft” MEK inhibitors, known MEK inhibitors have been historically designed for oral bioavailability, which requires good stability in plasma or blood and good stability to hepatic metabolism necessary to permit systemic delivery at therapeutically effective levels, and are more prone to unwanted side effects and increased toxicity. As a result,“soft” MEK inhibitors, e.g. , such as the soft MEK inhibitors described herein, are less systemically toxic. [0099] “A,”“an,” or“a(n)”, when used in reference to a group of substituents or "substituent group" herein, mean at least one. For example, where a compound is substituted with "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl, wherein each alkyl and/or aryl is optionally different. In another example, where a compound is substituted with "a" subsitutent group, the compound is substituted with at least one substituent group, wherein each subsitutent group is optionally different.

III. TOPICAL FORMULATION

[0100] In one aspect, the present invention provides a gelled topical formulation for the treatment of skin disorders. The gelled topical formulation includes:

a) a MEK inhibitor;

b) one or more organic solvents in an amount of about 70% to about 99% by weight; and c) a gelling agent;

wherein the one or more organic solvents are selected from the group consisting of C2-6 alcohol, a C2-6 alkylene glycol, a di-(C2-6 alkylene) glycol, a polyethylene glycol, C1-3 alkyHOCFLCFDi-s- OH, DMSO, ethyl acetate, acetone, N-methyl pyrrolidone, benzyl alcohol, glycerin, and an oil; the gelling agent is hydroxypropyl cellulose having a molecular weight ranging from about 40,000 Da to about 2,500,000 Da; and wherein the gelled topical formulation has a viscosity of from 1 to 25,000 cps; and DMSO, when present, is combined with at least one other of said organic solvents such that DMSO is present in an amount of less than 50% by weight.

[0101] In some embodiments, the MEK inhibitor is an aniline-based MEK inhibitor including a moiety of formula:

wherein

R² is halo, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R^2a is halo or C1-C6 alkyl; and

the wavy line indicates the point of attachment to the remainder of the MEK inhibitor. [0102] The MEK inhibitors in the gelled topical formulation include any known MEK inhibitors in the art. Non-limiting examples of known MEK inhibitors include Binimetinib, Cobimetinib, Pimasertib, Refametinib, Selumetinib, Trametinib, PD0325901, PD184352 (Cl- 1040), RO-4987655, GDC-0623, TAK-733, AZD-8330, WX-554, CH5126766 (also as R05126766), G-573, Airy 300, SHR 7390, MSC2015103B (also known as AS-703988),

CS 3006, and LY 2228820 (also know as Ralimetinib). In some embodiments, the MEK inhibitor is WX-554, CH5126766 (also as R05126766), G-573, Arry 300, SHR 7390, MSC2015103B, CS 3006, and LY 2228820. In some embodiments, the MEK inhibitor is Binimetinib, Cobimetinib, Pimasertib, Refametinib, Selumetinib, Trametinib, PD0325901 , PD184352 (CI-1040), RO-4987655, GDC-0623, TAK-733, and AZD 8330.

[0103] In some embodiments, the MEK inhibitor is an allosteric MEK inhibitor.

[0104] In some embodiments, the MEK inhibitor is represented by any one of formulae (1), (II), (III), (IV), and (V):

or a N-oxide, stereoisomer, mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof, wherein:

X¹ is -CR^13b or N; X² is Ci-C₆ alkyl; X³ is S or O;

subscript n is an integer from 0 to 2;

bond“a” is a single or double bond;

R¹ is -OR⁴, -NR⁵R^5a, -N(OR^5b)R^5a, or a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶;

R² is halo, C₁-C6 alkyl, -S-C₁-C6 alkyl, C3-C₈ cycloalkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R^2a is halo or C₁-C₆ alkyl;

R⁴, R⁵, and R^5b are each independently hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl-Ci-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-Ci-C6 alkyl, amino-Ci-C₆ alkyl, C1-C6 alkylamino-Ci-C6 alkyl, di-(Ci-Ce alkyl)amino-Ci -C6 alkyl, heterocycloalkyl, heterocycloalkyl-Ci-C₆ alkyl, or R⁷-C(0)-C_I -C₆ alkyl, wherein each of the C₃-C₈ cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R⁶;

R^5a is hydrogen or C₁-C₆ alkyl;

each R⁶ is independently halo, hydroxy, oxo, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆

alkoxy, Ci-C6-hydroxyalkyl, C₁-C₆ haloalkyl, amino, Ci-Cg alkylamino, di-(Ci-C₆ alkyl)amino, amino-Ci-C₆ alkyl, Ci-Ce alkylamino-Ci-C₆ alkyl, or di-(Ci-C₆

alkyl)amino-Ci-C6 alkyl;

R⁷ is hydroxy, C1-C6 alkoxy, amino, C₁-C₆ alkylamino, di-(Ci-Ce alkyl)amino,

hydroxyamino, or N-C_\-Ce alkyl hydroxyamino;

R¹³, R^{l 3a}, and R^{l 3b} are each independently hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R²³, R^23a, and R^23b are each independently hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C2-C₆ alkynyl, C₁-C₆ alkoxy, or C₃-C₈ cycloalkoxy;

R³³, R^33a, and R^33b are each independently hydrogen, halo, Ci-Ce alkyl, C₂-C₆ alkenyl, C2-C₆ alkynyl, C₁-C₆ alkoxy, or C₃-C₈ cycloalkoxy;

R⁴³ is cyano, -C(0)NR⁴⁸R^48a, or -C(0)R⁴⁶;

R^43a is hydrogen, halo, C₁-C₆ alkyl; or

R⁴³ and R^43a together form -CH₂CH2C(0)- or -CtfrCtfrCthC O)-, each of which is

unsubstituted or substituted with one or two R⁴⁹; R⁴⁶ is hydrogen, Ci-Ce alkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl or heterocycloalkyl;

R⁴⁸ and R^48a are independently hydrogen or C₁-C₆ alkyl; and

each R⁴⁹ is independently C1-C6 alkyl, C3-C8 cycloalkyl, or C3-C8 cycloalkyl-Ci-C6 alkyl;

R⁵¹ is hydrogen, C₁-C₆ alkyl, C3-C₈ cycloalkyl, C₃-C₈ cycloalkyl-Ci-Ce alkyl, C₁-C₆ hydroxyalkyl, C1-C6 alkoxy-Ci-Ce alkyl, amino-Ci-C6 alkyl, C1-C6 alkylamino-Ci-Ce alkyl, di-(Ci-C6 alkyl)amino-Ci-C₆ alkyl, heterocycloalkyl, heterocycloalkyl-Ci -C₆ alkyl, R⁷-C(0)-C_I -C₆ alkyl, or -OR⁵⁴, wherein each of the C₃-C₈ cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R⁶; each R⁵³ is independently halo or C₁-C₆ alkyl;

R^53a and R^53b are each independently hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; and

R⁵⁴ is hydrogen, C₁-C₆ alkyl, C3-C8 cycloalkyl, C₃-C8 cycloalkyl-Ci-C₆ alkyl, Ci-Ce hydroxyalkyl, C1-C6 alkoxy-Ci-C6 alkyl, amino-Ci -C6 alkyl, Ci-Ce alkylamino-Ci-C₆ alkyl, di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl, heterocycloalkyl, heterocycloalkyl-Ci-Ce alkyl, or R⁷-C(0)-C I-C₆ alkyl, wherein each of the C3-C₈ cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R⁶.

[0105] As will be appreciated, some excipients of the topical formulations described herein can possess multiple functions. For example, a given substance may act as both a solvent and an enhancer, or both an enhancer and a thickening agent. In some such cases, the function of a given substance can be considered singular, even though its properties may allow multiple functionality.

[0106] With reference to the gelled topical formulation, in some embodiments, the one or more organic solvents are selected from the group consisting of C_2-6 alcohol, a C_2-6 alkylene glycol, a di-(C_2-6 alkylene) glycol, C_{1 -3} alkyl-(OCH₂CH₂)i-₅-OH, DMSO, ethyl acetate, acetone, N-methyl pyrrolidone, benzyl alcohol, glycerin, and an oil.

[0107] In some embodiments, the one or more organic solvents include C_2-6 alcohol. In some embodiments, the C_2-6 alcohol is selected from the group consisting of ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, and combinations thereof. In some embodiments, the C2-6 alcohol is ethanol or isopropanol. In some embodiments, the C2-6 alcohol is ethanol. In some embodiments, the one or more organic solvents include ethanol.

[0108] In some embodiments, the C2-6 alcohol is present in an amount of from 0% to 60% by weight of the base formulation. In some embodiments, the C2-6 alcohol is present in an amount of from 10% to 60%, from 20% to 60%, from 30% to 60%, from 20% to 50%, from 30% to 50%, or from 40% to 50% by weight of the base formulation. In some embodiments, ethanol is present in an amount of from 0% to 60%, from 10% to 60%, from 20% to 60%, from 30% to 60%, from 20% to 50%, from 30% to 50%, or from 40% to 50% by weight of the base formulation. In some embodiments, isopropanol is present in an amount of from 0% to 60%, from 10% to 60%, from 20% to 60%, from 30% to 60%, from 20% to 50%, from 30% to 50%, or from 40% to 50% by weight of the base formulation. In some embodiments, ethanol is present in an amount of about 45% by weight of the base formulation.

[0109] In some embodiments, the one or more organic solvents include a glycol selected from a C2-6 alkylene glycol, a di-(C2-6 alkylene) glycol, a polyethylene glycol, or combinations thereof. In some embodiments, the C2-6 alkylene glycol is propylene glycol. In some embodiments, the di-(C2-6 alkylene) glycol is dipropylene glycol. In some embodiments, the polyethylene glycol is PEG200, PEG300, PEG400, PEG600, or PEG900. In some embodiments, the one or more organic solvents include propylene glycol, PEG400, PEG600, or combinations thereof. In some embodiments, the one or more organic solvents include propylene glycol.

[0110] In some embodiments, the glycol is present in an amount of about 1% to about 50% by weight of the base formulation. In some embodiments, the glycol is present in an amount of from 5% to 50%, from 5% to 40%, from 5% to 30%, from 10% to 40%, from 10% to 30%, or from 10% to 20% by weight of the base formulation. In some embodiments, propylene glycol is present in an amount of from 5% to 40%, from 5% to 30%, from 10% to 40%, from 10% to 30%, or from 10% to 20% by weight of the base formulation. In some embodiments, propylene glycol is present in an amount of about 10% by weight of the base formulation. In some embodiments, propylene glycol is present in an amount of about 15% by weight of the base formulation.

[0111] In some embodiments, the one or more organic solvents include C1-3 alkyl- (OCH₂CH₂)I-5-OH. In some embodiments, the C1 -3 alkyl-(OCH2CH2)i-5-OH is 2-(2-ethoxyethoxy)ethanol (i.e., Tanscutol). In some embodiments, the one or more organic solvents include 2-(2-ethoxyethoxy)ethanol.

[0112] In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 0% to about 50% by weight of the base formulation. In some embodiments,

2-(2-ethoxyethoxy)ethanol is present in an amount of from 5% to 50%, from 10% to 50%, from 10% to 40%, or form 10% to 30% by weight of the base formulation. In some embodiments, 2-(2-ethoxyethoxy)ethanol is absent. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 15% by weight of the base formulation. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 20% by weight of the base formulation. In some embodiments, 2-(2-ethoxyethoxy)ethanol is present in an amount of about 30% by weight of the base formulation.

[0113] In some embodiments, the one or more organic solvents include benzyl alcohol. In some embodiments, benzyl alcohol is present in an amount of about 0% to about 10% by weight of the base formulation. In some embodiments, benzyl alcohol is absent. In some embodiments, benzyl alcohol is present in an amount of from 0.5% to 5%, from 1% to 5%, from 1% to 4%, or form 1% to 3% by weight of the base formulation. In some embodiments, benzyl alcohol is present in an amount of about 2% by weight of the base formulation.

[0114] In some embodiments, the one or more organic solvents include an oil. The oil includes any oil commonly used in a topical product approved by a regulatory agent, for example the U.S. Food and Drug Administration. In some embodiments, the oil is almond oil, apricot kernel oil PEG-6 esters, castor oil, cedar leaf oil, coconut oil, hydrogenated castor oil, hydrogenated palm/palm kernel oil, lemon oil, mineral oil, olive oil, peanut oil PEG-54 hydrogenated castor oil, peppermint oil, safflower oil, soybean oil, spearmint oil, spermaceti, tall oil, vegetable oil, or combinations.

[0115] In some embodiments, the oil is present and combined with at least one other of the one or more organic solvents such that the oil is present in an amount of less than 90% or less than 80% by weight of the base formulation. In some embodiments, the oil is present and combined with at least one other of the one or more organic solvents such that the oil is present in an amount of from 85% to 40%, from 85% to 50%, from 85% to 60%, from 75% to 40%, from 75% to 50%, from 75% to 60%, 70% to 60%, or 70% to 65% by weight of the base formulation. In some embodiments, the oil is absent.

[0116] In some embodiments, DMSO is present and combined with at least one other of the one or more organic solvents such that DMSO is present in an amount of less than 40%, less than 40%, or less than 30% by weight of the base formulation. In some embodiments, DMSO is present and combined with at least one other of the one or more organic solvents such that DMSO is present in an amount of from 40% to 30%, from 40% to 20%, from 40% to 10%, from 30% to 20%, from 30% to 10%, or from 20% to 10% by weight of the base formulation. In some embodiments, DMSO is absent.

[0117] In some embodiments, water is present in an amount of less than 15%, less than 10%, or less than 5% by weight of the base formulation. In some embodiments, water is present in an amount of from 40% to 30%, from 40% to 20%, from 40% to 10%, from 30% to 20%, from 30% to 10%, or from 20% to 10% by weight of the base formulation. In some embodiments, water is absent.

[0118] In some embodiments, the gelled topical formulation further includes one or more additives. In some embodiments, the one or more additives are an enhancer, a thickening agent, or combinations thereof. In some embodiments, the one or more additives are dimethyl isosorbide, a fatty alcohol, a fatty acid, a fatty ester, a fatty acid amide, or combinations thereof.

[0119] In some embodiments, the gelled topical formulation includes dimethyl isosorbide. Dimethyl Isosorbide (DMI) is a high purity solvent and carrier which offers a safe, effective delivery enhancement mechanism for active ingredients in personal care products or topical formulations. In addition to improving performance, its use as an epidermal penetration enhancer may reduce the amount of actives required to achieve effects, resulting in reduced formulation costs, and lower skin irritation.

[0120] In some embodiments, the gelled topical formulation includes a fatty alcohol. As used herein, the term“fatty alcohol refers to an aliphatic alcohol that is saturated or unsaturated. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has between about 12-20, 14-20, 12-18, 14-18, or 16-18 carbons on average. Suitable fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, or mixtures thereof. In some embodiments, the gelled topical formulation includes one or more fatty alcohols selected from capric alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleyl alcohol, stearyl alcohol, oleyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, and lignoceryl alcohol. In some embodiments, the gelled topical formulation includes cetyl alcohol, oleyl alcohol, or a combination thereof. In some

embodiments, the gelled topical formulation includes cetyl alcohol. In some embodiments, the gelled topical formulation includes oleyl alcohol.

[0121] In some embodiments, the fatty alcohol is present in an amount of about 0% to about 30% by weight of the base formulation. In some embodiments, fatty alcohol is present in an amount of from 2% to 30%, from 2% to 20%, from 2% to 15%, from 2% to 10%, from 2% to 5%, from 3% to 20%, from 3% to 15%, from 3% to 10%, from 3% to 8%, from 3% to 6%, 4% to 6%, from 5% to 20%, from 10% to 20%, or from 5% to 15% by weight of the base formulation. In some embodiments, fatty alcohol is present in an amount of about 5% by weight of the base formulation. In some embodiments, fatty alcohol is present in an amount of about 10% by weight of the base formulation. In some embodiments, cetyl alcohol is present in an amount of about 5% by weight of the base formulation. In some embodiments, oleyl alcohol is present in an amount of about 5% by weight of the base formulation.

[0122] In some embodiments, the gelled topical formulation includes a fatty acid. As used herein, the term“fatty acid refers to an aliphatic acid that is saturated or unsaturated. In some embodiments, the fatty acid is in a mixture of different fatty acids. In some embodiments, the fatty acid has between about 8 to about 30 carbons on average. In some embodiments, the fatty acid has about 12-20, 14-20, 12-18, 14-18, or 16-18 carbons on average. Suitable fatty acids include, but are not limited to, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic acid, eicosenoic acid, emcic acid, brassidic acid, nervonic acid, linoleic acid, eicosadienoic acid, docosadienoic acid, alpha-linolenic acid, gamma-linolenic acid, columbinic acid, pinolenic acid, alpha-eleostearic acid, beta-eleostearic acid, mead acid, dihomo-y-linolenic acid, eicosatrienoic acid, stearidonic acid, arachidonic acid, eicosapentaenoic acid,

docosapentaenoic acid, docosahexaenoic acid, or mixtures thereof. In some embodiments, the gelled topical formulation includes one or more fatty acids selected from capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, caproleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, oleic acid, erucic acid, linolenic acid, hydroxystearic acid,

12-hydroxystearic acid, cetostearic acid, isostearic acid, sesquioleic acid, sesqui-9-octadecanoic acid, sesquisooctadecanoic acid, behenic acid, isobehenic acid, and arachidonic acid. In some embodiments, the gelled topical formulation includes oleic acid.

[0123] In some embodiments, the fatty acid is present in an amount of about 0% to about 40% by weight of the base formulation. In some embodiments, fatty acid is present in an amount of from 5% to 40%, from 5% to 30%, from 5% to 20%, from 5% to 15%, from 5% to 10%, from 10% to 20%, from 10% to 15%, from 20% to 40%, from 30% to 40%, or from 20% to 30% by weight of the base formulation. In some embodiments, fatty acid is present in an amount of about 5% by weight of the base formulation. In some embodiments, fatty acid is present in an amount of about 10% by weight of the base formulation. In some embodiments, oleic acid is present in an amount of about 5% by weight of the base formulation.

[0124] In some embodiments, the gelled topical formulation includes a fatty ester. In some embodiments, the fatty ester is a glyceryl fatty ester, ethylene glycol monoester and diester of a fatty acid, propylene glycol monoester and diester of a fatty acid, a Ci-₆ alkyl ester of a fatty acid, di-(Ci-₆ alkyl) ester of adipic acid, sebacic acid, or combinations thereof.

[0125] In some embodiments, the fatty ester is a glyceride. In some embodiments, the glyceride is monoglycerides, diglycerides, or triglycerides. The glycerides may be optionally substituted with sulfonic acid groups, or pharmaceutically acceptable salts thereof. Suitable fatty acids for deriving glycerides of fatty acids include, but are not limited to, those described herein. In some embodiments, the glyceride is a mono-glyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the glyceride is glycerol monolaurate, glycerol monocaprate, glycerol monocaprylate, glycerol monostearate, or glycerol monooleate. In some embodiments, the glyceride is glycerol monooleate. In some embodiments, the glyceride is a triglyceride of a faty acid having 12 to 18 carbon atoms. In some embodiments, the triglyceride is caprylic triglyceride, capric triglyceride, or a combination thereof.

[0126] In some embodiments, the gelled topical formulation includes a glyceride. In some embodiments, the gelled topical formulation includes a monoglyceride. In some embodiments, the gelled topical formulation includes a triglyceride. In some embodiments, the gelled topical formulation includes glycerol monooleate. In some embodiments, the gelled topical formulation includes caprylic triglyceride, capric triglyceride, or a combination thereof.

(0127] In some embodiments, the fatty ester is an ethylene glycol monoester of a fatty acid, a propylene glycol monoester of a fatty acid, or a Ci-₆ alkyl ester of a faty acid. In some embodiments, the faty ester is an ethylene glycol monoester, a propylene glycol monoester, or a Ci -₄ alkyl ester of a faty acid. Suitable fatty acids for deriving any one of the ethylene glycol monoester, propylene glycol monoester, and the C alkyl ester of fatty acids include, but are not limited to, those described herein. In some embodiments, the fatty ester is an ethylene glycol monoester, a propylene glycol monoester, or a C_M alkyl ester of a fatty acid having 12 to 18 carbon atoms. Non-limiting examples of esters of a faty acid include a laurate, a myristate, a palmitate, a stearate, or an oleate. In some embodiments, the fatty ester is methyl laurate. In some embodiments, the fatty ester is isopropyl myristate. In some embodiments, the fatty ester is isopropyl palmitate.

[0128] In some embodiments, the fatty ester is a di-(Ci-4 alkyl) ester of adipic acid (i.e., an adipate) or di-(CM alkyl) ester of sebacic acid (i.e., a sebacate). In some embodiments, the faty ester is diisopropyl adipate. In some embodiments, the fatty ester is diethyl sebacate.

[0129] In some embodiments, the gelled topical formulation includes a fatty ester. In some embodiments, the gelled topical formulation includes a C alkyl ester of a faty acid. In some embodiments, the gelled topical formulation includes a di-(C_M alkyl) ester of adipic acid. In some embodiments, the gelled topical formulation includes isopropyl myristate. In some embodiments, the gelled topical formulation includes isopropyl palmitate. In some

embodiments, the gelled topical formulation includes diisopropyl adipate.

[0130] In some embodiments, the fatty ester is present in an amount of about 1% to about 30% by weight of the base formulation. In some embodiments, fatty ester is present in an amount of from 5% to 30%, from 5% to 20%, from 5% to 15%, from 5% to 10%, from 10% to 20%, from 20% to 30%, or from 5% to 15% by weight of the base formulation. In some embodiments, fatty alcohol is present in an amount of about 10% by weight of the base formulation. In some embodiments, diisopropyl adipate is present in an amount of about 10% by weight of the base formulation.

[0131] In some embodiments, the gelled topical formulation includes a fatty acid amide. In some embodiments, the fatty acid amide is a N-acylethanolamine. Suitable fatty acids for deriving the N-acylethanolamine include, but are not limited to, those described herein. In some embodiments, the fatty acid amide is a N-acylethanolamine of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the fatty acid amide is lauric diethanolamide. In some embodiments, the gelled topical formulation includes lauric diethanolamide.

[0132] In some embodiments, the gelled topical topical formulation includes a stabilizer. In some embodiments, the stabilizer is a polysorbate. Examples of polysorbates include

Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). Suitable polysorbates include, but are not limited to the Tween™ series (available from Uniqema), which includes Tween 20 (POE(20) sorbitan monolaurate), 21 (POE(4) sorbitan monolaurate), 40 (POE (20) sorbitan monopalmitate), 60 (POE(20) sorbitan monostearate), 60K (POE(20) sorbitan monostearate),

61 (POE(4) sorbitan monostearate), 65 (POE(20) sorbitan tristearate), 80 (POE(20) sorbitan monooleate), 80K (POE (20) sorbitan monooleate), 81 (POE(5) sorbitan monooleate), and 85 (POE(20) sorbitan trioleate). As used herein, the abbreviation“POE¹ refers to

polyoxyethylene. The number following the POE abbreviation refers to the number of oxy ethylene repeat units in the compound. Other suitable polysorbates include the ones listed in R. C. Rowe and P. J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety. In some embodiments, the stabilizer is polysorbate 20. In some embodiments, the gelled topical topical formulation includes polysorbate 20.

[0133] In some embodiments, the gelling agent is hydroxypropyl cellulose having a molecular weight selected from the group consisting of 40,000 Da, 80,000 Da, 95,000 Da, 100,000 Da, 140,000 Da, 180,000 Da, 280,000 Da, 370,000 Da, 700,000 Da, 850,000 Da, 1,000,000 Da, 1 ,150,000 Da, and 2,500,000 Da. In some embodiments, the hydroxypropyl cellulose has the molecular weight selected from the group consisting of 95,000 Da, 100,000 Da, 370,000 Da, 850,000 Da, and 1,150,000 Da.

[0134] The hydroxypropyl cellulose (HPC) as described herein include HY 1 17, HY 1 19, HY121 , Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, Nisso VH, Klucel ELF, Klucel EF, Klucel LF, Klucel JF, Klucel GF, Klucel MF, and Klucel HF. HY117 has an average molecular weight of 95,000 Da; HY1 19 has an average molecular weight of 370,000 Da; and HY121 has an average molecular weight of 850,000 Da. Nisso SSL has an average molecular weight of 40,000 Da; Nisso SL has an average molecular weight of 100,000 Da; Nisso L has an average molecular weight of 140,000 Da; Nisso LM has an average molecular weight of 1800,000 Da; Nisso LMM has an average molecular weight of 280,000 Da; Nisso M has an average molecular weight of 700,000 Da; Nisso H has an average molecular weight of 1,000,000 Da; and Nisso VH has an average molecular weight of 2,500,000 Da. HPC Suitable particle sizes of Nisso HPC (i.e., Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, and Nisso VH) in the topical formulation include regular powder (40 mesh), fine powder (100 mesh), and super fine powder (300 mesh). See Technical date sheets of Nisso HPCs, the entirety of which is incorporated herein by reference for all purpose. Klucel ELF has an average molecular weight of 40,000 Da; Klucel EF has an average molecular weight of 80,000 Da; Klucel LF has an average molecular weight of 95,000 Da; Klucel JF has an average molecular weight of 140,000 Da; Klucel GF has an average molecular weight of 370,000 Da; Klucel MF has an average molecular weight of 850,000 Da; and Klucel HF has an average molecular weight of 1 , 150,000 Da. Suitable particle sizes of Klucel HPC in the topical formulation include regular grade and fine grade. See Technical date sheets of Klucel ILPC products, the entirety of which is incorporated herein by reference for all purpose.

[0135] In some embodiments, the gelling agent is present in an amount of about 0.1% to about 5% by weight of the base formulation. In some embodiments, the gelling agent is present in an amount of from 0.2% to 5%, from 0.5% to 5%, from 0.5% to 3%, from 0.5% to 2%, or from 1% to 3% by weight of the base formulation. In some embodiments, the agent is present in an amount of about 1.5% by weight of the base formulation. In some embodiments, the hydroxypropyl cellulose is present in an amount of about 1.5% by weight of the base formulation.

[0136] In some embodiments, the MEK inhibitor is present in an amount of from 0.005% to 10%, from 0.1% to 5%, or from 0.1 to 1% by weight of the base formulation on a free salt and anhydrous basis. In some embodiments, the MEK inhibitor is present in an amount of 0.5% by weight of the base formulation on a free salt and anhydrous basis. In some embodiments, the MEK inhibitor is present in an amount of 1 % by weight of the base formulation on a free salt and anhydrous basis. In some embodiments, the MEK inhibitor is present in an amount of 1.5% by weight of the base formulation on a free salt and anhydrous basis.

[0137] In some embodiments, DMSO is absent in the gelled topical formulation.

[0138] In some embodiments, the gelled topical fonnulation comprises:

a) from 0.005% to 10% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 30% to 70% by weight of a C2-6 alcohol;

c) from 5% to 20% by weight of a C2-6 alkylene glycol or a di-(C2-6 alkylene) glycol; d) from 20% to 60% by weight of dimethyl isosorbide, a fatty alcohol, a fatty acid, a fatty ester, a fatty acid amide, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100%.

[0139] In some embodiments, the gelled topical formulation comprises:

a) from 0.005% to 10% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 30% to 70% by weight of a C2-6 alcohol;

c) from 5% to 20% by weight of a C2-6 alkylene glycol or a di-(C2-6 alkylene) glycol; d) from 20% to 60% by weight of a fatty alcohol, a fatty ester, a fatty acid amide, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100%. [0140] In some embodiments, the gelled topical formulation comprises:

a) from 0.005% to 10% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 30% to 70% by weight of a C2-6 alcohol;

c) from 5% to 20% by weight of a C2-6 alkylene glycol or a di-(C2-6 alkylene) glycol; d) from 20% to 60% by weight of a fatty alcohol, a fatty ester, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0141] In some embodiments, the gelled topical formulation comprises:

a) from 0.005% to 10% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 35% to 60% by weight of a C2-6 alcohol;

c) from 5% to 20% by weight of a C2-6 alkylene glycol;

d) from 25% to 55% by weight of a fatty alcohol, a fatty ester, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0142] In some embodiments, the gelled topical formulation comprises:

a) from 0.01% to 5% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 35% to 60% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 20% to 40% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty alcohol; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%.

[0143] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 35% to 60% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 20% to 40% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty alcohol; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%.

[0144] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 20% to 40% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty alcohol; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%.

[0145] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 20% to 40% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty alcohol;

f) from 0.5 to 5% by weight of stabilizer; and

g) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0146] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol; d) from 20% to 40% by weight of a triglyceride and an adipate;

e) from 2% to 10% by weight of a fatty alcohol;

f) from 0.5 to 5% by weight of polysorbate; and

g) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0147] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 20% to 40% by weight of capric/caprylic triglyceride and diisopropyl adipate; e) from 2% to 10% by weight of oleyl alcohol;

f) from 0.5 to 5% by weight of polysorbate 20; and

g) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0148] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 48% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 30% by weight of capric/caprylic triglyceride and diisopropyl adipate;

e) about 5% by weight of oleyl alcohol;

f) about 2% by weight of polysorbate 20; and

g) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0149] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 48% by weight of ethanol;

c) about 15% by weight of propylene glycol; d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0150] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of a compound of any one of formula (I), (II), (III), (IV), and

(V) or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 48% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0151] In some embodiments, the gelled topical formulation comprises:

a) about 1.0% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 48% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 30% by weight of capric/caprylic triglyceride and diisopropyl adipate;

e) about 5% by weight of oleyl alcohol;

f) about 2% by weight of polysorbate 20; and

g) about 1.5% by weight of hydoxypropyl cellulose, wherein the total weight of b) to f) is 100.0%.

[0152] In some embodiments, the gelled topical formulation comprises:

a) about 1.0% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 48% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0153] In some embodiments, the gelled topical formulation comprises:

a) about 1.0% by weight of a compound of any one of formula (1), (II), (III), (IV), and

(V) or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 48% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0154] In some embodiments, the gelled topical formulation comprises:

a) about 1.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 48% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 30% by weight of capric/caprylic triglyceride and diisopropyl adipate; e) about 5% by weight of oleyl alcohol;

f) about 2% by weight of polysorbate 20; and

g) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0155] In some embodiments, the gelled topical formulation comprises:

a) about 1.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 48% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0156] In some embodiments, the gelled topical formulation comprises:

a) about 1.5% by weight of a compound of any one of formula (1), (II), (III), (IV), and

(V) or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 48% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0157] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 35% to 60% by weight of a C_2-6 alcohol;

c) from 10% to 20% by weight of a C2-₆ alkylene glycol;

d) from 20% to 40% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty alcohol;

f) from 0.5 to 5% by weight of stabilizer;

g) from 0.5% to 5% benzyl alcohol; and

h) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0158] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 20% to 40% by weight of a triglyceride and an adipate;

e) from 2% to 10% by weight of a fatty alcohol;

f) from 0.5 to 5% by weight of polysorbate;

g) from 0.5% to 5% benzyl alcohol; and

h) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0159] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 20% to 40% by weight of capric/caprylic triglyceride and diisopropyl adipate; e) from 2% to 10% by weight of oleyl alcohol;

f) from 0.5 to 5% by weight of polysorbate 20;

g) from 0.5% to 5% benzyl alcohol; and

h) from 0.5% to 5% by weight of hydoxypropyl cellulose, wherein the total weight of b) to g) is 100.0%.

[0160] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 46% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 30% by weight of capric/caprylic triglyceride and diisopropyl adipate;

e) about 5% by weight of oleyl alcohol;

f) about 2% by weight of polysorbate 20;

g) about 2% benzyl alcohol; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0161] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 46% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to h) is 100.0%.

[0162] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of a compound having any one of formulae (I), (II), (III), (IV), and (V) or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 46% by weight of ethanol;

c) about 15% by weight of propylene glycol; d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to h) is 100.0%.

[0163] In some embodiments, the gelled topical formulation comprises:

a) about 1.0% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 46% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 30% by weight of capric/caprylic triglyceride and diisopropyl adipate; e) about 5% by weight of oleyl alcohol;

f) about 2% by weight of polysorbate 20;

g) about 2% benzyl alcohol; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0164] In some embodiments, the gelled topical formulation comprises:

a) about 1.0% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 46% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose, wherein the total weight of b) to h) is 100.0%.

[0165] In some embodiments, the gelled topical formulation comprises:

a) about 1.0% by weight of a compound having any one of formulae (I), (11), (111), (IV), and (V) or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 46% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to h) is 100.0%.

[0166] In some embodiments, the gelled topical formulation comprises:

a) about 1.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 46% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 30% by weight of capric/caprylic triglyceride and diisopropyl adipate;

e) about 5% by weight of oleyl alcohol;

f) about 2% by weight of polysorbate 20;

g) about 2% benzyl alcohol; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0167] In some embodiments, the gelled topical formulation comprises:

a) about 1.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 46% by weight of ethanol;

c) about 15% by weight of propylene glycol; d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to h) is 100.0%.

[0168] In some embodiments, the gelled topical formulation comprises:

a) about 1.5% by weight of a compound having any one of formulae (1), (II), (III), (IV), and (V) or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 46% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 5% by weight of oleyl alcohol;

g) about 2% by weight of polysorbate 20;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to h) is 100.0%.

[0169] In some embodiments, the gelled topical formulation comprises:

a) from 0.01% to 5% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of a C2-6 alcohol;

c) from 5% to 15% by weight of a C2-6 alkylene glycol;

d) from 25% to 50% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty alcohol; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%. [0170J In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of a C2-6 alcohol;

c) from 5% to 15% by weight of a C2-6 alkylene glycol;

d) from 25% to 50% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty alcohol; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%.

[0171] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of a C2-6 alcohol;

c) from 5% to 15% by weight of a C2-6 alkylene glycol;

d) from 25% to 50% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty alcohol; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%.

[0172] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of a C2-6 alcohol;

c) from 5% to 15% by weight of a C2-6 alkylene glycol;

d) from 25% to 50% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty alcohol;

f) from 0.5% to 5% benzyl alcohol; and

g) from 0.5% to 5% by weight of hydoxypropyl cellulose, wherein the total weight of b) to f) is 100.0%.

[0173] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of ethanol;

c) from 5% to 15% by weight of propylene glycol;

d) from 25% to 50% by weight of a monoglyceride, a triglyceride, and an adipate;

e) from 2% to 10% by weight of a fatty alcohol;

f) from 0.5% to 5% benzyl alcohol; and

h) from 0.5% to 5% by weight of hydoxypropyl cellulose, - wherein the total weight of b) to f) is 100.0%.

[0174] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 60% by weight of ethanol;

c) from 5% to 15% by weight of propylene glycol;

d) from 25% to 50% by weight of glyceryl monooleate, capric/caprylic triglyceride, and diisopropyl adipate;

e) from 2% to 10% by weight of cetyl alcohol;

f) from 0.5% to 5% benzyl alcohol; and

g) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0175] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 10% by weight of propylene glycol;

d) about 38% by weight of glyceryl monooleate, capric/caprylic triglyceride and

diisopropyl adipate;

e) about 5% by weight of cetyl alcohol; f) about 2% benzyl alcohol; and

g) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0176] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 10% by weight of propylene glycol;

d) about 25% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 3% by weight of glyceryl monooleate;

g) about 5% by weight of cetyl alcohol;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to h) is 100.0%.

[0177] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of a compound having any one of formulae (I), (11), (III), (IV), and (V) or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 10% by weight of propylene glycol;

d) about 25% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 3% by weight of glyceryl monooleate;

g) about 5% by weight of cetyl alcohol;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose, wherein the total weight of b) to h) is 100.0%.

[0178] In some embodiments, the gelled topical formulation comprises:

a) about 1.0% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 10% by weight of propylene glycol;

d) about 38% by weight of glyceryl monooleate, capric/caprylic triglyceride and

diisopropyl adipate;

e) about 5% by weight of cetyl alcohol;

f) about 2% benzyl alcohol; and

g) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0179] In some embodiments, the gelled topical formulation comprises:

a) about 1.0% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 10% by weight of propylene glycol;

d) about 25% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 3% by weight of glyceryl monooleate;

g) about 5% by weight of cetyl alcohol;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to h) is 100.0%.

[0180] In some embodiments, the gelled topical formulation comprises:

a) about 1.0% by weight of a compound having any one of formulae (1), (II), (III), (IV), and (V) or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 10% by weight of propylene glycol; d) about 25% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 3% by weight of glyceryl monooleate;

g) about 5% by weight of cetyl alcohol;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to h) is 100.0%.

[0181] In some embodiments, the gelled topical formulation comprises:

a) about 1.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 10% by weight of propylene glycol;

d) about 38% by weight of glyceryl monooleate, capric/caprylic triglyceride and diisopropyl adipate;

e) about 5% by weight of cetyl alcohol;

f) about 2% benzyl alcohol; and

g) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0182] In some embodiments, the gelled topical formulation comprises:

a) about 1.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 10% by weight of propylene glycol;

d) about 25% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 3% by weight of glyceryl monooleate;

g) about 5% by weight of cetyl alcohol;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose, wherein the total weight of b) to h) is 100.0%.

[0183] In some embodiments, the gelled topical formulation comprises:

a) about 1.5% by weight of a compound having any one of formulae (1), (II), (111), (IV), and (V) or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 10% by weight of propylene glycol;

d) about 25% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 3% by weight of glyceryl monooleate;

g) about 5% by weight of cetyl alcohol;

h) about 2% benzyl alcohol; and

i) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to h) is 100.0%.

[0184] In some embodiments, the gelled topical formulation comprises:

a) from 0.005% to 10% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 40% to 70% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 20% to 40% by weight of a fatty ester; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of from b) to d) is 100.0%.

[0185] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 70% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 20% to 40% by weight of a fatty ester; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%. [0186] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 70% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 20% to 40% by weight of a fatty ester; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0187] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 70% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 20% to 40% by weight of a triglyceride and adipate; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0188] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 70% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 20% to 40% by weight of capric/caprylic triglyceride and diisopropyl adipate; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0189] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 55% by weight of ethanol;

c) about 15 by weight of propylene glycol; d) about 30% by weight of capric/caprylic triglyceride and diisopropyl adipate; and e) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0190] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 55% by weight of ethanol;

c) about 15 by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate; and

f) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%.

[0191] In some embodiments, the gelled topical formulation comprises:

a) from 0.005% to 10% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 35% to 55% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 50% by weight of a fatty alcohol, a fatty ester, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0192] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 55% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 50% by weight of a fatty alcohol, a fatty ester, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%. [0193] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 55% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 50% by weight of a fatty alcohol, a fatty ester, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0194] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 70% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 30% to 50% by weight of a triglyceride, adipate, and a fatty alcohol; and e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0195] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 70% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 30% to 50% by weight of capri c/caprylic triglyceride, diisopropyl adipate, and cetyl alcohol; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0196] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 55% by weight of ethanol; c) about 15 by weight of propylene glycol;

d) about 30% by weight of capric/caprylic triglyceride, diisopropyl adipate, and cetyl alcohol; and

e) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0197] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 15 by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 10% by weight of cetyl alcohol; and

g) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0198] In some embodiments, the gelled topical formulation comprises:

a) from 0.005% to 10% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 30% to 70% by weight of a C2-6 alcohol;

c) from 5% to 20% by weight of a C2-6 alkylene glycol;

d) from 20% to 50% by weight of a fatty alcohol, a fatty ester, a fatty acid amide, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0199] In some embodiments, the gelled topical formulation comprises:

a) from 0.005% to 10% by weight of the MEK inhibitor or a hydrate and or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 30% to 70% by weight of a C2-6 alcohol;

c) from 5% to 20% by weight of a C2-6 alkylene glycol; d) from 30% to 50% by weight of a fatty ester, a fatty acid amide, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0200] In some embodiments, the gelled topical formulation comprises:

a) from 0.005% to 5% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 40% to 50% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 40% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty acid amide; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%.

[0201] In some embodiments, the gelled topical formulation comprises:

a) from 0.01% to 5% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 40% to 50% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 40% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty acid amide; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%.

[0202] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 50% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 40% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty acid amide; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose, wherein the total weight of b) to e) is 100.0%.

[0203] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 50% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 40% by weight of a fatty ester;

e) from 2% to 10% by weight of a fatty acid amide; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%.

[0204] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 50% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 30% to 40% by weight of a triglyceride, an adipate, and a palmitate;

e) from 2% to 10% by weight of a N-acylethanolamine; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%.

[0205] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 50% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 30% to 40% by weight of capric/caprylic triglyceride, diisopropyl adipate, and isopropyl palmitate;

e) from 2% to 10% by weight of lauric diethanolamide; and

f) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to e) is 100.0%. [0206] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 43% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10%_> by weight of diisopropyl adipate;

f) about 7% by weight of isopropyl palmitate;

g) about 5% by weight of lauric diethanolamide; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0207] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of a compound having any one of formulae (I), (II), (III), (IV), and (V) or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 43% by weight of ethanol;

c) about 15% by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 7% by weight of isopropyl palmitate;

g) about 5% by weight of lauric diethanolamide; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%.

[0208] In some embodiments, the gelled topical formulation comprises:

a) from 0.005% to 10% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 55% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 50% by weight of a fatty ester; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose, wherein the total weight of b) to d) is 100.0%.

[0209] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 55% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 50% by weight of a fatty ester; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0210] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 55% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 50% by weight of a fatty ester; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0211] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 55% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 30% to 50% by weight of a triglyceride, an adipate, and a myristate; and e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0212] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 55% by weight of ethanol; c) from 10% to 20% by weight of propylene glycol;

d) from 30% to 50% by weight of capric/caprylic triglyceride, diisopropyl adipate, and isopropyl myristate; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0213] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 15 by weight of propylene glycol;

d) about 40% by weight of capric/caprylic triglyceride, diisopropyl adipate, and isopropyl myristate; and

e) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0214] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically

acceptable salt thereof, on a free salt and anhydrous basis;

b) about 45% by weight of ethanol;

c) about 15 by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 10% by weight of isopropyl myristate; and

g) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to f) is 100.0%.

[0215] In some embodiments, the gelled topical formulation comprises:

a) from 0.005% to 10% by weight of the MEK inhibitor or a hydrate and/or

pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis; b) from 35% to 55% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol; d) from 30% to 55% by weight of a fatty alcohol, a fatty ester, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0216] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 55% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 55% by weight of a fatty alcohol, a fatty ester, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0217] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 35% to 55% by weight of a C2-6 alcohol;

c) from 10% to 20% by weight of a C2-6 alkylene glycol;

d) from 30% to 55% by weight of a fatty alcohol, a fatty ester, or combinations thereof; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%_>.

[0218] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 70% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 30% to 55% by weight of a monoglyceride, a triglyceride, adipate, and a fatty alcohol; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose, wherein the total weight of b) to d) is 100.0%.

[0219] In some embodiments, the gelled topical formulation comprises:

a) from 0.1% to 2% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) from 40% to 70% by weight of ethanol;

c) from 10% to 20% by weight of propylene glycol;

d) from 30% to 55% by weight of glyceryl monooleate, capric/caprylic triglyceride, diisopropyl adipate, and cetyl alcohol; and

e) from 0.5% to 5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0220] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 42% by weight of ethanol;

c) about 15 by weight of propylene glycol;

d) about 43% by weight of glyceryl monooleate, capric/caprylic triglyceride, diisopropyl adipate, and cetyl alcohol; and

e) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to d) is 100.0%.

[0221] In some embodiments, the gelled topical formulation comprises:

a) about 0.5% by weight of the MEK inhibitor or a hydrate and/or pharmaceutically acceptable salt thereof, on a free salt and anhydrous basis;

b) about 42% by weight of ethanol;

c) about 15 by weight of propylene glycol;

d) about 20% by weight of capric/caprylic triglyceride;

e) about 10% by weight of diisopropyl adipate;

f) about 10% by weight of cetyl alcohol;

g) about 3% by weight of glyceryl monooleate; and

h) about 1.5% by weight of hydoxypropyl cellulose,

wherein the total weight of b) to g) is 100.0%. [0222] In some embodiments, the gelled topical formulations as described herein have a visual appearance as clear, transparent, or monophasic. In some embodiments, the visual appearance of the gelled topical formulation is maintained over a period of 4 weeks at a temperature of 40°C.

[0223] the gelled topical formulations as described herein have stable viscosity for a period of 4 weeks at a temperature of 40°C. In some embodiments, the viscosity of the gelled formulation is maintained from 500 to 5000 cps over a period of 4 weeks at a temperature of 40°C.

[0224] The gelled topical formulation used to deliver the MEK inhibitor is a lotion, a spray, an ointment, a cream, a gel, a paste, or a patch.

]0225] In some embodiments, the gelled topical formulation used to deliver the MEK inhibitor is a lotion or a cream. Creams and lotions that can be used as topical formulations and their preparation are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF

PHARMACY 282-291 (Alfonso R. Gennaro ed. 19th ed. 1995), hereby incorporated herein by reference.

[0226] In some embodiments, the gelled topical formulation used to deliver the MEK inhibitor is a gel, as described herein.

[0227] In some embodiments, the gelled topical formulation used to deliver the MEK inhibitor is an ointment. Ointments are oleaginous semisolids that contain little if any water. In some instances, the ointment is hydrocarbon based, such as a wax, petrolatum, or gelled mineral oil. Suitable ointments for use in the invention are well known in the art and are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1585-1591 (Alfonso R. Gennaro ed. 19th ed. 1995), hereby incorporated herein by reference.

[0228] In some embodiments, the topical administration may be achieved in the form of patches comprising the gelled topical formulation as described herein, where the patch is in contact with the affected area on the skin.

IV. COMPOUNDS

[0229] The present invention provides a compound for use in the gelled formulation for the treatment of skin disorders as defined and described herein, wherein the compound is selected from the group consisting of formula (I), (II), (III), (IV), and (V):

or a N-oxide, stereoisomer, mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof,

wherein:

X¹ is -CR^l3b or N; X² is Ci-C₆ alkyl; X³ is S or O;

subscript n is an integer from 0 to 2;

bond“a” is a single or double bond;

R¹ is -OR⁴, -NR⁵R^5a, -N(OR^5b)R^5a, or a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶;

R² is halo, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl;

R^2a is halo or C1-C6 alkyl;

R⁴, R⁵, and R^5b are each independently hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl-Ci-C₆ alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-Ci-C₆ alkyl, amino-Ci-Ce alkyl, C1-C6 alkylamino-Ci-C6 alkyl, di-(Ci-C6 alkyl)amino-Ci-C6 alkyl,

heterocycloalkyl, heterocycloalkyl -C₁-C₆ alkyl, or R⁷-C(0)-CI -C₆ alkyl, wherein each of the C₃-C₈ cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R⁶; R^5a is hydrogen or C1-C6 alkyl;

each R⁶ is independently halo, hydroxy, oxo, C₁-C₆ alkyl, C3-C₈ cycloalkyl, C₁-C₆

alkoxy, Ci-C6-hydroxyalkyl, C₁-C6 haloalkyl, amino, C₁-C₆ alkylamino, di-(Ci-C₆ alkyl)amino, amino-Ci-C6 alkyl, C1-C6 alkylamino-Ci-C6 alkyl, or di-(Ci-C6 alkyl)amino-Ci-C6 alkyl;

R⁷ is hydroxy, Ci-Ce alkoxy, amino, C₁-C₆ alkylamino, di-(Ci-C₆ alkyl)amino,

hydroxyamino, or N-Ci-Ce alkyl hydroxyamino;

R⁸ is hydroxy, C₁-C₃ alkyl, or C₁-C₃ alkoxy;

Rⁱ³, R^{l 3a}, and R^l3b are each independently hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, or Ci-C_f, alkynyl;

R²³, R^23a, and R^23b are each independently hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, or C₃-C₈ cycloalkoxy;

R³³, R^33a, and R^33b are each independently hydrogen, halo, C₁-C₆ alkyl, Ci-Ce alkenyl, C₂-C6 alkynyl, C₁-C₆ alkoxy, or C3-C₈ cycloalkoxy;

R⁴³ is cyano, -C(0)NR⁴⁸R^48a, or -C(0)R⁴⁶;

R^43a is hydrogen, halo, C₁-C₆ alkyl; or

R⁴³ and R^43a together form -CH₂CH C(0)- or -CH₂CH₂CH₂C(0)-, each of which is unsubstituted or substituted with one or two R⁴⁹;

R⁴⁶ is hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl or heterocycloalkyl;

R⁴⁸ and R^48a are independently hydrogen or C₁-C₆ alkyl; and

each R⁴⁹ is independently C₁-C6 alkyl, C3-C₈ cycloalkyl, or C3-C₈ cycloalkyl-Ci-C6 alkyl;

R⁵¹ is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl-Ci-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy-Ci-C₆ alkyl, amino-Ci-C₆ alkyl, C\-Ce alkylamino-Ci-C₆ alkyl, di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl, heterocycloalkyl, heterocycloalkyl-Ci-C₆ alkyl, R⁷-C(0)-C_I-C₆ alkyl, or -OR⁵⁴, wherein each of the C₃-C₈ cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R⁶;

each R⁵³ is independently halo or C₁-C₆ alkyl;

R^53a and R^53b are each independently hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl; and R⁵⁴ is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl-Ci-C6 alkyl, C₁-C₆ hydroxyalkyl, C1-C6 alkoxy-Ci-C6 alkyl, amino-Ci-C6 alkyl, C₁-C6 alkylamino- C₁-C₆ alkyl, di-(Ci-C6 alkyl)amino-Ci-C6 alkyl, heterocycloalkyl,

heterocycloalkyl-Ci-C6 alkyl, or R⁷-C(0)-CI -C₆ alkyl, wherein each of the C3-C8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R⁶.

[0230] In some embodiments, the cycloalkyl group provided in formulae (1), (11), (III), (IV) and (V) is a saturated monocyclic C3-C8 cycloalkyl. In some embodiments, the C3-C8 cycloalkyl group, as alone or as part of C3-C8 cycloalkyl-Ci-C6 alkyl is cyclopropyl or cyclobutyl. In some embodiments, the C3-C8 cycloalkyl group, as alone or as part of C3-C8 cycloalkyl-Ci-C₆ alkyl, is unsubstituted. In some embodiments, the C3-C8 cycloalkyl group, as alone or as part of C3-C8 cycloalkyl-Ci-C₆ alkyl, is substituted with one to six R⁶ and R⁶ is as defined and described herein.

[0231] With reference to R⁶ as one or more substituents of the C3-C8 cycloalkyl group, in some embodiments, each R⁶ is independently halo, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6- hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(Ci-C₆ alkyl)amino, amino-Ci-C₆ alkyl, Ci-Ce alkylamino-Ci-C6 alkyl, or di-(Ci-C6 alkyl)amino-Ci-C₆ alkyl. In some embodiments, each R⁶ is independently halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6- hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, or di-(Ci-C₆ alkyl)amino. In some embodiments, each R⁶ is independently halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or amino. In some embodiments, each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, each R⁶ is independently hydroxy or amino.

[0232] In some embodiments, heterocycloalkyl provided in formulae (I), (II), (III), (IV) and (V) is a 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms of N, O, or S. In some embodiments, heterocycloalkyl is a 3 to 6 membered heterocycloalkyl having 1 to 2 heteroatoms of N or O. In some embodiments, the heterocycloalkyl group, as alone or as part of

heterocycloalkyl -C1-C6 alkyl, is unsubstituted. In some embodiments, the heterocycloalkyl group, as alone or as part of heterocycloalkyl-Ci-C6 alkyl, is substituted one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, the N-linked heterocycloalkyl group is substituted one or two R⁶ and R⁶ is as defined and described herein. [0233] With reference to R⁶ as one or more substituents of the heterocycloalkyl group or the N-linked heterocycloalkyl, in some embodiments, each R⁶ is independently halo, hydroxy, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, Ci-C6-hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(Ci-C6 alkyl)amino, amino-Ci -C6 alkyl, Ci-Ce alkylamino-Ci-Ce alkyl, or di-(Ci-C6 alkyl)amino-Ci-C6 alkyl. In some embodiments, each R⁶ is independently halo, hydroxy, oxo, Ci-Ce alkyl, C1-C6 alkoxy, Ci-C₆-hydroxyalkyl, Ci-Ce haloalkyl, amino, C1-C6 alkylamino, or di-(Ci-C₆ alkyl)amino. In some embodiments, each R⁶ is independently halo, hydroxy, oxo, Ci-Ce alkyl, C1-C6 alkoxy, or amino. In some embodiments, each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, each R⁶ is independently hydroxy, oxo, or amino. In some embodiments, each R⁶ is independently hydroxy or amino.

[0234] In some embodiments, the compounds useful in the present gelled formulations and methods thereof are compounds of formula (I).

[0235] With reference to formula (I), in some embodiments, X¹ is -CR^{l 3b}, and the compound is represented by formula (la):

wherein R¹, R², R^2a, R¹³, R^{l 3a}, and R^13b are as defined herein in any aspect or embodiment described herein.

[0236] in some embodiments of formula (la), R¹³, R^{l 3a}, and R^{l 3b} are each independently hydrogen, halo, or C1-C6 alkyl.

[0237] In some embodiments of formula (la), R¹³ is hydrogen, halo, or Ci -C₆ alkyl. In some embodiments, R¹³ is hydrogen. In some embodiments, R¹³ is halo. In some embodiments, R¹³ is fluoro, chloro, bromo, or iodo. In some embodiments, R¹³ is fluoro. In some embodiments, R¹³ is Ci-Ce alkyl. In some embodiments, R¹³ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R¹³ is methyl. [0238] In some embodiments of formula (la), R^{l 3a} is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R^13a is hydrogen. In some embodiments, R^13a is halo. In some embodiments, R^l3a is fluoro, chloro, bromo, or iodo. In some embodiments, R^13a is fluoro. In some embodiments, R^13a is Ci-C₆ alkyl. In some embodiments, R^l3a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R^{l 3a} is methyl.

[0239] In some embodiments of formula (la), R^13b is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R^l3b is hydrogen. In some embodiments, R^!3b is halo. In some embodiments, R^13b is fluoro, chloro, bromo, or iodo. In some embodiments, R^{l 3b} is fluoro. In some embodiments, R^l3b is Ci-C₆ alkyl. In some embodiments, R^l3b is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R^{l 3b} is methyl.

[0240] In some embodiments of formula (la), R¹³, R^{l 3a}, and R^{, 3b} are each hydrogen. In some embodiments of formula (la), R¹³ and R^{l 3a} are each hydrogen and R^{l 3b} is halo. In some embodiments of formula (la), R¹³ and R^l3a are each hydrogen and R^{l 3b} is fluoro.

[0241] Returning to formula (I), in some embodiments, X' is N, and the compound is represented by formula (lb):

wherein R¹, R², R^2a, R¹³, and R^{l 3a} are as defined herein in any aspect or embodiment described herein.

[0242] In some embodiments of formula (lb), R¹³ and R^{l 3a} are each independently hydrogen, halo, or C1-C6 alkyl.

[0243] In some embodiments of formula (lb), R¹³ is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R¹³ is hydrogen. In some embodiments, R¹³ is halo. In some embodiments, R¹³ is fluoro, chloro, bromo, or iodo. In some embodiments, R¹³ is fluoro. In some embodiments, R¹³ is Ci-C₆ alkyl. In some embodiments, R¹³ is methyl. [0244] In some embodiments of formula (lb), R^{l 3a} is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R^{l 3a} is hydrogen. In some embodiments, R^l3a is halo. In some embodiments, R^{l 3a} is fluoro, chloro, bromo, or iodo. In some embodiments, R^l3a is fluoro. In some embodiments, R^13a is Ci-C₆ alkyl. In some embodiments, R^13a is methyl.

[0245] In some embodiments of formula (lb), R¹³ and R^13a are each independently hydrogen or halo. In some embodiments, R¹³ and R^l3a are each hydrogen. In some embodiments, one of R¹³ and R^{, 3a} is hydrogen and the other is halo. In some embodiments, one of R¹³ and R^13a is hydrogen and the other is fluoro.

[0246] With reference to any one of formulae (I), (la), and (lb), in some embodiments, R¹ is -OR⁴, -NR⁵R^5a, or -N(OR^5b)R^5a.

[0247] In some embodiments of any one of formulae (I), (la), and (lb), R¹ is -OR⁴. In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is C1-C6 alkyl. In some embodiments, R⁴ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is C3-C8 cycloalkyl-Ci-Ce alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the Cs-Cs cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is cyclopropyl, cyclobutyl, cyclopropyl- C1-C6 alkyl, or cyclobutyl-Ci-C6 alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, R⁴ is Ci-Ce hydroxyalkyl. In some embodiments, R⁴ is C1-C6 alkoxy-Ci-C₆ alkyl. In some embodiments, R⁴ is amino-Ci-C₆ alkyl. In some embodiments, R⁴ is C1-C6 alkylamino-Ci-C6 alkyl. In some embodiments, R⁴ is di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl. In some embodiments, R⁴ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-Ce alkyl, azetidinyl-Ci-C6 alkyl, pyrrolidinyl-Ci-C₆ alkyl, piperidinyl-Ci-C₆ alkyl, or 2,2-dimethyl- l ,3-dioxolan-4-yl-Ci-C₆ alkyl. In some embodiments, R⁴ is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1 -C6 alkoxy, amino, C1-C6 alkylamino, di-(Ci-C6 alkyl)amino, hydroxyamino, or N-Ci-Ce alkyl hydroxyamino. In some embodiments, R⁴ is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino.

[0248] In some embodiments of any one of formulae (I), (la), and (lb), R¹ is selected from the group consisting of -OH,

[0249] In some embodiments of any one of formulae (I), (la), and (lb), R¹ is -NR⁵R^5a. In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is C1-C6 alkyl. In some embodiments, R⁵ is C₃-Cg cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is C3-C8 cycloalkyl-Ci-Ce alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C6 alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopropyl- C1-C6 alkyl, or cyclobutyl-Ci-C6 alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is C1-C6 hydroxyalkyl. In some embodiments, R⁵ is C1-C6 alkoxy-Ci-C6 alkyl. In some embodiments, R⁵ is amino-Ci-C₆ alkyl. In some embodiments, R⁵ is Ci-Ce alkylamino-Ci-C6 alkyl. In some embodiments, R⁵ is di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl. In some embodiments, R⁵ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, R⁵ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-C₆ alkyl, azetidinyl-Ci-C6 alkyl, pyrrolidinyl-Ci-C₆ alkyl, piperidinyl-Ci-C₆ alkyl, or 2,2-dimethyl- l ,3-dioxolan-4-yl-Ci-C6 alkyl. In some embodiments, R⁵ is R⁷-C(0)-C_I-C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(Ci-C₆ alkyl)amino, hydroxyamino, or N- C1-C6 alkyl hydroxyamino. In some embodiments, R⁵ is R⁷-C(0)-C_I-C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino.

[0250] In some embodiments of any one of formulae (I), (la), and (lb), R¹ is -NR⁵R^5a and R⁵ is selected from the group consisting of hydrogen,

[0251] In some embodiments of any one of formulae (1), (la), and (lb), R¹ is -N(OR^5b)R^5a. In some embodiments, R^5b is hydrogen. In some embodiments, R^5b is Ci-Ce alkyl. In some embodiments, R^5b is C₃-C₈ cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is C₃-C₈ cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, R^5b is C3-C₈ cycloalkyl-Ci-C₆ alkyl, wherein the C₃-C₈ cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is C3-C₈ cycloalkyl-Ci-C6 alkyl, wherein the C₃-C₈ cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C₁-C₆ alkyl. In some embodiments, R^5b is cyclopropyl, cyclobutyl, cycloprop yl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C₁ -C₆ alkyl. In some embodiments, R^5b is C₁-C₆ hydroxyalkyl. In some embodiments, R^5b is Ci-Ce alkoxy-Ci-C₆ alkyl. In some embodiments, R^5b is amino-Ci-C₆ alkyl. In some embodiments, R^sb is C1-C6 alkylamino-Ci-C₆ alkyl. In some embodiments, R^5b is di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl. In some embodiments, R^sb is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some

embodiments, R^5b is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C₁-C₆ alkyl. In some embodiments, R^5b is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C₁-C₆ alkyl. In some embodiments, R^5b is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-C₆ alkyl, azetidinyl-Ci-Ce alkyl, pyrrolidinyl- C1-C6 alkyl, piperidinyl-Ci-C6 alkyl, or 2,2-dimethyl-l ,3-dioxolan-4-yl-Ci-C₆ alkyl. In some embodiments, R^5b is R⁷-C(0)-CI-C₆ alkyl; and R⁷ is hydroxy, C₁-C₆ alkoxy, amino, Ci-Ce alkylamino, di-(Ci-C6 alkyl)amino, hydroxyamino, or N-C ₁ -Ce alkyl hydroxyamino. In some embodiments, R^Sb is R⁷-C(0)-CI -C₆ alkyl; and R⁷ is hydroxy, C₁-C₆ alkoxy, amino, or hydroxyamino. [0252] In some embodiments of any one of formulae (I), (la), and (lb), R¹ is -N(OR^5b)R^5a and -OR^5b is selected from the group consisting of -OH,

[0253] In some embodiments of any one of formulae (1), (la), and (lb), R^5a is hydrogen. In some embodiments, R^5a is C1-C6 alkyl. In some embodiments, R^Sa is C1-C4 alkyl. In some embodiments, R^5a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R^5a is methyl.

[0254] With reference to any one of formulae (I), (la), and (lb), in some embodiments, R¹ is a

N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, the N-linked heterocycloalkyl is N-linked azetidinyl, N-linked pyrrolidinyl, N-linked isoxazolidinyl, N-linked piperidinyl, or N-linked morpholinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked azetidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked pyrrolidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked isoxazolidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked piperidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked morpholinyl. In some embodiments, R¹ is N-linked azetidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked pyrrolidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked piperidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked isoxazolidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked morpholinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein.

[0255] With reference to R⁶ as one or two substituents of the N-linked heterocycloalkyl in any one of formulae (I), (la), and (lb), in some embodiments, each R⁶ is independently hydroxyl, oxo, or amino. In some embodiments, each R⁶ is hydroxy. In some embodiments, each R⁶ is oxo. In some embodiments, each R⁶ is amino. In some embodiments, one of R⁶ is hydroxy and the other R⁶ is amino.

[0256] In some embodiments of any one of formulae (I), (la), and (lb), R¹ is a N-linked heterocycloalkyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked azetidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked pyrrolidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked piperidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked isoxazolidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked morpholinyl which is unsubstituted or substituted with hydroxy, oxo, or amino.

[0257] With reference to any one of formulae (I), (la), and (lb), in some embodiments, R² is halo, C,-C₆ alkyl, -S-Ci-C₆ alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R² is halo or C1 -C6 alkyl. In some embodiments, R² is halo,-CH3, -SCH3, C2-C3 alkenyl, or C2-C3 alkynyl.

[0258] In some embodiments of any one of formulae (I), (la), and (lb), R² is halo. In some embodiments, R² is fluoro. In some embodiments, R² is iodo. In some embodiments, R² is chloro. In some embodiments, R² is bromo.

[0259] In some embodiments of any one of formulae (I), (la), and (lb), R² is C1-C6 alkyl. In some embodiments, R² is C1-C3 alkyl. In some embodiments, R² is methyl. [0260] In some embodiments of any one of formulae (I), (la), and (lb), R² is -S-C1-C6 alkyl. In some embodiments, R² is -S-C1-C3 alkyl. In some embodiments, R² is -SCH3.

[0261] In some embodiments of any one of formulae (I), (la), and (lb), R² is C3-C8 cycloalkyl. In some embodiments, R² is cyclopropyl.

[0262] In some embodiments of any one of formulae (I), (la), and (lb), R² is C2-C6 alkenyl. In some embodiments, R² is C2-C4 alkenyl. In some embodiments, R² is vinyl (ethenyl), propenyl, isopropenyl, 1 -butenyl, 2-butenyl, isobutenyl, or butadienyl. In some embodiments, R² is vinyl.

[0263] In some embodiments of any one of formulae (I), (la), and (lb), R² is C2-C6 alkynyl. In some embodiments, R² is C2-C3 alkynyl. In some embodiments, R² is acetylenyl or propynyl. In some embodiments, R² is acetylenyl.

[0264] With reference to any one of formulae (I), (la), and (lb), in some embodiments, R^2a is halo or C1-C3 alkyl. In some embodiments, R^2a is halo or CH3. In some embodiments, R^2a is fluoro or CH3. In some embodiments, R^2a is iodo or CH3. In some embodiments, R^2a is chloro or CH3. In some embodiments, R^2a is bromo or C¾.

[0265] In some embodiments of any one of formulae (I), (la), and (lb), R^2a is halo. In some embodiments, R^2a is fluoro. In some embodiments, R^2a is iodo. In some embodiments, R^2a is chloro. In some embodiments, R^2a is bromo.

[0266] In some embodiments of any one of formulae (1), (la), and (lb), R^2a is C1-C6 alkyl. In some embodiments, R^2a is C1-C3 alkyl. In some embodiments, R^2a is CH3.

[0267] With reference to any one of formulae (I), (la), and (lb), in some embodiments, R² and R^2a are each halo. In some embodiments, R² is halo and R^2a is C1-C6 alkyl. In some

embodiments, R² is C1-C6 alkyl and R^2a is halo. In some embodiments, R² is -S-C1 -C6 alkyl and R^2a is halo. In some embodiments, R² is -SCH3 and R^2a is halo. In some embodiments, R² is C3-C8 cycloalkyl and R^2a is halo. In some embodiments, R² is cyclopropyl and R^2a is halo. In some embodiments, R² is C2-C6 alkenyl and R^2a is halo. In some embodiments, R² is C2-C6 alkynyl and R^2a is halo. In some embodiments, R² is acetylenyl and R^2a is halo. In some embodiments, R² and R^2a are each independently fluoro, chloro, bromo, or iodo. In some embodiments, R² is iodo and R^2a is fluoro. In some embodiments, R² is halo and R^2a is -CH3. In some embodiments, R² is bromo and R^2a is -CH3. In some embodiments, R² is iodo and R^2a is -CH3. In some embodiments, R² is -SCH3 and R^2a is fluoro. In some embodiments, R² is acetylenyl and R^2a is fluoro.

[0268] In some embodiments, the compound of formula (1) is represented by any one of the following formulae:

wherein X¹, R², R^2a, R¹³, and R^13a are as defined herein in any aspect or embodiment described herein.

[0269] In some embodiments of the above structures having formula (1), X¹ is -CR^{l 3b}, and R^13b is as defined herein in any aspect or embodiment described herein. In some embodiments of the above structures having formula (I), X¹ is N.

[0270] In some embodiments of the above structures having formula (I), R² is iodo and R^2a is fluoro. In some embodiments of the above structures, R² is iodo and R^2a is methyl. In some embodiments of the above structures, R² is acetylenyl and R^2a is fluoro. In some embodiments of the above structures, R² is acetylenyl and R^2a is methyl. In some embodiments of the above structures, R² is -SCH3 and R^2a is fluoro. In some embodiments of the above structures, R² is -SCH3 and R^2a is methyl.

[0271] In some embodiments of the above structures having formula (I), X¹ is -CR^{l 3b}; and R¹³, R^13a, and R^{l 3b} are each hydrogen. In some embodiments of the above structures having formula

(I), X¹ is -CR^{l 3b}; R¹³ and R^l3a are each hydrogen and R^l3b is halo. In some embodiments of the above structures having formula (I), X¹ is -CR^{l 3b}; R¹³ and R^{l 3a} are each hydrogen and R^{l 3b} is fluoro.

[0272] In some embodiments of the above structures having formula (I), X¹ is N; R¹³ and R^l3a are each hydrogen.

[0273] In some embodiments, the compounds useful in the present gelled formulations and methods thereof are compounds of formula (II).

[0274] With reference to formula (II), in some embodiments, X² is C1-C3 alkyl. In some embodiments, X² is methyl, ethyl, propyl, or isopropyl. In some embodiments, X² is methyl and the compound is represented by formula (Ila):

wherein R', R², R^2a, R²³, R^23a, and R^23b are as defined herein in any aspect or embodiment described herein.

[0275] In some embodiments of formula (II) or (Ila), R²³, R^23a, and R^23b are each

independently hydrogen, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0276] In some embodiments of formula (II) or (Ila), R²³ is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R²³ is hydrogen. In some embodiments, R²³ is halo. In some embodiments, R²³ is fluoro, chloro, bromo, or iodo. In some embodiments, R²³ is fluoro. In some

embodiments, R²³ is C1-C6 alkyl. In some embodiments, R²³ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R²³ is methyl.

[0277] In some embodiments of formula (II) or (11a), R^23a is hydrogen, halo, C1-C6 alkyl, or Ci-Ce alkoxy. In some embodiments, R^23a is hydrogen. In some embodiments, R^23a is halo. In some embodiments, R^23a is fluoro, chloro, bromo, or iodo. In some embodiments, R^23a is fluoro. In some embodiments, R^23a is C1-C6 alkyl. In some embodiments, R^23a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some

embodiments, R^23a is methyl. In some embodiments, R^23a is C1-C6 alkoxy. In some

embodiments, R^23a is methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy. In some embodiments, R^23a is methoxy.

[0278] In some embodiments of formula (II) or (Ila), R^23b is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R^23b is hydrogen. In some embodiments, R^23b is halo. In some

embodiments, R^23b is fluoro, chloro, bromo, or iodo. In some embodiments, R^23b is fluoro. In some embodiments, R^23b is C1-C6 alkyl. In some embodiments, R^23b is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some

embodiments, R^23b is methyl.

[0279] In some embodiments of formula (II) or (Ila), R²³, R^23a, and R^23b are each hydrogen. In some embodiments of formula (II) or (Ila), R²³ and R^23b are each hydrogen and R^23a is halo, Ci-Ce alkyl, or C1-C6 alkoxy. In some embodiments of formula (II) or (Ila), R²³ and R^23b are each hydrogen and R^23a is fluoro, methyl, or methoxy.

[0280] With reference to formula (II) or (Ha), in some embodiments, R¹ is -OR⁴, -NR⁵R^5a, or -N(OR^5b)R^5a.

[0281] In some embodiments of formula (II) or (Ila), R¹ is -OR⁴. In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is C_\-Ce alkyl. In some embodiments, R⁴ is C3-Cg cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, R⁴ is C3-C8 cycloalkyl-Ci-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is cyclopropyl, cyclobutyl, cyclopropyl- C1-C6 alkyl, or cyclobutyl-Ci-C₆ alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is Ci-Ce hydroxyalkyl. In some embodiments, R⁴ is C1-C6 alkoxy-Ci-C6 alkyl. In some embodiments, R⁴ is amino-Ci-C₆ alkyl. In some embodiments, R⁴ is C1-C6 alkylamino-Ci-C6 alkyl. In some embodiments, R⁴ is di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl. In some embodiments, R⁴ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-C₆ alkyl, azetidinyl-Ci-Ce alkyl, pyrrolidinyl-Ci-Ce alkyl, piperidinyl-Ci-C₆ alkyl, or 2,2-dimethyl- l ,3-dioxolan-4-yl-Ci-C6 alkyl. In some embodiments, R⁴ is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(Ci-C₆ alkyl)amino, hydroxyamino, or N-C -C alkyl hydroxyamino. In some embodiments, R⁴ is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino.

[0282] In some embodiments of formula (II) or (Ila), R¹ is selected from the group consisting of -OH,

[0283] In some embodiments of formula (II) or (Ila), R¹ is -NR⁵R^5a. In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is C1-C6 alkyl. In some embodiments, R⁵ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is C3-C8 cycloalkyl-Ci-Ce alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopropyl- C1-C6 alkyl, or cyclobutyl-Ci-C₆ alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is C1-C6 hydroxyalkyl. In some embodiments, R⁵ is Ci-Ce alkoxy-Ci-C₆ alkyl. In some embodiments, R⁵ is amino-Ci-C₆ alkyl. In some embodiments, R⁵ is C1-C6 alkylamino-Ci-C6 alkyl. In some embodiments, R⁵ is di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl. In some embodiments, R⁵ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-C₆ alkyl, azetidinyl-Ci-C6 alkyl, pyrrolidinyl-Ci-C₆ alkyl, piperidinyl-Ci-C₆ alkyl, or 2,2-dimethyl- l,3-dioxolan-4-yl-Ci-C6 alkyl. In some embodiments, R⁵ is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, Ci-Ce alkylamino, di-(Ci-C6 alkyl)amino, hydroxyamino, or N-C -Ce alkyl hydroxyamino. In some embodiments, R⁵ is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino. [0284] In some embodiments of formula (II) or (Ila), R⁵ is selected from the group consisting of hydrogen,

[0285] In some embodiments of formula (II) or (Ila), R¹ is -N(OR^5b)R^5a. In some

embodiments, R^5b is hydrogen. In some embodiments, R^5b is C₁-C₆ alkyl. In some

embodiments, R^5b is C₃-C₈ cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is C₃-C₈ cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, R^Sb is C3-C₈ cycloalkyl-Ci-C6 alkyl, wherein the C₃-C₈ cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is C3-C8 cycloalkyl-Ci-C6 alkyl, wherein the C₃-C₈ cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C₁-C₆ alkyl. In some embodiments, R^5b is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C6 alkyl, or cyclobutyl-Ci-C6 alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is cyclopropyl, cyclobutyl, cyclopropyl -C ₁ -Ce alkyl, or cyclobutyl-Ci-C6 alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C₁-C₆ alkyl. In some embodiments, R^5b is C₁-C₆ hydroxyalkyl. In some embodiments, R^5b is C1-C6 alkoxy-Ci-C6 alkyl. In some embodiments, R^5b is amino-Ci-C6 alkyl. In some embodiments, R^5b is C₁-C₆ alkylamino-Ci-C6 alkyl. In some embodiments, R^5b is di-(Ci-C6 alkyl)amino-Ci-C6 alkyl. In some embodiments, R^5b is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some

embodiments, R^5b is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C₁-C₆ alkyl. In some embodiments, R^5b is heterocycloalkyl-Ci-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is heterocycloalkyl-Ci-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C₁-C₆ alkyl. In some embodiments, R^5b is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-C6 alkyl, azetidinyl-Ci-C₆ alkyl, pyrrolidinyl- C1-C6 alkyl, piperidinyl-Ci-C6 alkyl, or 2, 2-dimethyl- l ,3-dioxolan-4-yl-Ci-C6 alkyl. In some embodiments, R^5b is R⁷-C(0)-CI-C6 alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(Ci-C6 alkyl)amino, hydroxyamino, or N-C -Ce alkyl hydroxyamino. In some embodiments, R^5b is R⁷-C(0)-CI-C6 alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino.

[0286] In some embodiments of formula (II) or (Ila), R¹ is -N(OR^5b)R^5a and -OR^5b is selected from the group consisting of -OH,

[0287J In some embodiments of formula (II) or (Ila), R^5a is hydrogen. In some embodiments, R^5a is C1-C6 alkyl. In some embodiments, R^5a is C1-C4 alkyl. In some embodiments, R^5a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R^5a is methyl.

[0288] With reference to formula (II) or (Ila), in some embodiments, R¹ is a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, the N-linked heterocycloalkyl is N-linked azetidinyl, N-linked pyrrolidinyl, N-linked isoxazolidinyl, N-linked piperidinyl, or N-linked morpholinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked azetidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked pyrrolidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked isoxazolidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked piperidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked morpholinyl. In some embodiments, R¹ is N-linked azetidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked pyrrolidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked piperidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked isoxazolidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein.

In some embodiments, R¹ is N-linked morpholinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein.

[0289] With reference to R⁶ as one or two substituents of the N-linked heterocycloalkyl in formula (II) or (Ila), in some embodiments, each R⁶ is independently hydroxyl, oxo, or amino.

In some embodiments, each R⁶ is hydroxy. In some embodiments, each R⁶ is oxo. In some embodiments, each R⁶ is amino. In some embodiments, one of R⁶ is hydroxy and the other R⁶ is amino.

[0290] In some embodiments of formula (II) or (Ila), R¹ is a N-linked heterocycloalkyl which is unsubstituted or substituted with hydroxyl, oxo, or amino. In some embodiments, R¹ is N- linked azetidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked pyrrolidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked piperidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked isoxazolidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked morpholinyl which is unsubstituted or substituted with hydroxy, oxo, or amino.

[0291] With reference to formulae (II) or (Ila), in some embodiments, R² is halo, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R² is halo or C1-C6 alkyl. In some embodiments, R² is halo -Ct , -SCH3, C2-C3 alkenyl, or C2-C3 alkynyl.

[0292] In some embodiments of formulae (II) or (Ila), R² is halo. In some embodiments, R² is fluoro. In some embodiments, R² is iodo. In some embodiments, R² is chloro. In some embodiments, R² is bromo.

[0293] In some embodiments of formulae (II) or (Ila), R² is C1-C6 alkyl. In some

embodiments, R² is Ci -C3 alkyl. In some embodiments, R² is methyl.

[0294] In some embodiments of formulae (II) or (Ila), R² is -S-C1-C6 alkyl. In some embodiments, R² is -S-C1-C3 alkyl. In some embodiments, R² is -SCH3. [0295] In some embodiments of formulae (II) or (Ila), R² is C3-C8 cycloalkyl. In some embodiments, R² is cyclopropyl.

[0296] In some embodiments of formulae (II) or (Ila), R² is C2-C6 alkenyl. In some embodiments, R² is C₂-C₄ alkenyl. In some embodiments, R² is vinyl (ethenyl), propenyl, isopropenyl, 1 -butenyl, 2-butenyl, isobutenyl, or butadienyl. In some embodiments, R² is vinyl.

[0297] In some embodiments of formulae (II) or (Ila), R² is C2-C6 alkynyl. In some embodiments, R² is C2-C3 alkynyl. In some embodiments, R² is acetylenyl or propynyl. In some embodiments, R² is acetylenyl.

[0298] With reference to formulae (II) or (Ila), in some embodiments, R^2a is halo or C1-C3 alkyl. In some embodiments, R^2a is halo or CH3. In some embodiments, R^2a is fluoro or CH3. In some embodiments, R^2a is iodo or CH3. In some embodiments, R^2a is chloro or CH3. In some embodiments, R^2a is bromo or CH3.

[0299] In some embodiments of formulae (II) or (Ila), R^2a is halo. In some embodiments, R^2a is fluoro. In some embodiments, R^2a is iodo. In some embodiments, R^2a is chloro. In some embodiments, R^2a is bromo.

[0300] In some embodiments of formulae (II) or (Ila), R^2a is C1-C6 alkyl. In some embodiments, R^2a is C1-C3 alkyl. In some embodiments, R^2a is C¾.

[0301] With reference to formulae (II) or (Ila), in some embodiments, R² and R^2a are each halo. In some embodiments, R² is halo and R^2a is C1-C6 alkyl. In some embodiments, R² is Ci-Ce alkyl and R^2a is halo. In some embodiments, R² is -S-C1-C6 alkyl and R^2a is halo. In some embodiments, R² is -SCH3 and R^2a is halo. In some embodiments, R² is C3-C8 cycloalkyl and R^2a is halo. In some embodiments, R² is cyclopropyl and R^2a is halo. In some embodiments, R² is C2-C6 alkenyl and R^2a is halo. In some embodiments, R² is Ci-Ce alkynyl and R^2a is halo. In some embodiments, R² is acetylenyl and R^2a is halo. In some embodiments, R² and R^2a are each independently fluoro, chloro, bromo, or iodo. In some embodiments, R² is iodo and R^2a is fluoro. In some embodiments, R² is halo and R^2a is -CH3. In some embodiments, R² is bromo and R^2a is -CH3. In some embodiments, R² is iodo and R^2a is -CH3. In some embodiments, R² is -SCH3 and R^2a is fluoro. In some embodiments, R² is acetylenyl and R^2a is fluoro. [0302] In some embodiments, the compound of formula (II) or formula (Ila) is represented by any one of the following formulae:

wherein R², R^2a, R²³, R^23a, and R^23b are as defined herein in any aspect or embodiment described herein.

[0303] In some embodiments of the above structures having formula (II) or (Ila), R² is iodo and R^2a is fluoro. In some embodiments of the above structures, R² is iodo and R^2a is methyl. In some embodiments of the above structures, R² is acetylenyl and R^2a is fluoro. In some embodiments of the above structures, R² is acetylenyl and R^2a is methyl. In some embodiments of the above structures, R² is -SCtb and R^2a is fluoro. In some embodiments of the above structures, R² is -SCH3 and R^2a is methyl.

[0304] In some embodiments of the above structures having formula (II) or (Ila), R²³, R^23a, and R^23b are each hydrogen. In some embodiments of the above structures, R²³ and R^23b are each hydrogen and R^23a is fluoro. In some embodiments of the above structures, R²³ and R^23b are each hydrogen and R^23a is methoxy.

[0305J In some embodiments, the compounds useful in the present gelled formulations and methods thereof are compounds of formula (III).

[0306] With reference to formula (III), in some embodiments, X³ is S and the compound is represented by formula (Ilia):

(Ilia),

wherein R², R^2a, R³³, R^33a, and R^33b are as defined herein in any aspect or embodiment described herein.

[0307] In some embodiments of formula (III), X³ is O and the compound is represented by formula (Illb):

(Illb),

wherein R², R^2a, R³³, R^33a, and R^33b are as defined herein in any aspect or embodiment described herein.

[0308] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R³³, R^33a, and R^33b are each independently hydrogen, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0309] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R³³ is hydrogen, halo, Ci-C₆ alkyl, or C1-C6 alkoxy. In some embodiments, R³³ is hydrogen. In some embodiments, R³³ is halo. In some embodiments, R³³ is fluoro, chloro, bromo, or iodo. In some embodiments, R³³ is fluoro. In some embodiments, R³³ is C1-C6 alkyl. In some embodiments, R³³ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R³³ is methyl. In some embodiments, R³³ is C1-C6 alkoxy. In some embodiments, R³³ is methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy. In some embodiments, R³³ is methoxy.

[0310] In some embodiments of any one of formulae (111), (Ilia), and (lllb), R^33a is hydrogen, halo, Ci-C₆ alkyl, or Ci-Ce alkoxy. In some embodiments, R^33a is hydrogen. In some embodiments, R^33a is halo. In some embodiments, R^33a is fluoro, chloro, bromo, or iodo. In some embodiments, R^33a is fluoro. In some embodiments, R^33a is C1-C6 alkyl. In some embodiments, R^33a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R^33a is methyl. In some embodiments, R^33a is C,-C₆ alkoxy. In some embodiments, R^33a is methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy. In some embodiments, R^33a is methoxy.

[0311] In some embodiments of any one of formulae (Ill), (Ilia), and (Mb), R^33b is hydrogen, halo, Ci-C₆ alkyl, or C1-C6 alkoxy. In some embodiments, R^33b is hydrogen. In some embodiments, R^33b is halo. In some embodiments, R^33b is fluoro, chloro, bromo, or iodo. In some embodiments, R^33b is fluoro. In some embodiments, R^33b is Ci-Ce alkyl. In some embodiments, R^33b is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R^33b is methyl. In some embodiments, R^33b is Ci-Ce alkoxy. In some embodiments, R^33b is methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy. In some embodiments, R^33b is methoxy.

[0312] In some embodiments of any one of formulae (III), (Ilia), and (Mb), R³³, R^33a, and R^33b are each hydrogen. In some embodiments of any one of formulae (III), (Ilia), and (Mb), R^33a and R^33b are each hydrogen and R³³ is halo, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments of any one of formulae (III), (Ilia), and (Mb), R³³ and R^33b are each hydrogen and R^33a is fluoro, methyl, or methoxy. In some embodiments of any one of formulae (III), (Ilia), and (Mb), R³³ and R^33a are each hydrogen and R^33b is halo, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments of any one of formulae (111), (Ma), and (Mb), R^33a and R^33b are each hydrogen and R³³ is fluoro, methyl, or methoxy. In some embodiments of any one of formulae (III), (Ilia), and (Mb), R³³ and R^33b are each hydrogen and R^33a is fluoro, methyl, or methoxy. In some embodiments of any one of formulae (III), (Ilia), and (Illb), R³³ and R^33a are each hydrogen and R^33b is fluoro, methyl, or methoxy.

[0313] With reference to any one of formulae (III), (Ilia), and (Mb), in some embodiments, R¹ is -OR⁴, -NR⁵R^5a, or -N(OR^5b)R^5a.

[0314] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R¹ is -OR⁴. In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is C1-C6 alkyl. In some embodiments, R⁴ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein in some embodiments, R⁴ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is C1-C6 hydroxyalkyl. In some embodiments, R⁴ is C1-C6 alkoxy-Ci-C₆ alkyl. In some embodiments, R⁴ is amino-Ci-C₆ alkyl. In some embodiments, R⁴ is C1-C6 alkylamino-Ci-C₆ alkyl. In some embodiments, R⁴ is di-(Ci-C6 alkyl)amino-Ci-C₆ alkyl. In some embodiments, R⁴ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some

embodiments, R⁴ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, R⁴ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-C₆ alkyl, azetidinyl-Ci-C₆ alkyl, pyrrolidinyl-Ci-C₆ alkyl, piperidinyl-Ci-C₆ alkyl, or 2,2-dimethyl-l ,3-dioxolan-4-yl-Ci-C₆ alkyl. In some embodiments, R⁴ is R⁷-C(0)-CI-C6 alkyl; and R⁷ is hydroxy, Ci-Ce alkoxy, amino, Ci-Ce alkylamino, di-(Ci-C6 alkyl)amino, hydroxyamino, or N-C_\-Ce alkyl hydroxyamino. In some embodiments, R⁴ is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, Ci-Ce alkoxy, amino, or hydroxyamino.

[0315] In some embodiments of any one of formulae (111), (111a), and (111b), R¹ is selected from the group consisting of -OH,

[0316] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R¹ is -NR⁵R^5a. In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is C1-C6 alkyl. In some embodiments, R⁵ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is C3-C8 cycloalkyl-Ci-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is C3-C8 cycloalkyl-Ci-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is Ci-Ce hydroxyalkyl. In some embodiments, R⁵ is C1-C6 alkoxy-Ci-C₆ alkyl. In some embodiments, R⁵ is amino-Ci-Ce alkyl. In some embodiments, R⁵ is C1-C6 alkylamino-Ci-C₆ alkyl. In some embodiments, R⁵ is di-(Ci-C6 alkyl)amino-Ci-C₆ alkyl. In some embodiments, R⁵ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some

embodiments, R⁵ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is heterocycloalkyl-Ci-Ce alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1 -C6 alkyl. In some embodiments, R⁵ is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-Ce alkyl, azetidinyl-Ci-C6 alkyl, pyrrolidinyl-Ci-C6 alkyl, piperidinyl-Ci-C6 alkyl, or 2,2-dimethyl-l ,3-dioxolan-4-yl-Ci-C₆ alkyl. In some embodiments, R⁵ is R⁷-C(0)-CI -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(Ci-C₆ alkyl)amino, hydroxyamino, or N-Ci-Ce alkyl hydroxyamino. In some embodiments, R⁵ is R⁷-C(0)-CI -C6 alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino.

[0317] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R⁵ is selected from the group consisting of hydrogen,

[0318] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R¹ is

-N(OR^5b)R^5a. In some embodiments, R^5b is hydrogen. In some embodiments, R^5b is C1-C6 alkyl. In some embodiments, R^Sb is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^sb is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R^5b is C3-C8 cycloalkyl-Ci-Ce alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, R^5b is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-Ce alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C6 alkyl, or cyclobutyl-Ci-Ce alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R^5b is C1-C6 hydroxyalkyl. In some embodiments, R^5b is C1-C6 alkoxy-Ci-C6 alkyl. In some embodiments, R^5b is amino-Ci-C₆ alkyl. In some embodiments, R^5b is Ci-Ce alkylamino-Ci-C6 alkyl. In some embodiments, R^5b is di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl. In some embodiments, R^5b is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some

embodiments, R^5b is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R^5b is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, R^5b is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-C₆ alkyl, azetidinyl-Ci-C₆ alkyl, pyrrolidinyl- C1-C6 alkyl, piperidinyl-Ci-C6 alkyl, or 2,2-dimethyl-l ,3-dioxolan-4-yl-Ci-C₆ alkyl. In some embodiments, R^5b is R⁷-C(0)-C I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(Ci-C6 alkyl)amino, hydroxyamino, or TV-Ci-Ce alkyl hydroxyamino. In some embodiments, R^5b is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino.

[0319] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R¹ is -N(OR^5b)R^5a and -OR^5b is selected from the group consisting of -OH,

[0320] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R^5a is hydrogen. In some embodiments, R^5a is C1-C6 alkyl. In some embodiments, R^5a is C1-C4 alkyl. In some embodiments, R^5a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R^Sa is methyl.

[0321] With reference to any one of formulae (III), (Ilia), and (Illb), in some embodiments, R¹ is a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, the N-linked heterocycloalkyl is N-linked azetidinyl, N-linked pyrrolidinyl, N-linked isoxazolidinyl, N-linked piperidinyl, or N-linked morpholinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked azetidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked pyrrolidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked isoxazolidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked piperidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked morpholinyl. In some embodiments, R¹ is N-linked azetidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked pyrrolidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked piperidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked isoxazolidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked morpholinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein.

[0322] With reference to R⁶ as one or two substituents of the N-linked heterocycloalkyl in any one of formulae (Ill), (Ma), and (Mb), in some embodiments, each R⁶ is independently hydroxy, oxo, or amino. In some embodiments, each R⁶ is hydroxy. In some embodiments, each R⁶ is oxo. In some embodiments, each R⁶ is amino. In some embodiments, one of R⁶ is hydroxy and the other R⁶ is amino.

[0323] In some embodiments of any one of formulae (III), (Ilia), and (lllb), R¹ is a N-linked heterocycloalkyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked azetidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked pyrrolidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked piperidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked isoxazolidinyl which is unsubstituted or substituted with hydroxy, oxo, or amino. In some embodiments, R¹ is N-linked morpholinyl which is unsubstituted or substituted with hydroxy, oxo, or amino.

[0324] With reference to any one of formulae (III), (Ma), and (Mb), in some embodiments, R² is halo, Ci-C₆ alkyl, -S-Ci-Ce alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R² is halo or C1-C6 alkyl. In some embodiments, R² is halo -Ctb, -SCH3, C2-C3 alkenyl, or C2-C3 alkynyl.

[0325] In some embodiments of any one of formulae (111), (Ilia), and (Illb), R² is halo. In some embodiments, R² is fluoro. In some embodiments, R² is iodo. In some embodiments, R² is chloro. In some embodiments, R² is bromo.

[0326] In some embodiments of any one of formulae (III), (Ilia), and (lllb), R² is C1-C6 alkyl. In some embodiments, R² is C1-C3 alkyl. In some embodiments, R² is methyl.

[0327] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R² is -S-C1-C6 alkyl. In some embodiments, R² is -S-C1-C3 alkyl. In some embodiments, R² is -SCH3.

[0328J In some embodiments of any one of formulae (III), (Ilia), and (Mb), R² is C3-C8 cycloalkyl. In some embodiments, R² is cyclopropyl.

[0329] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R² is C2-C6 alkenyl. In some embodiments, R² is C2-C4 alkenyl. In some embodiments, R² is vinyl (ethenyl), propenyl, isopropenyl, 1 -butenyl, 2-butenyl, isobutenyl, or butadienyl. In some embodiments, R² is vinyl.

[0330] In some embodiments of any one of formulae (III), (Ilia), and (Illb), R² is C2-C6 alkynyl. In some embodiments, R² is C2-C3 alkynyl. In some embodiments, R² is acetylenyl or propynyl. In some embodiments, R² is acetylenyl.

[0331] With reference to any one of formulae (III), (Ilia), and (Illb), in some embodiments,

R^2a is halo or C1-C3 alkyl. In some embodiments, R^2a is halo or CH3. In some embodiments, R^2a is fluoro or CH3. In some embodiments, R^2a is iodo or CH3. In some embodiments, R^2a is chloro or CH3. In some embodiments, R^2a is bromo or CH3.

[0332] In some embodiments of any one of formulae (III), (Ilia), and (Mb), R^2a is halo. In some embodiments, R^2a is fluoro. In some embodiments, R^2a is iodo. In some embodiments, R^2a is chloro. In some embodiments, R^2a is bromo.

[0333] In some embodiments of any one of formulae (III), (Ilia), and (Mb), R^2a is C1-C6 alkyl. In some embodiments, R^2a is C1-C3 alkyl. In some embodiments, R^2a is CH3. [0334] With reference to any one of formulae (111), (Ilia), and (lllb), in some embodiments, R² and R^2a are each halo. In some embodiments, R² is halo and R^2a is C1-C6 alkyl. In some embodiments, R² is Ci-Ce alkyl and R^2a is halo. In some embodiments, R² is -S-C1-C6 alkyl and R^2a is halo. In some embodiments, R² is -SCH3 and R^2a is halo. In some embodiments, R² is C3-C8 cycloalkyl and R^2a is halo. In some embodiments, R² is cyclopropyl and R^2a is halo. In some embodiments, R² is C2-C6 alkenyl and R^2a is halo. In some embodiments, R² is C2-C6 alkynyl and R^2a is halo. In some embodiments, R² is acetylenyl and R^2a is halo. In some embodiments, R² and R^2a are each independently fluoro, chloro, bromo, or iodo. In some embodiments, R² is iodo and R^2a is fluoro. In some embodiments, R² is halo and R^2a is -CH3. In some embodiments, R² is bromo and R^2a is -CH3. In some embodiments, R² is iodo and R^2a is -CH3. In some embodiments, R² is -SCH3 and R^2a is fluoro. In some embodiments, R² is acetylenyl and R^2a is fluoro.

[0335] In some embodiments, the compound of formula (III) is represented by any one of the following formulae:

wherein X³, R², R^2a, R³³, R^33a, and R^33b are as defined herein in any aspect or embodiment described herein.

[0336] In some embodiments of the above structures having any one of formulae (111), (Ilia), and (IHb), R² is iodo and R^2a is fluoro. In some embodiments of the above structures, R² is iodo and R^2a is methyl. In some embodiments of the above structures, R² is acetylenyl and R^2a is fluoro. In some embodiments of the above structures, R² is acetylenyl and R^2a is methyl. In some embodiments of the above structures, R² is -SCH3 and R^2a is fluoro. In some embodiments of the above structures, R² is -SCH3 and R^2a is methyl.

[0337] In some embodiments of the above structures having any one of formulae (III), (Ilia), and (Illb), R³³, R^33a, and R^33b are each hydrogen. In some embodiments of the above structures, R³³ and R^33b are each hydrogen and R^33a is fluoro. In some embodiments of the above structures, R³³ and R^33b are each hydrogen and R^33a is methyl. In some embodiments of the above structures, R³³ and R^33b are each hydrogen and R^33a is methoxy. In some embodiments of the above structures, R³³ and R^33a are each hydrogen and R^33b is methyl. In some embodiments of the above structures, R³³ and R^33a are each hydrogen and R^33b is methoxy. In some embodiments of the above structures, R^33a and R^33b are each hydrogen and R³³ is methyl.

[0338] In some embodiments, the compounds useful in the present gelled formulations and methods thereof are compounds of formula (IV).

[0339] With reference to formula (IV), in some embodiments, R⁴³ is cyano, -C(0)NR⁴⁸R^48a, or -C(0)R⁴⁶, and R^43a is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R^43a is hydrogen. In some embodiments, R^43a is halo. In some embodiments, R^43a is fluoro, chloro, bromo, or iodo. In some embodiments, R^43a is fluoro. In some embodiments, R^43a is Ci-Ce alkyl. In some embodiments, R^43a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R^43a is methyl.

[0340] In some embodiments of formula (IV), R⁴³ is cyano and the compound is represented by formula (IVa):

wherein R¹, R², R^2a, and R^43a are as defined herein in any aspect or embodiment described herein.

(0341] In some embodiments of formula (IV a), R^43a is hydrogen, halo, or C1 -C6 alkyl. In some embodiments, R^43a is hydrogen, halo, or methyl. In some embodiments, R^43a is methyl.

[0342] With reference to formula (IV), in some embodiments, R⁴³ is -C(0)NR⁴⁸R^48a and the compound is represented by formula (IVb):

wherein R¹, R², R^2a, R^43a, R⁴⁸, and R^48a are as defined herein in any aspect or embodiment described herein. [0343] In some embodiments of formula (IVb), R^43a is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R^43a is hydrogen, halo, or methyl. In some embodiments, R^43a is methyl.

[0344] In some embodiments of formula (IVb), R⁴⁸ and R^48a are each independently hydrogen or C1-C6 alkyl. In some embodiments, R⁴⁸ and R^48a are each hydrogen. In some embodiments, R⁴⁸ and R^48a are each independently C1-C6 alkyl. In some embodiments, one of R⁴⁸ and R^48a is hydrogen and the other is C1-C6 alkyl. [0345] In some embodiments of formula (IV), R⁴³ is -C(0)NH₂, and R^43a is methyl.

[0346] With reference to formula (IV), in some embodiments, R⁴³ is -C(0)R⁴⁶, and the compound is represented by formula (IVc):

wherein R¹, R², R^2a, R^43a, and R⁴⁶ are as defined herein in any aspect or embodiment described herein.

[0347] In some embodiments of formula (IVc), R^43a is hydrogen, halo, or Ci-Ce alkyl. In some embodiments, R^43a is hydrogen, halo, or methyl. In some embodiments, R^43a is methyl.

[0348] In some embodiments of formula (IVc), R⁴⁶ is hydrogen, C1 -C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R⁴⁶ is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein the haloalkyl is alkyl substituted with 1 , 2, or 3 fluoro.

[0349] In some embodiments of formula (IVc), R⁴⁶ is hydrogen. In some embodiments of formula (IVc), R⁴⁶ is C1-C6 alkyl. In some embodiments, R⁴⁶ is C1-C4 alkyl. In some embodiments, R⁶ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl.

[0350] In some embodiments of formula (IVc), R⁴⁶ is C1-C6 haloalkyl wherein the haloalkyl is alkyl substituted with 1 , 2, or 3 fluoro. In some embodiments, R⁴⁶ is C1-C4 haloalkyl wherein the C1-C4 haloalkyl is C1-C4 alkyl substituted with 1 , 2, or 3 fluoro. In some embodiments, R⁴⁶ is trifluoromethyl, fluoromethyl, or 2,2,2 -trifluoroethyl.

[0351] In some embodiments of formula (IVc), R⁴⁶ is C3-C8 cycloalkyl or heterocycloalkyl. In some embodiments, R⁴⁶ is C3-C8 cycloalkyl. In some embodiments, R⁴⁶ is cyclopropyl or cyclobutyl. In some embodiments, R⁶ is heterocycloalkyl. In some embodiments, R⁴⁶ is a 3 to 8 membered heterocycloalkyl having 1 to 3 heteroatoms of N, O, or S. In some embodiments, R⁴⁶ is a 3 to 6 membered heterocycloalkyl having 1 to 2 heteroatoms of N or O. In some embodiments, R⁴⁶ is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, isoxazolidinyl, or morpholinyl. [0352] Returning to formula (IV), in some embodiments, R⁴³ and R^43a together

form -CH2CH2C(0)- or -CH2CH2CH2C(0)-, each of which is unsubstituted or substituted with one or two R⁴⁹. In some embodiments, R⁴³ and R^43a together form -CH₂CH₂C(0)- or

-CH₂CH₂CH₂C(0)-.

[0353] In some embodiments of formula (IV), the compound is represented by

formula (IVd-l) or (IVd-2):

wherein R¹, R², R^2a, and R⁴⁹ are as defined herein in any aspect or embodiment described herein.

[0354] In some embodiments of formula (IV), the compound is represented by

formula (

wherein R¹, R², R^2a, and R⁴⁹ are as defined herein in any aspect or embodiment described herein.

[0355] In some embodiments of any one of formulae (IVd-l), (IVd-2), (IVe-1), and (IVe-2), each R⁴⁹ is independently C1-C6 alkyl. In some embodiments of formula (IVd-l), (IVd-2), (IVe- 1), or (IVe-2), R⁴⁹ is absent.

[0356] With reference to any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-l), (IVd-2), (IVe-1) and (IVe-2), in some embodiments, R¹ is -OR⁴, -NR⁵R^5a, or -N(OR^5b)R^5a.

[0357] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-l), (IVd-2), (IVe-1) and (IVe-2), R¹ is -OR⁴. In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is C1-C6 alkyl. In some embodiments, R⁴ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is

independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is cyclopropyl, cyclobutyl, cycloprop yl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is C1-C6 hydroxyalkyl. In some embodiments, R⁴ is C1-C6 alkoxy-Ci-C₆ alkyl. In some embodiments, R⁴ is amino-Ci-C₆ alkyl. In some embodiments, R⁴ is C1-C6 alkylamino- C1-C6 alkyl. In some embodiments, R⁴ is di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl. In some embodiments, R⁴ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁴ is heterocycloalkyl-Ci-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁴ is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-C₆ alkyl, azetidinyl-Ci-C₆ alkyl, pyrrolidinyl-Ci-C₆ alkyl, piperidinyl-Ci-Ce alkyl, or 2,2-dimethyl- l,3-dioxolan-4-yl-Ci-C6 alkyl. In some embodiments, R⁴ is R⁷-C(0)-CI-C6 alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(Ci-C6 alkyl)amino, hydroxyamino, or N-C_\-Ce alkyl hydroxyamino. In some embodiments, R⁴ is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino.

[0358] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1),

(IVd-2), (IVe-1) and (IVe-2), R¹ is selected from the group consisting of -OH,

[0359] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1 ), (lVd-2), (IVe-1) and (lVe-2), R¹ is -NR⁵R^5a. In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is C1-C6 alkyl. In some embodiments, R⁵ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is

independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is C3-C8 cycloalkyl-Ci-Ce alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is cyclopropyl, cyclobutyl, cycloprop yl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-Ce alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is C1-C6 hydroxyalkyl. In some embodiments, R⁵ is C1-C6 alkoxy-Ci-C₆ alkyl. In some embodiments, R⁵ is amino-Ci-C₆ alkyl. In some embodiments, R⁵ is C1-C6 alkylamino- C1-C6 alkyl. In some embodiments, R⁵ is di-(Ci-C6 alkyl)amino-Ci-C₆ alkyl. In some embodiments, R⁵ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is heterocycloalkyl-Ci-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵ is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-C₆ alkyl, azetidinyl-Ci-Ce alkyl, pyrrolidinyl-Ct-C6 alkyl, piperidinyl-Ci-Ce alkyl, 2,2-dimethyl-l ,3- dioxolan-4-yl-Ci-C₆ alkyl. In some embodiments, R⁵ is R⁷-C(0)-C_I-C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(Ci-C6 alkyl)amino, hydroxyamino, or N-Ci-Ce alkyl hydroxyamino. In some embodiments, R⁵ is R⁷-C(0)-CI -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino.

[0360] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1) and (IVe-2), R¹ is -NR⁵R^5a and R⁵ is selected from the group consisting of hydrogen,

[0361] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1) and (IVe-2), R¹ is -N(OR^5b)R^5a. In some embodiments, R^5b is hydrogen. In some embodiments, R^5b is C1-C6 alkyl. In some embodiments, R^5b is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R^5b is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C_\-Ce alkyl. In some embodiments, R^5b is cyclopropyl, cyclobutyl, cycloprop yl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C6 alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R^5b is C1-C6 hydroxyalkyl. In some embodiments, R^5b is C1-C6 alkoxy-Ci-C₆ alkyl. In some embodiments, R^5b is amino-Ci-C₆ alkyl. In some embodiments, R^5b is C1-C6 alkylamino-Ci-C6 alkyl. In some embodiments, R^5b is di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl. In some embodiments, R^5b is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R^5b is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R^5b is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R^5b is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl- Ci-Ci alkyl, azetidinyl-Ci-Ce alkyl, pyrrolidinyl-Ci-C₆ alkyl, piperidinyl-Ci-C₆ alkyl, or 2,2- dimethyl- 1 ,3 -dioxolan-4-yl-Ci-C₆ alkyl. In some embodiments, R^5b is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(Ci-C6 alkyl)amino, hydroxyamino, or W-C1-C6 alkyl hydroxyamino. In some embodiments, R^5b is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino.

[0362] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1),

(lVd-2), (IVe-1) and (IVe-2), R¹ is -N(OR^5b)R^5a and -OR^5b is selected from the group consisting of-OH,

[0363] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-l) and (lVe-2), R^5a is hydrogen. In some embodiments, R^5a is C1-C6 alkyl. In some embodiments, R^5a is C1-C4 alkyl. In some embodiments, R^Sa is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R^5a is methyl.

[0364] With reference to any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-l) and (lVe-2), in some embodiments, R¹ is a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein.

In some embodiments, the N-linked heterocycloalkyl is N-linked azetidinyl, N-linked pyrrolidinyl, N-linked isoxazolidinyl, N-linked piperidinyl, or N-linked morpholinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked azetidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked pyrrolidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked isoxazolidinyl. In some embodiments, the N-linked

heterocycloalkyl is N-linked piperidinyl. In some embodiments, the N-linked heterocycloalkyl is N-linked morpholinyl. In some embodiments, R¹ is N-linked azetidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked pyrrolidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked piperidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked isoxazolidinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein. In some embodiments, R¹ is N-linked morpholinyl which is unsubstituted or substituted with one or two R⁶, wherein R⁶ is as defined and described herein.

[0365] With reference to R⁶ as one or two substituents of the N-linked heterocycloalkyl in any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-l) and (IVe-2), in some embodiments, each R⁶ is independently hydroxyl, oxo, or amino. In some embodiments, each R⁶ is hydroxy. In some embodiments, each R⁶ is oxo. In some embodiments, each R⁶ is amino. In some embodiments, one of R⁶ is hydroxy and the other R⁶ is amino.

[0366] In some embodiments of any one of formulae (IV), (lVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1) and (IVe-2), R¹ is a N-linked heterocycloalkyl which is unsubstituted or substituted with hydroxyl, oxo, or amino. In some embodiments, R¹ is N-linked azetidinyl which is unsubstituted or substituted with hydroxyl, oxo, or amino. In some embodiments, R¹ is N-linked pyrrolidinyl which is unsubstituted or substituted with hydroxyl, oxo, or amino. In some embodiments, R¹ is N-linked piperidinyl which is unsubstituted or substituted with hydroxyl, oxo, or amino. In some embodiments, R¹ is N-linked isoxazolidinyl which is unsubstituted or substituted with hydroxyl, oxo, or amino. In some embodiments, R’ is N-linked morpholinyl which is unsubstituted or substituted with hydroxyl, oxo, or amino.

[0367] With reference to any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1) and (IVe-2), in some embodiments, R² is halo, Ci-Ce alkyl, -S-Ci-Ce alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R² is halo or C1-C6 alkyl. In some embodiments, R² is R² is halo,-CH3, -SCH3, C2-C3 alkenyl, or C2-C3 alkynyl.

[0368] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1),

(IVd-2), (IVe-1) and (IVe-2), R² is halo. In some embodiments, R² is fluoro. In some embodiments, R² is iodo. In some embodiments, R² is chloro. In some embodiments, R² is bromo.

[0369] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1),

(IVd-2), (IVe-1) and (IVe-2), R² is C1-C6 alkyl. In some embodiments, R² is C1-C3 alkyl. In some embodiments, R² is methyl.

[0370] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1),

(IVd-2), (IVe-1) and (IVe-2), R² is -S-C1-C6 alkyl. In some embodiments, R² is -S-C1-C3 alkyl.

In some embodiments, R² is -SCH3.

[0371] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1),

(IVd-2), (IVe-1) and (IVe-2), R² is C3-C8 cycloalkyl. In some embodiments, R² is cyclopropyl. [0372] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-l), (IVd-2), (IVe-1) and (IVe-2), R² is C2-C6 alkenyl. In some embodiments, R² is C2-C4 alkenyl.

In some embodiments, R² is vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, or butadienyl. In some embodiments, R² is vinyl.

[0373] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-l), (IVd-2), (IVe-1) and (IVe-2), R² is C2-C6 alkynyl. In some embodiments, R² is C2-C3 alkynyl.

In some embodiments, R² is acetylenyl or propynyl. In some embodiments, R² is acetylenyl.

[0374] With reference to any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-l), (IVd-2), (IVe-1) and (IVe-2), in some embodiments, R^2a is halo or C1-C3 alkyl. In some embodiments, R^2a is halo or CH3. In some embodiments, R^2a is fluoro or CH3. In some embodiments, R^2a is iodo or CH3. In some embodiments, R^2a is chloro or CH3. In some embodiments, R^2a is bromo or CH3.

[0375] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-l), (IVd-2), (IVe-1) and (IVe-2), R^2a is halo. In some embodiments, R^2a is fluoro. In some embodiments, R^2a is iodo. In some embodiments, R^2a is chloro. In some embodiments, R^2a is bromo.

[0376] In some embodiments of any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-l ), (IVd-2), (IVe-1) and (IVe-2), R^2a is Ci-Ce alkyl. In some embodiments, R^2a is C1-C3 alkyl. In some embodiments, R^2a is CH3.

[0377J With reference to any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-l), (IVd-2), (IVe-1) and (IVe-2), in some embodiments, R² and R^2a are each halo. In some embodiments, R² is halo and R^2a is C1-C6 alkyl. In some embodiments, R² is C1-C6 alkyl and R^2a is halo. In some embodiments, R² is -S-C1-C6 alkyl and R^2a is halo. In some embodiments, R² is -SCH3 and R^2a is halo. In some embodiments, R² is C3-C8 cycloalkyl and R^2a is halo. In some embodiments, R² is cyclopropyl and R^2a is halo. In some embodiments, R² is C2-C6 alkenyl and R^2a is halo. In some embodiments, R² is C2-C6 alkynyl and R^2a is halo. In some embodiments, R² is acetylenyl and R^2a is halo. In some embodiments, R² and R^2a are each independently fluoro, chloro, bromo, or iodo. In some embodiments, R² is iodo and R^2a is fluoro. In some embodiments, R² is halo and R^2a is -CH3. In some embodiments, R² is bromo and R^2a is -CH3. In some embodiments, R² is iodo and R^2a is -CH3. In some embodiments, R² is -SCH3 and R^2a is fluoro. In some embodiments, R² is acetylenyl and R^2a is fluoro.

[0378] In some embodiments, the compound of formula (IV) is represented by any one of the following formulae:

wherein R², R^2a, R⁴³, and R^43a are as defined herein in any aspect or embodiment described herein. [0379] In some embodiments of the above structures having formula (IV), R² is iodo and R^2a is fluoro. In some embodiments of the above structures, R² is iodo and R^2a is methyl. In some embodiments of the above structures, R² is acetylenyl and R^2a is fluoro. In some embodiments of the above structures, R² is acetylenyl and R^2a is methyl. In some embodiments of the above structures, R² is -SCH3 and R^2a is fluoro. In some embodiments of the above structures, R² is -SCH3 and R^2a is methyl.

[0380] In some embodiments of the above structures having formula (IV), R⁴³ is cyano, -C(0)NR⁴⁸R^48a, or -C(0)R⁴⁶, and R^43a is C1-C6 alkyl. In some embodiments of the above structures, R⁴³ is cyano and R^43a is methyl. In some embodiments of the above structures, R⁴³ is -C(0)NR⁴⁸R^48a; R⁴⁸ and R^48a are each hydrogen; and R^43a is methyl. In some embodiments of the above structures, R⁴³ is -C(0)R⁴⁶, R⁴⁶ is C1-C4 alkyl; and R^43a is C1-C4 alkyl. In some embodiments of the above structures, R⁴³ is -C(0)R⁴⁶, R⁴⁶ is C1-C4 alkyl; and R^43a is methyl. In some embodiments of the above structures, R⁴³ and R^43a together form -CH₂CH₂C(0)- or -CH₂CH₂CH₂C(0)-.

[0381] In some embodiments, the compounds useful in the present gelled formulations and methods thereof are compounds of formula (V).

[0382] With reference to formula (V), in some embodiments, bond“a” is a double bond and the compound is represented by formula (Va):

wherein subscript n, R², R^2a, R⁵¹ , R⁵³, R^53a, and R^53b are as defined herein in any aspect or embodiment described herein.

[0383] In some embodiments of formula (V), bond“a” is a single bond and the compound is represented by formula (Vb):

wherein subscript n, R², R^2a, R⁵¹, R⁵³, R^53a, and R^53b, are as defined herein in any aspect or embodiment described herein.

[0384] In some embodiments of any one of formulae (V), (Va), and (Vb), each R⁵³ is independently halo or C1-C3 alkyl. In some embodiments, each R⁵³ is independently fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, or isopropyl. In some embodiments, each R³ is methyl.

[0385] In some embodiments of any one of formulae (V), (Va), and (Vb), subscript n is 0 or 1. In some embodiments, subscript n is 0 and the compound is represented by formula

(Va-1) or (Vb-1):

wherein R², R^2a, R⁵', R^53a, and R^53b are as defined herein in any aspect or embodiment described herein.

[0386] With reference to any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R^53a and R^53b are each independently hydrogen, halo, or Ci-Ce alkyl.

[0387] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R^53a is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R^53a is hydrogen. In some

embodiments, R^53a is halo. In some embodiments, R^53a is fluoro, chloro, bromo, or iodo. In some embodiments, R^53a is fluoro. In some embodiments, R^53a is C1-C6 alkyl. In some embodiments, R^53a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R^53a is methyl.

I l l [0388] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R^53b is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R^53b is hydrogen. In some embodiments, R^53b is halo. In some embodiments, R^53b is fluoro, chloro, bromo, or iodo. In some embodiments, R^53b is fluoro. In some embodiments, R^53b is C1-C6 alkyl. In some embodiments, R^53b is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R^53b is methyl.

[0389] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1 ), R^53a and R^53b are each hydrogen. In some embodiments, R^53a is hydrogen and R^53b is halo. In some embodiments, R^53a is hydrogen and R^53b is fluoro.

[0390] with reference to any one of formulae (V), (Va), (Vb), (Va-1 ), and (Vb-1), in some embodiments, R⁵¹ is C1-C6 alkyl. In some embodiments, R⁵ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵¹ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵¹ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵¹ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵¹ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵¹ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵¹ is C1-C6 hydroxyalkyl. In some embodiments, R⁵¹ is C1-C6 alkoxy-Ci-C₆ alkyl. In some embodiments, R⁵¹ is amino-Ci-C₆ alkyl. In some embodiments, R⁵¹ is C1-C6 alkylamino-Ci-C6 alkyl. In some embodiments, R⁵¹ is di-(Ci-Ce alkyl)amino-Ci-C₆ alkyl. In some embodiments, R⁵¹ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵¹ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, R⁵ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵¹ is heterocycloalkyl-Ci-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵¹ is oxetanyl-Ci-C6 alkyl, azetidinyl-Ci-C₆ alkyl, pyrrolidinyl- C1-C6 alkyl, piperidinyl-Ci-C6 alkyl, or 2,2-dimethyl-l ,3-dioxolan-4-yl-Ci-C6 alkyl. In some embodiments, R⁵¹ is R⁷-C(0)-C I -C₆ alkyl; and R⁷ is hydroxy, Ci-Ce alkoxy, amino, C1-C6 alkylamino, di-(Ci-C₆ alkyl)amino, hydroxyamino, or N-Ci-C alkyl hydroxyamino. In some embodiments, R⁵¹ is R⁷-C(0)-C_I -C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, or hydroxyamino.

[0391] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R⁵¹ is selected from the group consisting of hydrogen,

[0392] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R⁵¹ is OR⁵⁴. In some embodiments, R⁵⁴ is hydrogen. In some embodiments, R⁵⁴ is C1-C6 alkyl. In some embodiments, R⁵⁴ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵⁴ is C3-C8 cycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C 1 -C₆ alkyl. In some embodiments, R⁵⁴ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵⁴ is C3-C8 cycloalkyl-Ci-C₆ alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or Ci-Ce alkyl. In some embodiments, R⁵⁴ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C₆ alkyl, or cyclobutyl-Ci-C₆ alkyl; and each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopropyl-Ci-C6 alkyl, or cyclobutyl-Ci-C₆ alkyl, each of the cyclopropyl and cyclobutyl groups is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵⁴ is C_\-Ce hydroxyalkyl. In some embodiments, R⁵⁴ is C1-C6 alkoxy-Ci-C₆ alkyl. In some embodiments, R⁵⁴ is amino-Ci-C₆ alkyl. In some embodiments, R⁵⁴ is C1-C6 alkylamino-Ci-C₆ alkyl. In some embodiments, R⁵⁴ is di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl. In some embodiments, R⁵⁴ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some

embodiments, R⁵⁴ is heterocycloalkyl unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵⁴ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and R⁶ is as defined and described herein. In some embodiments, R⁵⁴ is heterocycloalkyl-Ci-C₆ alkyl, wherein the heterocycloalkyl group is unsubstituted or substituted with one to six R⁶ and each R⁶ is independently hydroxy or C1-C6 alkyl. In some embodiments, R⁵⁴ is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-Ci-C₆ alkyl, azetidinyl-Ci-C₆ alkyl, pyrrolidinyl- C1-C6 alkyl, piperidinyl-Ci-C6 alkyl, or 2, 2-dimethyl- l ,3-dioxolan-4-yl-Ci-C6 alkyl. In some embodiments, R⁵⁴ is R⁷-C(0)-CI-C₆ alkyl; and R⁷ is hydroxy, C1-C6 alkoxy, amino, Ci-C₆ alkylamino, di-(Ci-C₆ alkyl)amino, hydroxyamino, or N-Ci-Ce alkyl hydroxyamino. In some embodiments, R⁵⁴ is R⁷-C(0)-CI-C₆ alkyl; and R⁷ is hydroxy, Ci-Cs alkoxy, amino, or hydroxyamino.

[0393] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R⁵¹ is selected from the group consisting of -OH,

[0394] With reference to any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), in some embodiments, R² is halo, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R² is halo or C1-C6 alkyl. In some embodiments, R² is halo, -SCH3, -CH3, C2-C3 alkenyl, or C2-C3 alkynyl.

[0395] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R² is halo. In some embodiments, R² is fluoro. In some embodiments, R² is iodo. In some embodiments, R² is chloro. In some embodiments, R² is bromo.

[0396] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R² is

C1-C6 alkyl. In some embodiments, R² is C1-C3 alkyl. In some embodiments, R² is methyl.

[0397] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R² is -S-C1-C6 alkyl. In some embodiments, R² is -S-C1-C3 alkyl. In some embodiments, R² is -SCH3.

[0398] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R² is

C3-C8 cycloalkyl. In some embodiments, R² is cyclopropyl.

[0399] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R² is C2-C6 alkenyl. In some embodiments, R² is C2-C4 alkenyl. In some embodiments, R² is vinyl (ethenyl), propenyl, isopropenyl, 1 -butenyl, 2-butenyl, isobutenyl, or butadienyl. In some embodiments, R² is vinyl. [0400] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R² is C2-C₆ alkynyl. In some embodiments, R² is C₂-C₃ alkynyl. In some embodiments, R² is acetylenyl or propynyl. In some embodiments, R² is acetylenyl.

[0401] With reference to any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), in some embodiments, R^2a is halo or C1-C3 alkyl. In some embodiments, R^2a is halo or CH3. In some embodiments, R^2a is fluoro or CH3. In some embodiments, R^2a is iodo or CH3. In some embodiments, R^2a is chloro or CH3. In some embodiments, R^2a is bromo or CH3.

[0402] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R^2a is halo. In some embodiments, R^2a is fluoro. In some embodiments, R^2a is iodo. In some embodiments, R^2a is chloro. In some embodiments, R^2a is bromo.

[0403] In some embodiments of any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), R^2a is C1-C6 alkyl. In some embodiments, R^2a is C₁-C3 alkyl. In some embodiments, R^2a is CH₃.

[0404] With reference to any one of formulae (V), (Va), (Vb), (Va-1), and (Vb-1), in some embodiments, R² and R^2a are each halo. In some embodiments, R² is halo and R^2a is C1-C6 alkyl. In some embodiments, R² is Ci-Ce alkyl and R^2a is halo. In some embodiments, R² is -S-C₁-C₆ alkyl and R^2a is halo. In some embodiments, R² is -SCH₃ and R^2a is halo. In some

embodiments, R² is C3-C8 cycloalkyl and R^2a is halo. In some embodiments, R² is cyclopropyl and R^2a is halo. In some embodiments, R² is C2-C6 alkenyl and R^2a is halo. In some

embodiments, R² is C2-C6 alkynyl and R^2a is halo. In some embodiments, R² is acetylenyl and R^2a is halo. In some embodiments, R² and R^2a are each independently fluoro, chloro, bromo, or iodo. In some embodiments, R² is iodo and R^2a is fluoro. In some embodiments, R² is halo and R^2a is -CH₃. In some embodiments, R² is bromo and R^2a is -CH₃. In some embodiments, R² is iodo and R^2a is -CH₃. In some embodiments, R² is -SCH₃ and R^2a is fluoro. In some embodiments, R² is acetylenyl and R^2a is fluoro.

[0405] In some embodiments, the compound of formula (V) is represented by any one of the following formulae:

wherein bond“a”, R², R^2a, R^53a, and R^53b are as defined herein in any aspect or embodiment described herein. [0406] In some embodiments of the above structures having formula (V), bond“a” is a double bond. In some embodiments of the above structures having formula (V), bond“a” is a single bond.

[0407] In some embodiments of the above structures having formula (V), R² is iodo and R^2a is fluoro. In some embodiments of the above structures, R² is iodo and R^2a is methyl. In some embodiments of the above structures, R² is acetylenyl and R^2a is fluoro. In some embodiments of the above structures, R² is acetylenyl and R^2a is methyl. In some embodiments of the above structures, R² is -SCH3 and R^2a is fluoro. In some embodiments of the above structures, R² is -SCH3 and R^2a is methyl.

[0408] In some embodiments of the above structures having formula (V), R^53a and R^53b are each hydrogen. In some embodiments of the above structures, R^53a is hydrogen and R^53b is halo. In some embodiments of the above structures, R^53a is hydrogen and R^53b is fluoro.

[0409] Exemplified compounds having any one of formulae (I), (II), (III), (IV), and (V) are listed in Tables 1-5.

Table 1 : Compounds of formula (I)

Table 2: Compounds of formula (II)

Table 3: Compounds of formula (II)

Table 4: Compounds of formula (IV)

Table 5: Compounds of formula (V)

[0410] The compounds of the present invention may exist as salts. The present invention includes such salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (eg (+)- tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in art. Also included are base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,

monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,

methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0411] Other salts include acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing

Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0412] Pharmaceutically acceptable salts includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0413] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0414] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0415] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention. The compounds of the present invention do not include those which are known in art to be too unstable to synthesize and/or isolate. The present invention is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0416] Isomers include compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.

[0417] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention. Tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0418] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0419] Unless otherwise stated, the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present invention may be labeled with radioactive or stable isotopes, such as for example deuterium (²H), tritium (³H), iodine-125 (^{l 25}I), fluorine-18 (^{l 8}F), nitrogen-15 (^{l 5}N), oxygen-17 (¹⁷0), oxygen-18 (¹⁸0), carbon-13 (¹³C), or carbon-14 (^l4C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0420] In addition to salt forms, the present invention provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0421] The compounds of the present application are designed for topical, subcutaneous, intradermal, or intralesional application, resulting in inhibition of MEK activity in the dermal and epidermal layers (or in the birthmark) for treatment of a birthmark. After acting to treat the birthmark, in some embodiments, the compound is designed to be metabolically labile in order to limit systemic toxicity after topical, subcutaneous, transdermal, intradermal, of intralesional application by limiting the amount of time the compound remains in the peripheral circulation. The present application provides a solution for the treatment of a birthmark with compounds which demonstrate the ability to penetrate the skin and suppress phospho-ERK.

V. KITS

[0422] Also provided are kits for use in methods of treatment of a MEK-inhibitor responsive disorder or disease, a MEK-inhibitor responsive dermal disorder or disease, a MEK-mediated disorder or disease, or a MEK-mediated dermal disorder or disease where the subject is in need thereof; or a MEK-inhibitor responsive disorder or disease, a MEK-inhibitor responsive dermal disorder or disease, a MEK-mediated disorder or disease, or a MEK-mediated dermal disorder or disease. The kits can include a gelled topical formulation including a MEK inhibitor or compound provided herein, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating a MEK-inhibitor responsive disorder or disease, a MEK-inhibitor responsive dermal disorder or disease, a MEK-mediated disorder or disease, or a MEK-mediated dermal disorder or disease. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained. A unit dose of a compound or a gelled topical formulation provided herein, or a second agent or composition, can include a dosage such that when administered to a subject, a therapeutically or

prophylactically effective plasma level of the compound or the gelled topical formulation can be maintained in the subject for at least 1 day.

[0423] Also provided are kits for use in methods of treatment of a birthmark (e.g., a MEK- inhibitor responsive or MEK-mediated birthmark), where the subject is in need thereof. The kits can include a gelled topical formulation including a MEK inhibitor or compound provided herein, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating a birthmark (e.g., a MEK-inhibitor responsive or MEK- mediated birthmark). Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained. A unit dose of a compound or a gelled topical formulation provided herein, or a second agent or composition, can include a dosage such that when administered to a subject, a therapeutically effective plasma level of the compound or the gelled topical formulation can be maintained in the subject for at least 1 day.

[0424] In some embodiments, suitable packaging is provided. As used herein,“packaging” includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and/or a second agent suitable for administration to a subject. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.

VI. METHODS

[0425] In another aspect, the present invention provides a method of treating a skin disorder. The method includes administering a gelled topical formulation including a MEK inhibitor, thereby treating the skin disease, wherein the gelled topical formulation and the MEK inhibitor are as defined and described herein.

[0426] In some embodiments, provided herein is a method for treating a skin disorder where the subject is in need thereof and the skin disorder is a MEK-inhibitor responsive dermal disorder or disease or a MEK-mediated dermal disorder or disease in a subject. The method includes administering the subject with a therapeutically or prophylactically effective amount of a gelled topical formulation including a MEK inhibitor, wherein the gelled topical formulation and the MEK inhibitor are as defined and described herein.

[0427] In some embodiments, the MEK-inhibitor responsive dermal disorder or MEK- mediated dermal disorder is selected from the group consisting of dermal rasopathy, neurofibromatosis type 1 , dermal neurofibroma, subdermal neurofibroma, and superficial plexiform neurofibroma.

[0428] In some embodiments, the MEK-inhibitor responsive dermal disorder or MEK- mediated dermal disorder is neurofibromatosis type 1.

[0429] In some embodiments, administering includes contacting the gelled topical formulation including the MEK inhibitor with the skin, mucous membranes, vagina, penis, larynx, vulva, cervix, or anus of the subject, by local or non-systemic application, e.g., topical application.

[0430] In some embodiments, the tumor associated with neurofibromatosis type 1 (NF1), e.g., a dermal neurofibroma, a subdermal neurofibroma, or a superficial plexiform neurofibroma, is reduced, e.g., the size or the total tumor volume is reduced, by at least about 15% relative to the reference standard (e.g., from about 15% to about 60%), thereby treating the subject. In some embodiments, the reference standard is the size or the total tumor volume in an untreated control, e.g., from the same subject or a different subject.

[0431] In some embodiments, the size or total tumor volume of the tumor associated with neurofibromatosis type 1 (NF1), e.g., a dermal neurofibroma, a subdermal neurofibroma, or a superficial plexiform neurofibroma, is reduced by at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, by at least about 50%, by at least about 55%, by at least about 60% relative to the reference standard. In some embodiments, the reference standard is the size or the total tumor volume in an untreated control, e.g., from the same subject or a different subject.

[0432] In some embodiments, the method includes evaluating the subject with magnetic resonance imaging (MRI), or optical imaging, e.g. , evaluating the volume of tumors obtained from the subject, e.g., prior to, during and/or after treatment.

[0433] Neurofibromatosis type 1 (NF1): In some embodiments, the dermal disorder is associated with NF1. NF1 , also known as von Recklinghausen Neurofibromatosis or Peripheral Neurofibromatosis, occurs in approximately 1 :3,000 births, and is one of the most prevalent genetic disorders and the most common neurocutaneous disorders. NF1 is caused by a deficiency in neurofibromin, which leads to hyperactivation of various cell-signaling pathways, e.g., Ras and Rho, is associated with several dermal disorders, including dermal neurofibromas (DFs); subdermal neurofibromas; superficial plexiform neurofibromas (PFs); cutaneous neurofibromas (CFs); cafe au lait spots; and axillary and inguinal freckling. DFs occur in over 95% of NF1 patients. DFs can appear anywhere on the body, with 88% of NF1 patients over 40 years of age having over 100 DFs. DFs can cause both severe physical pain, disfigurement, as well as social anxiety. Facial DFs can create significant social anxiety issues and pain among affected individuals. DFs (also known as cutaneous neurofibromas or discrete neurofibromas) grow from small nerves in the skin or just under the skin and appear as small bumps typically beginning around the time of puberty. Current treatment options for DF are limited to surgical excisin and CO2 laser removal, both of which cause scarring and neither of which is preventative.

[0434] Other Dermal Rasopathies: In some embodiments, the dermal disorder is associated with enhanced activation of Ras. In some embodiments, the dermal disorder is selected from: psoriasis, keratocanthoma (KA), hyperkeratosis, papilloma, Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), Costello syndrome (faciocutaneoskeletal syndrome or FCS syndrome), oculoectodermal syndrome, cafe au lait spots and Multiple lentigines syndrome (formerly called Leopard syndrome).

[0435] In some or any embodiments, the disease to be reduced, ameliorated, treated, or prevented is not cancer (e.g. melanoma).

[0436] In some embodiments, the disease to be reduced, ameliorated, treated, or prevented is cancer, a dermal rasopathy, a dermal disorder associated with neurofibromatosis type 1 , a dermal neurofibroma, a subdermal neurofibroma, or a superficial plexiform neurofibroma, psoriasis, keratocanthoma (KA), hyperkeratosis, papilloma, Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), Costello syndrome (faciocutaneoskeletal syndrome or FCS syndrome), oculoectodermal syndrome, cafe au lait spots, and Multiple lentigines syndrome (formerly called Leopard syndrome).

[0437] In some embodiments, the disease to be reduced, ameliorated, treated, or prevented is cancer. In some embodiments, the disease to be reduced, ameliorated, treated, or prevented is selected from the group consisting of basal cell carcinoma, squamous cell carcinoma, aktinic keratosis, Kaposi's sarcoma, dermal lymphoma, cervical cancer, HPV-related squamous cell carcinoma, and melanoma.

[0438] In some embodiments, the disease to be reduced, ameliorated, treated, or prevented is a dermal rasopathy, a dermal disorder associated with neurofibromatosis type 1 , a dermal neurofibroma, a subdermal neurofibroma, or a superficial plexiform neurofibroma, psoriasis, keratocanthoma (KA), hyperkeratosis, papilloma, Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), Costello syndrome (faciocutaneoskeletal syndrome or FCS syndrome), oculoectodermal syndrome, cafe au lait spots, and Multiple lentigines syndrome (formerly called Leopard syndrome).

[0439] In some embodiments, the gelled formulations described herein are used for the reduction of a MEK-inhibitor responsive dermal disorder or disease or a MEK-mediated dermal disorder or disease where the subject is in need thereof

[0440] In some embodiments, the gelled topical formulations described herein are used for the amelioration of a MEK-inhibitor responsive dermal disorder or disease or a MEK-mediated dermal disorder or disease where the subject is in need thereof

[0441] In some embodiments, the gelled topical formulations described herein are used for prevention of a MEK-inhibitor responsive dermal disorder or disease or a MEK-mediated dermal disorder or disease where the subject is in need thereof.

[0442] In some embodiments, the gelled topical formulations described herein are used for treatment of a MEK-inhibitor responsive dermal disorder or disease or a MEK-mediated dermal disorder or disease where the subject is in need thereof.

[0443] In some embodiments, provided herein is a method for treating a skin disorder where the subject is in need thereof and the skin disorder is a birthmark in a subject. The method includes administering the subject with a therapeutically or prophylactically effective amount of a gelled topical formulation including a MEK inhibitor, wherein the gelled topical formulation and the MEK inhibitor are as defined and described herein.

[0444] In some embodiments, the birthmark is a port-wine stain (capillary malformation). Port-wine stains may be present at birth. Port-wine stains may be present at birth. Port-wine stains can occur anywhere on the body and the area of affected skin grows in proportion to general growth. Thickening of the lesion or the development of small lumps may occur in adulthood and can interfere with normal function (e.g., where the port-wine stain is near the eye or mouth). Port-wine stains may, in some cases, be part of a syndrome such as Sturge-Weber syndrome or Klippel-Trenaunay-Weber syndrome.

[0445] In some embodiments, provided herein is a method of treating a port-wine stain (capillary malformation) birthmark to reduce the cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein is a method of prophylactically treating a port-wine stain (capillary malformation) birthmark to prevent the progression of the birthmark, delaying the onset of the birthmark, or delaying the progression of the birthmark.

[0446] In some embodiments, the birthmark is epidermal nevi. Epidermal nevus is a benign skin growth with localized epidermal thickening that is often present at birth or within the first year of life. It typically appears as one or more oblong or linear growths that are skin colored, brown or gray in color. The surface can be wart-like or velvety with sharp borders. Malignant transformation can occur in some cases in middle aged or elderly subjects. Epidermal nevi are subdivided into keratinocytic and organoid nevi. Organoid nevi include nevus sebaceous (NS). In some embodiments, the birthmark is nevus sebaceous. Non-organoid keratinocytic epidermal nevus (KEN) is characterized by benign congenital hyperpigmented skin lesions. Contemplated within the scope of embodiments presented herein are other types of epidermal nevi, including nevus comedonicus. Nevus comedonicus (NC) is a hamartoma of the pilosebaceous unit that, like other epidermal nevi, typically presents at birth or during childhood. Clinically, NC lesions consist of linear arrays or clusters of dilated, keratin-plugged follicular orifices resembling comedones.

[0447] In some embodiments, provided herein is a method of treating epidermal nevi to reduce the cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein is a method of prophylactically treating epidermal nevi to prevent the progression of the birthmark, delaying the onset of the birthmark, or delaying the progression of the birthmark.

[0448] In some embodiments, the birthmark is nevus sebaceous. In some embodiments, provided herein is a method of treating a nevus sebaceous birthmark to reduce the cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein is a method of prophylactically treating a nevus sebaceous birthmark to prevent the progression of the birthmark, delaying the onset of the birthmark, or delaying the progression of the birthmark.

[0449] In some embodiments the birthmark is melanocytic nevus, including congenital nevi, blue nevi, and acquired melanocytic nevi. Malignant melanoma occasionally develops from the melanocytic nevus (also known as nevocytic nevus, nevus-cell nevus and commonly as a mole). Reasons for treatment of pigmented nevi (i.e., nevus cellular nevus) include prevention of malignant change, limiting malignant progression, cosmetic improvement, or prevention of other functional or anatomical changes.

[0450] In some embodiments, provided herein is a method of treating a melanocytic nevus to reduce the risk of cosmetic disfigurement or progression of the birthmark. In some

embodiments, provided herein is a method of prophylactically treating a melanocytic nevus to prevent the progression of the birthmark, delaying the onset of the birthmark, or delaying the progression of the birthmark.

[0451] In some embodiments, the birthmark is dysplastic nevi. Dysplastic nevi (or atypical moles) are unusual-looking benign moles and may resemble melanoma. People who have atypical moles are at increased risk of developing melanoma in a mole or elsewhere on the body.

[0452] In some embodiments, provided herein is a method of treating dysplastic nevi to reduce the cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein is a method of prophylactically treating dysplastic nevi to prevent the progression of the birthmark, delaying the onset of the birthmark, or delaying the progression of the birthmark.

[0453] In some embodiments, the birthmark is a nevus spilus. Nevus spilus (also known as speckled lentiginous nevus and zosteriform lentiginous nevus) is a skin lesion that presents as a light brown patch of pigmentation, and within this patch, are multiple tiny dark brown spots.

[0454] In some embodiments, provided herein is a method of treating a nevus spilus birthmark to reduce the cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein is a method of prophylactically treating a nevus spilus birthmark to prevent the progression of the birthmark, delaying the onset of the birthmark, or delaying the progression of the birthmark. [0455] In some embodiments, the birthmark is an arterio-venous malformation in the skin (e.g., blue rubber bleb nevus syndrome) which may present as skin lesions comprised of compressible blue subcutaneous nodules.

[0456] In some embodiments, provided herein is a method of treating an arterio-venous malformation to reduce the cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein is a method of prophylactically treating an arterio-venous malformation to prevent the progression of the birthmark, delaying the onset of the birthmark, or delaying the progression of the birthmark.

[0457] In some embodiments, the birthmark is a lymphatic malformation. A lymphatic malformation is a type of vascular nevus or birthmark due to malformed and dilated lymphatic vessels. The cystic hygroma (also called‘cystic lymphangioma’ and‘lymphangioma cysticum’) is a‘macrocytic’ lymphatic malformation, and is composed of large fluid-filled spaces. It appears as a skin colored, red or bluish, somewhat transparent, swelling under the skin.

Cavernous lymphangioma can affect any site on the body, including the tongue. Lymphangioma circumscriptum is a‘microcytic’ lymphatic malformation. It appears as a cluster of small firm blisters filled with lymph fluid, resembling frogspawn.

[0458] In some embodiments, provided herein is a method of treating a lymphatic

malformation to reduce the risk of the cosmetic disfigurement or progression of the birthmark.

In some embodiments, provided herein is a method of prophylactically treating a lymphatic malformation to prevent the progression of the birthmark, delaying the onset of the birthmark, or delaying the progression of the birthmark.

[0459] In some embodiments, the birthmark is a congenital melanocytic nevus. The congenital melanocytic nevus appears as a circumscribed, light brown to black patch or plaque, heterogeneous in consistency, covering any size surface area and any part of the body.

Congenital melanocytic nevus poses a risk for malignancy degeneration.

[0460] In some embodiments, provided herein is a method of treating a congenital melanocytic nevus to reduce the risk of cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein is a method of prophylactically treating a congenital melanocytic nevus to prevent the progression of the birthmark, delaying the onset of the birthmark, or delaying the progression of the birthmark.

[0461] In some embodiments, the compounds described herein are used for the reduction of a birthmark in a subject in need thereof.

[0462] In some embodiments, the compounds described herein are used for the amelioration of a birthmark in a subject in need thereof

[0463] In some embodiments, the compounds described herein are used for prevention of a birthmark (e.g., MEK-inhibitor responsive or MEK-mediated birthmarks) and/or prevention of worsening of a birthmark (e.g., where the birthmark may progress to a proliferative disease) in a subject in need thereof.

[0464] In some embodiments, the subject in need thereof is a human.

[0465] The birthmark is not cafe au lait spots.

[0466] In some embodiments, administering includes contacting the gelled topical formulation including the MEK inhibitor with the skin of the subject, e.g., an affected region of the skin, e.g., a region of the skin having a birthmark.

[0467] In some embodiments, the appearance of a birthmark is reduced, e.g., the size, volume, or the total surface area is reduced, by at least about 15% relative to the reference standard (e.g., the size of the birthmark prior to start of treatment), thereby treating the subject. In some embodiments, the size, volume, or the total surface area on skin is reduced, by at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, by at least about 50%, by at least about 55%, by at least about 60% relative to the reference standard. In one embodiment, the reference standard is the size of the birthmark prior to start of treatment.

VII. COMBINATION THERAPIES

[0468] In some embodiments, the gelled topical formulation including the MEK inhibitor provided herein are useful in methods of treatment of a skin disorder where the subject is in need thereof, that comprise further administration of a second agent effective for the treatment of a skin disorder. The second agent can be any agent known to those of skill in the art to be effective for the treatment of dermal disorders or diseases, including those currently approved by the United States Food and Drug Administration, or other similar body of a country foreign to the United States.

[0469] In some embodiments, a gelled topical formulation including a MEK inhibitor or compound provided herein is administered in combination with one second agent. In further embodiments, a gelled topical formulation including a MEK inhibitor or compound provided herein is administered in combination with two second agents. In still further embodiments, a a gelled topical formulation including a MEK inhibitor or compound provided herein is administered in combination with two or more second agents.

[0470] In some embodiments, the methods encompass the step of administering (e.g., topically) to the subject in need thereof an amount of a gelled topical formulation including a MEK inhibitor or compound provided herein in combination with a second agent effective for the treatment or prevention of skin disorders (e.g., MEK-inhibitor responsive or MEK-mediated skin disorders). The gelled formulation can be any topical formulation as described herein; the MEK inhibitor or compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein.

[0471] As used herein, the term“in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the term“in combination” does not restrict the order in which therapies (e.g, prophylactic and or therapeutic agents) are administered to a subject with a disorder. A first therapy (e.g , a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject with a disorder. [0472J As used herein, the term“synergistic” includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention or treatment of a disorder). In addition, a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder. Finally, a synergistic effect of a combination of therapies (e.g. , a combination of prophylactic or therapeutic agents) may avoid or reduce one or more adverse or unwanted side effects associated with the use of either therapy alone.

[0473] The gelled topical formulations including active compounds provided herein can be administered in combination or alternation with another therapeutic agent, in particular an agent effective in the treatment of a skin disorder(e.g., MEK-inhibitor responsive or MEK-mediated skin disorders) where the subject is in need thereof. In combination therapy, effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially. The dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the birthmark to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0474] In some embodiments, dosages of the second agents to be used in a combination therapy are provided herein. In some embodiments, dosages lower than those which have been or are currently being used to treat MEK-inhibitor responsive or MEK-mediated skin conditions are used in the combination therapies provided herein. The recommended dosages of second agents can be obtained from the knowledge of those of skill in the art. For those second agents that are approved for clinical use, recommended dosages are described in, for example, Hardman et al, eds., 1996, Goodman & Gilman’s The Pharmacological Basis Of Therapeutics 9^th Ed, McGraw-Hill, New York; Physician’s Desk Reference (PDR) 57^th Ed., 2003, Medical

Economics Co., Inc., Montvale, NJ; which are incorporated herein by reference in their entirety.

[0475] The disclosure provides combination treatments by administration of a gelled topical formulation including a MEK inhibitor, e.g. a soft MEK inhibitor, described herein with one or more additional agent(s) or a composition thereof. In some embodiments, the one or more additional agent(s) is selected from:

agents that treat acne (e.g., Accutane, Azelaic acid, Benzoyl Peroxide, Salicylic acid); analgesics (e.g., Acetaminophen, Capsaicin), e.g., a Cox2 Inhibitor, e.g. Celecoxib); anesthetics (e.g., Benzocaine, Benzocaine/Menthol, Dibucaine, Diperodon, Lidocaine, Lidocaine/ Prilocaine, Pramoxine);

anti-infectives (e.g., Crotamiton);

anti-prurittus (e.g. , Ammonium lactate, Benzocaine, an ascomycin macrolactam, e.g., Pimecrolimus);

anti-prurittus/5HT3 receptor antagonists (e.g., Ondansetron);

antibiotics (e.g. , clindamycin, doxycycline, erythromycin, tetracycline);

anticholinergic antiemetics (e.g., diphenhydramine);

antifibrotics (e.g., Collagenase, Pirfenidone);

antihistamines (e.g., Triprolidine (Actifed®), Fexofenadine (Allergra®, Allegra® D-12, Allegra®-24), Astepro/Astelin Nasal Spray (Azalastine) (Dymista®), Hydroxyzine hydrochloride (Atarax®), Diphenhydramine Hydrochloride (Benadryl®),

Brompheniramine (Dimetapp® Cold and Allergy Elixir), Zyrtec® (Cetirizine), Chlor- Trimeton® (Chlorpheniramine), Descoratadine (Clarinex®, Clarinex® D-12, and Clarinex® D-24), Loratadine (Claritin®, Claritin® D-12, Claritin® D-24, and Alavert®), Dimenhydrinate (Dramamine®), Diphenhydramine (Benadryl® Allergy, Nytol®, Sominex®), Doxylamine (Vicks® NyQuil®, Alka-Seltzer® Plus Night- Time Cold Medicine), Cyproheptadine (Periactin®), Promethazine (Phenergan®), Acrivastine (Semprex®, Semprex®-D), Clemastine (Tavist®), doxylamine

(Unisom®), Levoceterizine (Xyzal®);

mast cell stabalizers ( e.g . Beta2 -adrenergic agonists, Cromoglicic acid, cromolyn sodium, Gastrocrom®, Ketotifen, Methylxanthines, Omalizumab, Pemirolast, Quercetin, Ketotifen (Zaditen®));

anti-inflammatory agents (e.g., NS AID (e.g. Aspirin, Choline and magnesium salicylates, Diclofenac potassium (Cataflam®), Diclofenac sodium (Voltaren®, Voltaren® XR), Diclofenac sodium with misoprostol (Arthrotec®), Diflunisal (Dolobid®), Etodolac (Lodine®, Lodine® XL), Fenoprofen calcium (Nalfon®), Flurbiprofen (Ansaid®), Ibuprofen (Advil®, Motrin®, Motrin® IB, Nuprin®), Indomethacin (Indocin®, Indocin® SR), Ketoprofen (Actron®, Orudis®, Orudis® KT, Oruvail®), Magnesium salicylate (Arthritab, Bayer® Select, Doan's Pills, Magan, Mobidin, Mobogesic) Meclofenamate sodium (Meclomen®), Mefenamic acid (Ponstel®), Meloxicam (Mobic®), Nabumetone (Relafen®), Naproxen (Naprosyn®, Naprelan®), Naproxen sodium (Aleve®, Anaprox®), Oxaprozin (Daypro®), Piroxicam (Feldene®), Rofecoxib (Vioxx®), Salsalate (Amigesic, Anaflex 750, Disalcid, Marthritic, Mono- Gesic, Salflex, Salsitab), Sodium salicylate, Sulindac (Clinoril®), Tolmetin sodium (Tolectin®), Valdecoxib (Bextra®));

Receptor Tyrosine Kinase Inhibitor (e.g. Sunitinib);

Alkylating Agents (e.g., Dacarbazine, Carboplatin);

CDK 4/6 Inhibitors (e.g, LEE01 1);

PKC Inhibitors (e.g., AEB071);

MAPK inhibitors (e.g., RAS Inhibitors/Famesyltransferase inhibitor (e.g. Tipifamib), Raf Kinase Inhibitor (e.g. Sorafenib (BAY 43-9006, Nexavar), Vemurafenib, Dabrafenib, LGX818, TAK-632, MLN2480, PLX-4720), ERK Inhibitors (e.g, SCH772984, VTXl le);

BRAF inhibitors (e.g., vemurafenib, dabrafenib)

P13K Inhibitor (e.g., LY294002);

AKT Inhibitor (e.g, MK 2206);

P13K/AKT Inhibitor (e.g. buparlisib, Cixutumumab); mTOR Inhibitors (e.g. Topical Rapamycin, RAD001 (Everolimus/Rapamycin),

Temsirolimus, Sirolimus);

Tyrosine Kinase Inhibitors (e.g. Imatinib (Gleevec®), Cabozantinib (inhibitor of tyrosine kinases c-Met and VEGFR2), Nilotinib (Tasigna®);

VEGF Inhibitor (e.g. Ranibizumab (Lucentis®), Cediranib);

Immune Response Modifier (e.g. Topical Imiquimod, Interferon, PEG Interferon);

Calcium Channel Blocker (e.g. Avocil (Mederma)/15% Verapamil, vitamin D separately, Doxycyline Injections);

Statin (e.g. Lovastatin, Methotrexate, Vinblastine, Pregabalin, Temozolomide,

PLX3397);

HD AC Inhibitor (e.g. AR-42);

HSP- 90 Inhibitors (e.g. Ganetespib);

retinoids (e.g. adapalene, Isotretinoin, tazarotene, tretinoin);

steroids (e.g. Alclometasone, Amcinonide, Betamethasone, Betamethasone dipropionate, Betamethasone dipropionate, augmented, Budesonide, Clobetasol propionate, Cortisone, Desonide, Dexamethasone, Diflorasone diacetate, Fluocinolone acetonide, Fluocinonide, Flurandrenolide, Fluticasone propionate, Halobetasol propionate, Halocinonide, Hydrocortisone, Hydrocortisone butyrate, Hydrocortisone valerate, Methylprednisolone, Mometasone, Mometasone furoate, Prednicarbate, Prednisolone, Prednisone, Triamcinolone, Triamcinolone acetonide);

topical calcineurin inhibitors (e.g., pimecrolimus (Elidel® Cream 1 %, Novartis,

tacrolimus (Protopic® Ointment, Astellas)); and

Non-pharmaceutical Interventions (e.g. photodynamic Therapy (Levulan Kerastick

Topical + light), Electrodesication (ED), YAG Laser).

[0476] In various embodiments, the therapies (e.g., a compound provided herein and the second agent) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 1 1 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart. In various embodiments, the therapies are administered no more than 24 hours apart or no more than 48 hours apart. In some embodiments, two or more therapies are administered within the same patient visit. In some embodiments, the compound provided herein and the second agent are administered concurrently.

[0477] In some embodiments, the compound provided herein and the second agent are administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.

[0478] In some embodiments, administration of the same agent may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In some embodiments, administration of the same agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0479] In some embodiments, a compound provided herein and a second agent are administered to a patient, in some embodiments, a mammal, such as a human, in a sequence and within a time interval such that the compound provided herein can act together with the other agent to provide an increased benefit than if they were administered otherwise. In some embodiments, the second active agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. In some embodiments, the compound provided herein and the second active agent exert their effect at times which overlap. Each second active agent can be administered separately, in any appropriate form and by any suitable route. In some embodiments, the compound provided herein is administered before, concurrently or after administration of the second active agent.

[0480] In some embodiments, the compound provided herein and the second agent are cyclically administered to a patient. Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the

administration of a second agent and/or third agent (e.g., a second and/or third prophylactic or therapeutic agent) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce one or more of the side effects of one of the therapies, and/or improve the efficacy of the treatment.

[0481] In some embodiments, the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week. One cycle can comprise the administration of a compound provided herein and the second agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle. Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.

[0482] In some embodiments, courses of treatment are administered concurrently to a patient, i.e., individual doses of the second agent are administered separately yet within a time interval such that the compound provided herein can work together with the second active agent. In some embodiments, one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.

[0483] The second agent can act additively or synergistically with the compound provided herein. In some embodiments, the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition, such as the gelled topical formulation as decribed herein. In some embodiments, a compound provided herein is administered concurrently with one or more second agents in separate pharmaceutical compositions. In some embodiments, a compound provided herein is administered prior to or subsequent to administration of a second agent. Also contemplated are administration of a compound provided herein and a second agent by the same or different routes of administration, e.g. , oral and parenteral. In some embodiments, when the compound provided herein is administered concurrently with a second agent that potentially produces one or more adverse side effects including, but not limited to, toxicity, the second active agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.

VIII. EXAMPLES

General Synthetic Methods

[0484] The compounds provided herein can be prepared, isolated or obtained by any method apparent to those of skill in the art. Compounds provided herein can be prepared according to the Exemplary Preparation Schemes provided below. Reaction conditions, steps and reactants not provided in the Exemplary Preparation Schemes would be apparent to, and known by, those skilled in the art. As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); pL (microliters); mM (millimolar); mM (micromolar); Hz (Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin layer

chromatography); HPLC (high pressure liquid chromatography); THF (tetrahydrofuran); CDCb (deuterated chloroform); AcOH (acetic acid); DCM (dichloromethane); DMSO

(dimethylsulfoxide); DMSO-i¾ (deuterated dimethylsulfoxide); EtOAc (ethyl acetate); MeOH (methanol); Tees (2,2,2-trichloroethoxysulfonyl); -Si(ier/-Bu)(Ph)2 and -Si‘BuPh2 (tert-butyl- diphenylsilyl); and BOC (/-butyloxycarbonyl).

[0485] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius). All reactions are conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure. Compounds of formula (T)

[0486] Compounds of formula (la) can be prepared according to Scheme 1-1 , as shown in FIG. 1 1 , in which R¹ is -OR⁴, -NR⁵R^5a, -N(OR^5b)R^5a, or a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶; and X¹, R², R^2a, R¹³, R^l3a, R⁴, R⁵, R^5a, R^5b, and R⁶ are as defined in any aspect, embodiment, or claim as described herein. In some embodiments, R¹³ and R^l3a are each hydrogen.

[0487] Starting from commercially-available or routinely-accessible acids of formula (I- 101) and commercially-available or routinely-accessible anilines of formula (1-102), compounds of formula (1-103) can be prepared by methods apparent to those of skill in the art. The acid- containing compound of formula (1-103) can be activated with numerous reagents apparent to those of skill in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(0)OH acid group, for example an acid chloride produced from the reaction of (1-103) with thionyl chloride or an active ester produced from the reaction of (1-103) with reagents such as EDCI or HOBt. The acid chlorides or active esters can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a, HN(OR^5b)R^5a, R^a-H (where R^a is a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of formula (la).

[0488] Compounds of formula (la) can be prepared according to Scheme 1-2, as shown in FIG. 12, in which R¹ is -OR⁴, -NR⁵R^5a, -N(OR^5b)R^5a, or a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶; R² is iodo; R^l3b is fluoro; and R^2a, R¹³, R^{l 3a}, R⁴, R⁵, R^5a, R^5b, and R⁶ are as defined in any aspect, embodiment, or claim as described herein. In some embodiments, R¹³ and R^13a are each hydrogen.

[0489] Starting from commercially-available or routinely-accessible acids of formula (1-104) and commercially-available or routinely-accessible anilines of formula (1-105), compounds of formula (1-106) can be prepared by methods apparent to those of skill in the art. A compound of formula (1-106) is then treated with Zn(CN)2 in the presence of a catalyst such as Pd(PPh3)4. The compound of formula (1-108) is prepared by treating (1-107) with iodine in the presence of siver trifluoroacetate or alternatively with iodine monochloride. The acid-containing compound of formula (1-108) can be activated with numerous reagents apparent to those of skill in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(0)OH acid group, for example an acid chloride produced from the reaction of (1-108) with thionyl chloride or an active ester produced from the reaction of (1-108) with reagents such as EDC1 or HOBt. The acid chlorides or active esters can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a, HN(OR^5b)R^5a, R^a-H (where R^a is a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of formula (la), in which R² is iodo and R^l3b is fluoro.

[0490] Compounds of formula (lb) can be prepared according to Scheme 1-3, as shown in FIG. 13, in which R¹ is -OR⁴, -NR⁵R^5a, -N(OR^5b)R^5a, or a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶; R² is iodo; R^3b is fluoro; and R^2a, R¹³, R^{l 3a}, R⁴, R⁵, R^5a, R^5b, and R⁶ are as defined in any aspect, embodiment, or claim as described herein. In some embodiments, R¹³ and R^{l 3a} are each hydrogen. In some embodiments, R³ is hydrogen and R^l3a is fluoro.

[0491] Starting from commercially-available or routinely-accessible acids of formula (1-109) and commercially-available or routinely-accessible anilines of formula (1-105), compounds of formula (1-110) can be prepared by methods apparent to those of skill in the art. Alternatively, compounds of formula (1-110) can be converted to methyl ester of formula (1-1 11) by methods known in the art. A compound of formula (1-1 10) or formula (1-1 1 1) is then treated with Zn(CN)2 in the presence of a catalyst such as Pd(PPh3)4. The compound of formula (1-114) or formula (1-115) is prepared by treating the compound of formula (1-110) or formula (1-11 1) with iodine in the presence of siver trifluoroacetate or alternatively with iodine monochloride. In the case of the compound of formula (1-115), the methyl ester is then hydrolyzed to the

corresponding acid. The acid-containing compound of formula (1-1 14) can be activated with numerous reagents apparent to those of skill in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(0)OH acid group, for example an acid chloride produced from the reaction of (1-114) with thionyl chloride or an active ester produced from the reaction of (1-1 14) with reagents such as EDCI or HOBt. The acid chlorides or active esters can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a, HN(OR^5b)R^5a, R^a-H (where R^a is a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of formula (lb). Compounds of formula (Ill

[0492] Compounds of formula (II) can be prepared according to any one of Schemes II- 1 ,

II-2, II-3, 11-4, and 11-5, as shown in FIGs. 14-18, respectively. As shown in Schemes II- 1,

II-2, II-3, II-4, and II-5, R¹ is -OR⁴, -NR⁵R^5a, -N(OR^5b)R^5a, or a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶; and X², R², R^2a, R²³, R^23a, R^23b, R⁴, R⁵, R^5a, R^5b, and R⁶ are as defined in any aspect, embodiment, or claim as described herein. In some embodiments, X² is methyl. In some embodiments, X² is methyl; R²³ and R^23b are each hydrogen; and R^23a is fluoro, methyl, or methoxy. In some embodiments, X² is methyl and R²³, R^23a, and R^23b are each hydrogen.

[0493] Compounds of formula (II) may be prepared according to Scheme II- 1 , as shown in FIG. 14, starting from the commercially available intermediate (11-101 ). Compounds of formula (11-102) are prepared by alkylation of the intermediates (II- 101 ) with X²-LG, wherein LG is a suitable leaving group. Compounds of formula (11-103) can be prepared by methods apparent to those of skill in the art and are converted to compounds of formula (11-104) by iodination. A compound of formula (11-104) is then reacted with an aniline in the presence of a Pd catalyst to provide a compound of formula (11-105). The compound of formula (11-106) is prepared by treating (11-106) with iodine in the presence of siver trifluoroacetate or alternatively with iodine monochloride. The acid-containing compound of formula (II- 106) can be activated with numerous reagents apparent to those of skill in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(0)OH acid group, for example an acid chloride produced from the reaction of (11-106) with thionyl chloride. The acid chlorides can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a, HN(OR^5b)R^5a, R^a-H (where R^a is a Fl unked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of formula (II), in which R² is iodo.

[0494] Compounds of formula (II) may be prepared according to Scheme II-2, as shown in FIG. 15, starting from the commercially available or readily accessible intermediate of formula (11-107). Compounds of formula (11-108) are prepared by alkylation of the intermediates (11-107) with X²-LG, wherein LG is a suitable leaving group. Compounds of formula (11-109) can be prepared by methods apparent to those of skill in the art by chlorination. A compound of formula (11-109) is then reacted with an aniline to provide a compound of formula (II- 1 10), which is further converted to an acid of formula (11-1 1 1). The acid-containing compound of formula (11- 1 1 1) can be activated with numerous reagents apparent to those of skill in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(0)OH acid group, for example an acid chloride produced from the reaction of (11- 1 1 1) with thionyl chloride. The acid chlorides can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a,

HN(OR^5b)R^5a, R^a-H (where R^a is a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of formula (II).

[0495] Compounds of formula (II) may be prepared according to Scheme II-3, as shown in FIG. 16, starting from the commercially available or readily accessible intermediate of formula (11-107). Compounds of formula (11-108) are prepared by alkylation of the intermediates (11-107) with X²-LG, wherein LG is a suitable leaving group. Compounds of formula (II- 1 12) can be prepared by methods apparent to those of skill in the art by hydrolysis of the nitrile group to an acid, protection of the acid group, and chlorination. A compound of formula (II- 1 12) is then reacted with an aniline to provide a compound of formula (II- 1 13), which is further hydrolyzed to an acid of formula (II- 1 14). The acid-containing compound of formula (II- 1 14) can be activated with numerous reagents apparent to those of skill in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(0)OH acid group, for example an acid chloride produced from the reaction of (II- 114) with thionyl chloride. Alternatively, compounds of formula (II- 1 13) can be directly converted to acid chlorides or activated esters as described in Scheme II-4 or 11-5. The acid chlorides or activated esters can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a, HN(OR^5b)R^5a, R^a-H (where R^a is a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of formula (II).

[0496] Compounds of formula (II) may be prepared according to Scheme 11-4, as shown in FIG. 17, starting from the commercially available or readily accessible intermediate of formula (II- 1 15). Intermediate (II-l 16) which is prepared by N-alkylation on the pyrrole nitrogen of (II- 115) is readily converted to the trifluoromethyl ketone intermediate (II-l 17), hydrolyzed to the corresponding acid (II-l 18), and converted to the tert-butyl ester (II- 1 19) by esterification by methods apparent to those of skill in the art. Chlorination in the 2-position of intermediate (II- 1 19) by treating (II-l 19) with a base such as LDA followed by treatment with a chlorinating agent such as perchloroethane affords the chlorinated intermediate (11-120). Displacement of the chlorine of intermediate (11-120) with a suitable aniline in the presence of a base gives intermediate (11-121) which can be readily converted to the corresponding acid chloride (11-122) by treatment with thionyl chloride, with or without the addition of 4 N HC1 in dioxane (J. Org. Chem., 2017, 82 (6), pp 3245-3251). Alternatively, Intermediate (11-122) can be converted to an activated ester by treatment with an alcohol such as pentafluorophenol. The acid chlorides or activated esters can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a, HN(OR^5b)R^5a, R^a-H (where R^a is a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of formula (II).

[0497] In addition, compounds of formula (II) may be prepared by the synthetic route given in Scheme II-5, as shown in FIG. 18. Nitriles (11-108) which are prepared by N-alkylation on the pyrrole nitrogen of (11-107) can be hydrolyzed to the corresponding acids and esterified to form t-butyl esters (11-120). Then, following the sequence of Scheme 11-4, compounds of formul (II) may be prepared.

Compounds of formula (Ill)

[0498] Compounds of formula (Ilia) can be prepared according to Scheme I1I-1 or III-2, as shown in FIGs. 19-20, respectively. As shown in Scheme III- 1 or II1-2, R¹ is -OR⁴, -NR⁵R^5a, -N(OR^5b)R^5a, or a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶; and R², R^2a, R³³, R^33a, R^33b, R⁴, R⁵, R^5a, R^5b, and R⁶ are as defined in any aspect, embodiment, or claim as described herein. In some embodiments, R^33a and R^33b are each hydrogen and R³³ is fluoro, methyl, or methoxy. In some embodiments, R³³ and R^33b are each hydrogen and R^33a is fluoro, methyl, or methoxy. In some embodiments, R³³ and R^33a are each hydrogen and R^33b is fluoro, methyl, or methoxy. In some embodiments, X² is methyl and R³³, R^33a, and R^33b are each hydrogen.

[0499] Compounds of formula (Ilia) can be prepared according to Scheme III- 1 , as shown in FIG. 19. Starting from commercially-available or routinely-accessible substituted phenyl isothiocyanate (III- 101) and intermediate (III- 102), intermediate (III- 103) can be prepared by methods apparent to those of skill in the art. Intermediate (III- 103) can be readily hydrolyzed by contact with an appropriate acid such as hydrochloric acid or trifluoroacetic acid in an appropriate solvent such as dichloromethane or dioxane to give intermediate (111-104). The acid intermediate (III- 104), can be activated with numerous reagents apparent to those of skill in the art to produce compounds with a suitable leaving group attached to the carbonyl, for example an acid chloride produced from the reaction of (III- 104) with thionyl chloride or an active ester produced from the reaction of (III- 104) with reagents such as EDC1 or HOBt. The acid chlorides or active esters can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a, HN(OR^5b)R^5a, R^a-H (where R^a is a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of formula (Ilia).

[0500] Alternatively, compounds of formula (Ilia) wherein R² is C2-C6 alkynyl group can be prepared according to Scheme III-2, as shown in FIG. 20, from compounds of formula (Ilia) wherein R² is initially iodo (i.e., formula III- 105). Reactions conditions similar to those published in the Journal of Medicinal Chemistry 2007, 50, 5090-5102 can be employed to afford the transformation from an aromatic iodo group to alkyne. Intermediate (Ilia- 107) can be converted to a compound of Formula (Ilia) using procedures described herein and above for Scheme III- 1.

Compounds of formula (IVl

[0501] Compounds of formula (IV) wherein R⁴³ is cyano, -C(0)NR⁴⁸R^48a, or -C(0)R⁴⁶ can be prepared according to Scheme IV-1 , as shown in FIG. 21, in which R¹ is -OR⁴, -NR⁵R^5a, -N(OR^5b)R^5a, or a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶; and R², R^2a, R^43a, R⁴, R⁵, R^5a, R^5b, R⁶, R⁴⁶, R⁴⁸, and R^48a are as defined in any aspect, embodiment, or claim as described herein.

[0502] Starting from commercially-available or routinely-accessible anilines of formula (IV- 101) and thiophosgene, intermediate (IV- 102) can be prepared by methods apparent to those of skill in the art. Intermediate (IV- 102) can be readily be condensed with an intermediate of formula (IV- 103) in the presence of a base and solvent, followed by treatment with an intermediate of formula (IV- 104) to yield the intermediate of formula (IV- 105). The

intermediate (IV- 105) is then hydrolyzed by contact with an appropriate base such as LiOH in an appropriate solvent such as THF and/or ethanol and or water to give intermediate (IV- 106). The acid intermediate (IV- 106) can be activated with numerous reagents apparent to those of skill in the art to produce compounds with a suitable leaving group attached to the carbonyl, for example an acid chloride produced from the reaction of intermediate (1V-106) with thionyl chloride or an active ester produced from the reaction of intermediate (1V-106) with reagents such as EDCI or HOBt. The acid chlorides or active esters can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a, HN(OR^5b)R^5a, R^a-H (where R^a is a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of formula (1) wherein R⁴³ is cyano, -C(0)NR⁴⁸R^48a, or -C(0)R⁴⁶.

[0503] Compounds of formula (IV) wherein R^3a and R³ together form -CthCthCiO)- or -CH₂CH₂CH₂C(0)- can be prepared using procedures described in W02008/020206 or by Scheme 1V-2 as showun in FIG. 22. As shown in Scheme IV-2, R¹ is -OR⁴, -NR⁵R^5a,

-N(OR^5b)R^5a, or a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶; and R^2a, R⁴, R⁵, R^5a, R^5b, and R⁶ are as defined in any aspect, embodiment, or claim as described herein. In some embodiments, R^2a is fluoro.

[0504] Starting from a commercially-available or routinely-accessible compound of formula (IV-108) and commercially-available or routinely-accessible anilines of formula (IV-109), compounds of formula (IV-1 10) can be prepared by methods apparent to those of skill in the art. The compound of formula (IV-1 1 1) is prepared by treating (IV- 1 10) with iodine in the presence of siver trifluoroacetate or alternatively with iodine monochloride. Compounds of formula (IV-

11 1) are then subjected to ester hydrolysis to provide the acid-containing compound of formula (IV-1 12). The acid group of the compound (IV-1 12) can be activated with numerous reagents apparent to those of skill in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(0)OH acid group, for example an acid chloride produced from the reaction of (IV-112) with thionyl chloride or an active ester produced from the reaction of (IV-

1 12) with reagents such as EDCI or HOBt. The acid chlorides or active esters can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a, HN(OR^5b)R^5a, R^a-H (where R^a is a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of any one of formulae (IVd-1), (IVd-2), (IVe-1) and (IVe-2), in which R² is iodo.

[0505] Compounds of formula (IVa) can be prepared according to Scheme IV-3, as shown in FIG. 23, in which R¹ is -OR⁴, -NR⁵R^5a, -N(OR^5b)R^5a, or a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶; and R^2a, R^43a, R⁴, R⁵, R^5a, R^5b, and R⁶ are as defined in any aspect, embodiment, or claim as described herein. In some embodiments, R^2a is fluoro. In some embodiments, R^43a is methyl.

[0506] Starting from commercially-available or routinely-accessible compounds of formula (IV-l 13), compounds of formula (IV- 1 15) can be prepared by methods known in the art. From compounds of formula (IV-l 15) and commercially-available or routinely-accessible anilines of formula (IV- 109), compounds of formula (IV-l 16) can be prepared by methods apparent to those of skill in the art. The compound of formula (IV-l 17) is prepared by treating (IV-l 16) with iodine in the presence of siver trifluoroacetate or alternatively with iodine monochloride.

Compounds of formula (IV-l 17) are then subjected to ester hydrolysis to provide the acid- containing compound of formula (IV-l 18). The acid group of the compound (IV-l 18) can be activated with numerous reagents apparent to those of skill in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(0)OH acid group, for example an acid chloride produced from the reaction of (IV-l 18) with thionyl chloride or an active ester produced from the reaction of (IV-l 18) with reagents such as EDCI or HOBt. The acid chlorides or active esters can then be reacted with compounds of formula R⁴OH, HNR⁵R^5a, HN(OR^5b)R^5a, R^a-H (where R^a is a N-linked heterocycloalkyl unsubstituted or substituted with one or two R⁶), or suitable protected forms thereof to produce compounds of formula (IV a), in which R² is iodo.

Compounds of formula (V)

[0507] Compounds of Formula (la) can be prepared according to Scheme V-l , as shown in FIG. 24, in which subscript n is 0; R⁵¹ is not -OR⁵⁴; and R², R^2a, R⁵¹, R^53a, and R^53b are as defined in any aspect, embodiment, or claim as described herein. In some embodiments, R^53a and R^53b are each hydrogen.

[0508] Starting from commercially-available or routinely-accessible pyridines of formula (V- 101), and commercially-available methyl chloroformate, compounds of formula (V-l 02) can be prepared by methods apparent to those of skill in the art. A compound of formula (V-l 02) is then reacted with a compound of formula (V-l 03) in the presence of CS2CO3 and a catalyst, for example PdXPhos G2, wherein the compound of formul (V-103) is prepared from pinacolborane and ethyl vinyl ether. Cyclization of the compound of formula (V-l 04) under an acidic conditions provides the intermediate of formula (V-105). Various commercially-available or routinely-accessible amines or protected amines of R^{5 I}NH2 can react with the intermediate of formula (V-105) to provide compounds of formula (V-106). Compounds of formula (Va) can be prepaed by a coupling reaction of the compounds of formula (V-106) with commercially- available or routinely-accessible anilines by methods apparent to those of skill in the art, followed by optional deprotection. In some embodiments of compounds of formula (Va) wherein R⁵¹ is HOC(0)-CI-C₆ alkyl, after further activation of the -C(0)OH group by methods known in the art, these compounds are converted to compounds of formula (Va), in which R⁵¹ is R⁷C(0)-CI -C₆ alkyl.

[0509] Compounds of Formula (Va) can be prepared according to Scheme V-2, as shown in FIG. 25, in which subscript n is 0; R⁵¹ is -OR⁵⁴; and R², R^2a, R^53a, R^53b, and R⁵⁴ are as defined in any aspect, embodiment, or claim as described herein. In some embodiments, R^53a and R^53b are each hydrogen.

[0510] Starting from the common intermediate of formula (V-104) as shown in Scheme V-l , various commercially-available or routinely-accessible hydroxyamines or pretected

hydroxyamines of R⁵⁴ONFl2 can react with the compound of formula (V-104) to provide compounds of formula (V-l 07). Cyclization of the compound of formula (V-l 07) under a base provides a compound of formula (V-l 08) (note any ester group in R⁵¹ is also hydrolyzed to a corresponding acid). Compounds of formula (Va) can be prepaed by a coupling reaction of the compounds of formula (V-108) with commercially-available or routinely-accessible anilines by methods apparent to those of skill in the art, followed by optional deprotection. In some embodiments of compounds of formula (Va) wherein R⁵¹ is -OR⁵⁴ and R⁵⁴ is FIOC(0)-C_I-C₆ alkyl, after further activation of the C(0)OH group by methods known in the art, these compounds are converted to compounds of formula (la), in which R⁵¹ is -OR⁵⁴ and R⁵⁴ is R⁷C(0)-CI-C₆ alkyl. In some ebodiments, when R⁵¹ is -OH, the corresponding compound of formula (Va) is prepared according to Scheme V-l .

[0511] Compounds of Formula (lb) can be prepared according to Scheme V-3, as shown in FIG. 26, in which subscript n is 0 and R², R^2a, R⁵¹, R^53a, and R^53b are as defined in any aspect, embodiment, or claim as described herein. In some embodiments, R^53a and R^53b are each hydrogen. [0512] Starting from the common intermediate of formula (V-104) as shown in Scheme V-l, various commercially-available or routinely-accessible amines, hydroxyamines, pretected amines, or protected hydroxyamines of R^{5 I}NH2 can react with the compound of formula (V-104) to provide compounds of formula (V-109). Reductive cyclization of the compound of formula (V-109) under a reducing agent (e.g., NaCNBFb) provides a compound of formula (V-l 10) (note that an ester group in R⁵¹ is also hydrolyzed to a corresponding acid). Compounds of formula (Va) can be prepaed by a coupling reaction of the compounds of formula (V-l 10) with commercially-available or routinely-accessible anilines by methods apparent to those of skill in the art, followed by optional deprotection. In some embodiments of compounds of formula (Va) wherein R⁵¹ is HOC(0)-C_I-C₆ alkyl or -OR⁵⁴ and R⁵⁴ is HOC(0)-C_I-C₆ alkyl, after further activation of the C(0)OH group by methods known in the art, these compounds are converted to compounds of formula (la), in which R⁵¹ is R⁷C(0)-Ci-Ce alkyl or -OR⁵⁴ and R⁵⁴ is R⁷C(0)-Ci- C₆ alkyl.

[0513] Utilizing the Exemplary Preparation Schemes provided herein and procedures known to one of ordinary skill in the art, the compounds in Tables 1-5 can be prepared.

Example 1: Preparation of formulation A

[0514] The gelled topical formulation of the present invention can be prepared according to the procedure provided below. Reaction conditions, steps and reactants not provided in the procedure below would be apparent to, and known by, those skilled in the art.

[0515] The gelled topical formulation without a MEK was prepared according to the following procedure:

[0516] Different organic solvents as defined and described herein were aliquoted into individual vials to form a base formulation. The MEK inhibitor was added to the base formulation in an amout of a desired concentration by weight of the base formulation. Then the gelling agent was added to the base formulation in an amout of 1.5% by weight of the base formulation. The vials were vortexed to mix and spin overnight. Afterwards, a viscosity and a visual inspection were immediately recorded, then stored at ambient conditions for 7 days.

[0517] The formulation of Example 1 (as Formulation A, or FA) was prepared according to the general procedure.

Example 2: Preparation of formulation B

[0518] The formulation of Example 2 (as Formulation B, or FB) was prepared according to Example 1.

Example 3: Preparation of formulation C

[0519] The formulation of Example 3 (as Formulation C, or FC) was prepared according to in Example 1.

Example 4: Skin Flux in Human Cadaver Skin by Franz Chamber Method

[0520] The skin flux of the tested compound (e.g., Compound 2.003) was measured by the

Franz Chamber Method, known in the art.

[0521] The Franz Cell chamber is an in vitro skin permeation assay frequently used in formulation development. The Franz Cell apparatus consists of two primary chambers separated by a membrane. Human cadaver skin was used in the assay. A 5 pL of the test formulation including a MEK inhibitor was applied to the membrane via the top chamber. The bottom chamber contains fluid from which samples were taken at regular intervals (e.g., every 4 hours) for analysis. This testing determined the amount of the MEK inhibitor that permeated the membrane at each time point. The chamber was maintained at a constant temperature of 37°C. The rate of permeation for a tested compound was determined via Franz cell analysis. [0522] hydoxypropyl cellulose (HPC) Evaluation: Evaluation: a total of 6 topical formulations were tested for skin permeation using in this model. The compositions of the topical formulations are listed in the following Table:

[0523] Test Results: FIG. 1 shows the skin permeation of the Formulations A and B including

Compound No. 2.003 at 0.5% by weight of the base formulation, in which the hydoxypropyl cellulose (HPC) is absent or present in an amount of 1.5% or 3.0% by weight of the base formulation.

[0524] Dose Evaluation: a total of 6 topical formulations as prepared in Examples 2 and 3 were tested for skin permeation using in this model.

[0525] Test Results: FIG. 2 shows the skin permeation of the FA and FC formulations including Compound 2.003, in which the tested compound is present in an amount of 0.5, 1.0, or 1.5% by weight of the base formulation. Example 5: In Vivo Evaluation of Skin Permeation

Mouse Model

[0526] 8 week old 129 mice were obtained from Jackson Laboratories and were shaved prior to the start of the study. 21 mice were used for study. Different doses of topical formulations including Compound 2.003 in the FA gel formulation (0.01%, 0.15%, 1.0% by weight of the base formulation) were applied to the hairless dorsal skin of the mouse. Skin biopsies were obtained prior to treatment and at different time points using 6mm punches and subjected to Western blotting and immunohistochemistry. There was no observed dermal toxicity in this study.

[0527] Test Results: FIG. 3 shows the skin permeation of the FA formulation including

Compound 2.003, in which the tested compound is present in an amount of 0.5, 1.0, or 1.5% by weight of the base formulation.

Minipig Model

[0528] A 7 day study in minipigs where a topical formulation including compound 2.003 was applied to 10% body surface area of Gottingen minipigs twice daily for 7 days. This study was conducted by MP1 Research, now a wholly owned subsidiary of Charles River Labs using guidance published by FDA for topical drug candidates for dermatology toxicology studies.

[0529] Compound 2.003 penetrated the stratum comeum of minipigs as evidenced by the concentrations of drug in the skin measured via LCMS, as shown below. The following Table lists average concentrations of Compound 2.003 measured in skin after 7 days of treatment (ng/g)

[0530] Test Results: FIG. 4 shows effective suppression of p-ERK in skin after the 7-day study in minipig with relatively low levels of the test compound in plasma. [0531] To understand relative rates of exposure, plasma levels of Compound 2.003 was evaluated from the highest dose from a 7 day minipig study relative to levels necessary to inhibit peripheral mononuclear cells (pBMCs). The Cmax and AUC values of the tested compound in minipig plasma following topical application in the FA gel formulation twice daily from the 7 day study are shown in Table 6.

Table 6: : Cmax and AUC values of Compound 2.003 in minipig plasma after 7 days of twice daily topical application to 10% body surface area

[0532] After topical administration to minipigs, overall systemic exposure was low. At the maximum concentration applied (1.5% over 10% BSA, twice daily), the Cmax of Compound 2.003 averaged 40 ng/mL or 85 nM. This value was well below the IC50 observed for p-ERK suppression by Compound 2.003 in human whole blood (~250 nM) and well below the biochemical IC50 against MEK1 (135 nM). Compound 2.003 was efficiently cleared from minipig plasma with little compound remaining 12 hours after topical application. As discussed above, p-ERK in skin was still fully suppressed at this time point, even at the lowest applied concentration of the tested compound (0.15% over 10% BSA, twice daily).

[0533] There were no observed dermal tolerability issues after 7 days of application of the formulation containing Compound 2.003, confirming its safety and tolerability.

Example 6: Ex Vivo Evaluation in Human Dermal Neurofibroma or Cutaneous

Neurofibroma Explants

[0534] An ex vivo study was conducted to determine whether Compound 2.003 in the formulation of Example 1 would penetrate a human cutaneous lesion with dysregulation in the RAF-MEK-ERK pathway and successfully suppress elevated p-ERK. Biopsies of human cutaneous neurofibroma which are driven by dysregulation of RAS upstream and have elevated p-ERK.

[0535] Human cutaneous neurofibroma explant samples were collected in DMEM/F-12 supplemented with 1 ><B27 supplement, 2.5 pg/ml of Amphotericin B, and 50 units/ml of Penicillin-50 pg/ml of Streptomycin, and incubated in the same medium for subsequent treatment. The specimen was cut into 2mmx2mm cubes containing both epidermis and dermis. The tissues were partially submerged in the medium in 384-well plate with the epidermis exposed to the air. 2.5 pi of the topical formulation of Example 1 containing Compound 2.003 or the formulation alone was applied topically to the partially submerged tissue. After 4 h incubation at 37°C and 5% CO2, the tissues were harvested the same way as described above. After 4 hours incubation at 37°C and 5% CO2, half of the specimen was flash frozen in liquid nitrogen for Western Blot analysis. The other half of the specimen was fixed for 24 hours in 10% formalin and then transferred to 70% ethanol for immunohistochemistry as above.

[0536] Test Results: FIG. 5 shows effective suppression of p-ERK in neurofibroma explants after application of the gel formulation containing Compound 2.003. As a comparison, the p- ERK suppression was not observed in neurofibroma explants treated with the gel formulation of Example 1 only, as shown in FIG. 6. A dose response of Compound 2.003 was observed in suppression of p-ERK in neurofibroma explants after application of the gel formulation containing Compound 2.003, as shown in FIG. 7.

[0537] FIG. 8 shows that Compound 2.003 penetrated the stratum comeum and suppressed the p-ERK biomarker and the concentration of Compound 2.003 in top and bottom of explant section.

Example 7: Human Birthmark Explant Protocol

[0538] This study establishes an in vitro birthmark explant model.

[0539] Study Objectives: The primary objective was to assess the efficacy of a topically- formulated compound described herein in suppressing p-ERK, a downstream biomarker of RAS/MAPK signaling in epidermal nevus and nevus sebaceous. The secondary objectives was to assess permeability (where the compound was applied topically) in birthmark explants treated with a compound described herein.

[0540] Sample Collection and Eligibility: Discarded human birthmark (epidermal nevus and nevus sebaceous) samples were obtained from the Stanford Surgery Clinic, using an approved human subjects protocol (Stanford 1RJB#18325). Specimens were identified under the direction of the Principal Investigator and placed in cell proliferation media (DMEM/F12 containing penicillin/streptomycin (0.1%); fungizone (40 pg/mL); B27 (without vitamin A).

[0541] Patients had the following data to be enrolled in the study:

Patient must be older than 18 years of age.

Samples must be birthmarks of at least 6mm in size

Samples will be excised by a shave, punch biopsy or elliptical excision.

Patient cannot be undergoing chemotherapy treatment at time of biopsy.

Study procedures

[0542J Samples were primary, untreated birthmarks of at least 6 mm in size; samples were excised by a shave, punch biopsy or elliptical excision. Specimens were identified under the direction of the Principal Investigator. Specimens were chopped into 2mm fragments and placed in 24-well plates containing cell proliferation media (DMEM/F12 containing

penicillin/streptomycin (0.1%); fungizone (40 pg/mL); B27 (without vitamin A) and submerged in media with drug. For topical gel application, samples were placed in 96 well plates with epidermal surface exposed to air.

[0543] For the data provided in FIG. 9, a gelled topical gel formulation of Compound No.

2.003 or the gel topical formulation of vehicle only were topically applied to the surface of a birthmark explant at 4 hours for analysis. The gel formulation was 1.5% hydroxypropyl cellulose in the base formulation of Example 1 and the tested compound was 0.01% by weight of the base formulation. Samples were harvested at 4 hours for analysis. Harvested tissue was bisected and with half snap frozen and half fixed in 10% formalin and paraffin embedded for further analysis.

[0544] For the data provided in FIG. 10, three gelled topical gel formulations of Compound No. 2.003 at different concentrations or the gel topical formulation of vehicle only were topically applied to the surface of a birthmark explant at 4 hours for analysis. The gel formulation was 1.5% hydroxypropyl cellulose in the base formulation of Example 1 and the tested compound was 0.01%. 0.15%, or 1.00% by weight of the base formulation. Samples were harvested at 4 hours for analysis. Harvested tissue was bisected and with half snap frozen and half fixed in 10% formalin and paraffin embedded for further analysis.

[0545] Western Blot analysis: For immunoblotting, total skin biopies were lysed in lysis buffer and run on Western blots. Antibodies used for immunoblotting included rabbit anti- phospho-p44/42 MAPK (1 :3000, Cell Signaling) and rabbit anti-p44/42 MAPK (1 :3000, Cell Signaling), rabbit anti-phospho-Mekl/2 (1 : 3000, Cell Signaling), mouse anti-actin (1 :5000, Sigma-Aldrich), donkey anti-mouse IgG conjugated to horseradish peroxidase (HRP; 1 :40,000, Amersham Biosciences) and goat anti-rabbit IgG conjugated HRP (1 :40,000, Jackson

ImmunoResearch).

[0546] Immunohistochemistry: Immunohistochemistry was performed on 5 pm paraffin sections. Antigen retrieval with enzyme treatment (1 : 1000) using standard protocols.

Antibodies used were rabbit p-ERK (Cell Signaling, 4307S, 1 : 100). Bond Polymer Refine anti rabbit HRP Detection (Leica Biosystems) was used according to manufacturer’s protocol. Sections were then counterstained with hematoxylin, dehydrated and film coverslipped using a TissueTek-Prisma and Coverslipper (Sakura).

[0547] Data Analysis: Semi-quantative Western blot was used to assess differences in p-ERK in samples treated with a compound described herein compared to vehicle control.

[0548] Study Management: The study was conducted with oversight from an 1RB with patient informed consent and HIPAA authorization.

[0549] Results: See FIGs. 9-10.

Example 8: Human Dermal Neurofibroma Explant Protocol

[0550] Dermal neurofibromas (or cutaneous neurofibromas) are benign tumors which develop in individuals affected with Neurofibromatosis- 1 (NF1), a rare genetic disease caused by mutations in the NF1 gene, leading to downstream activation of the RAS/MAPK pathway. Recent studies have demonstrated that inhibition of MEK1 using systemic MEK inhibitors can suppress neurofibromas and other NF-1 related tumors in murine models. See, for example, New Engl J Med 2016, 375;26; J Clin Invest. 2013, 123(1), 340-347; and Pediatr Blood Cancer 2015, 62(10), 1709-1716. This study establishes an in vitro neurofibroma explant model.

[0551] Study Objectives: The primary objective is to assess the efficacy of a topically- formulated compound described herein in suppressing p-ERK, a downstream biomarker of RAS/MAPK signaling in neurofibroma explants. The secondary objectives is to assess permeability (where the compound was applied topically) of neurofibroma explants treated with a compound described herein.

Sample Collection and Eligibility:

[0552] Primary dermal neurofibromas or cutaneous neurofibromas are obtained from patients with clinical or genetic diagnoses of NF1. Discarded human neurofibromas samples are obtained from the Stanford Surgery Clinic, using an approved human subjects protocol (Stanford

IRB#18325). Specimens are identified under the direction of the Principal Investigator and placed in cell proliferation media (DMEM/F12 containing penicillin/streptomycin (0.1%);

fungizone (40 pg/mL); B27 (without vitamin A).

[0553] Patients have the following data to be enrolled in the study: Patient is older than 18 years of age; patient is not undergoing chemotherapy treatment at time of biopsy; and patients met clinical and/or genetic diagnosis of NFlbased on presence of two of the following:

1. Six or more cafe-au-lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals.

2. Two or more neurofibromas of any type or one plexiform neurofibroma.

3. Freckling in the axillary or inguinal regions.

4. Two or more Lisch nodules (iris hamartomas).

5. Optic glioma.

6. A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis.

7. First-degree relative (parent, sibling, or offspring) with NF-1 by the above criteria. Study procedures

[0554] Samples are primary, untreated neurofibromas of at least 6 mm in size; samples are excised by a shave, punch biopsy or elliptical excision; samples have a histologic diagnosis of dermal neurofibroma or cutaneous neurofibroma. Specimens are identified under the direction of the Principal Investigator

[0555] Specimens are chopped into 2mm fragments and placed in 24-well plates containing cell proliferation media (DMEM/F12 containing penicillin/streptomycin (0.1%); fungizone (40 pg/mL); B27 (without vitamin A) and submerged in media with drug. For topical gel application, samples are placed in 96 well plates with epidermal surface exposed to air.

[0556] Western Blot analysis: For immunoblotting, total skin biopies are lysed in lysis buffer and run on Western blots. Antibodies used for immunoblotting includ rabbit anti-phospho- p44/42 MAPK (1 :3000, Cell Signaling) and rabbit anti-p44/42 MAPK (1 :3000, Cell Signaling), rabbit anti -phospho-Mek 1/2 (1 : 3000, Cell Signaling), mouse anti-actin (1 :5000, Sigma-Aldrich), donkey anti-mouse IgG conjugated to horseradish peroxidase (PLRP; 1 :40,000, Amersham Biosciences) and goat anti-rabbit IgG conjugated HRP (1 :40,000, Jackson ImmunoResearch).

[0557] Immunohistochemistrv: Immunohistochemistry is performed on 5 pm paraffin sections. Antigen retrieval is accomplished with enzyme treatment (1 : 1000) using standard protocols. Antibodies used are rabbit p-ERK (Cell Signaling, 4307S, 1 :100). Bond Polymer Refine anti rabbit HRP Detection (Leica Biosystems) is used according to manufacturer’s protocol. Sections are then counterstained with hematoxylin, dehydrated and film coverslipped using a TissueTek- Prisma and Coverslipper (Sakura).

[0558] Data Analysis: Semi-quantative Western blot is used to assess differences in p-ERK in samples treated with a compound described herein compared to vehicle control.

[0559] Study Management: The study is conducted with oversight from an IRB with patient informed consent and HIPAA authorization.

Example 9: MEK Inhibition Assay-1

[0560] The following procedure can be used to measure biochemical activity. MEK1 inhibitory activity of compounds were tested using the following procedure. See Anastassiadis T, et al. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol. 2011, 29(11), 1039-45.

Reagents:

Reaction buffer: 20 mM Hepes (pH 7.5), 10 mM MgCh, 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na₃V0₄, 2 mM DTT, 1% DMSO

Enzyme: MEK1 , Invitrogen cat# PV3303

N-terminal His-tagged recombinant human full length protein, expressed in insect cells.

Activated in vitro by RAF1. MW=49.2 kDa, GenBank Accession No. NP_002746. Substrate: 5 mM ERK2 (K52R),

Kinase-dead mutant, (GenBank Accession No. NM_001 1949), aa2-358 with N-terminal

His6 tag, MW=43.63 kDa, expressed in E.coli.

[0561] The substrate was prepared in freshly prepared Reaction Buffer. The kinase was delivered into the substrate solution and gently mixed. Test compounds were delivered in 100% DMSO into the kinase reaction mixture by Acoustic technology (Echo550; nanolitter range), and incubated for 20 min at room temperature. ³³P-ATP was delivered into the reaction mixture to initiate the reaction. The reaction mixture was incubated for 2 hours at room temperature.

Kinase activity was detected by P81 filter-binding method.

Example 10: MEK Inhibition Assay-2

[0562] MEK1 inhibitory activity of compounds were tested using the following procedure (protocol available at thermofisher.com/content/dam/LifeTech/migration/files/drug- discovery/pdfs.par.60256.file.dat/20130430%20ssbk%20customer%20protocol%20and%20assa y%20conditions.pdf). The Z'-LYTE biochemical assay (ThermoFisher) employs a fluorescence- based, coupled-enzyme format and is based on the differential sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage.

[0563] Test compounds in 100% DMSO were screened in 1% DMSO (final) in the well. For

10 point titrations, 3-fold serial dilutions are conducted from the starting concentration of 30 mM.

[0564] The peptide/kinase, MAP2K1 (MEK1) / inactive MAPKl (ERK2) / Ser/Thr 03, mixture (“Peptide/kinase Mixture”) was diluted to a 2X working concentration in the following buffer (“Kinase Buffer”): 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgC12, 1 mM EGTA. The final 10 pL kinase reaction consisted of 0.06 - 0.25 ng MAP2K1 (MEK1), 105 ng inactive MAPK1 (ERK2), and 2 mM Ser/Thr 03 in 50 mM HEPES pH 7.5, 0.01 % BRIJ-35, 10 mM MgC , 1 mM EGTA. After the 1 hour incubation, 5 pL of a 1 : 1024 dilution of

Development Reagent A (available from Invitrogen, catalog no. PV3295) was added.

[0565] ATP solutions were diluted to a 4X working concentration in Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgC12, 1 mM EGTA). ATP Km apparent was previously determined using a Z'-LYTE assay. The Development Reagent was diluted in Development Buffer (available from Invitrogen, catalog no. P3127).

[0566] Assay Protocol: 2.5 pL of 4X test compound or 100 nL of 100X Test Compound plus 2.4 pL Kinase Buffer, 5 pL of the 2X Peptide/Kinase Mixture, 2.5 pL of 4X ATP Solution were added to the plates and placed on a shake plate for 30-seconds. The kinase reaction was allowed to proceed for 60-minute at room temperature, before 5 pL of Development Reagent Solution was added, and the mixture agitated for 30-seconds on a shake plate. The mixture was incubated for 60-minute at room temperature. Fluorescence was measured using a plate reader and the data were analyzed.

[0567] The maximum emission ratio was established by the 0% Phosphorylation Control (100% Inhibition Control), which contained no ATP and therefore exhibited no kinase activity. This control yielded 100% cleaved peptide in the Development Reaction. The 100%

Phosphorylation Control, which consisted of a synthetically phosphorylated peptide of the same sequence as the peptide substrate, was designed to allow for the calculation of percent phosphorylation. This control yielded a very low percentage of cleaved peptide in the

Development Reaction. The 0% Phosphorylation and 100% Phosphorylation Controls allow for the calculation of the percent phosphorylation achieved in a specific reaction well. Control wells did not include any kinase inhibitors.

[0568] The minimum emission ratio in a screen was established by the 0% Inhibition Control, which contained active kinase. This control was designed to produce a 10-50% phosphorylated peptide in the Kinase Reaction. Cascade assays may produce up to 70% phosphorylated peptide. [0569] A known inhibitor control standard curve, 10 point titration, was run for each individual kinase on the same plate as the kinase to ensure the kinase was inhibited within an expected IC50 range previously determined.

[0570] The following controls are prepared for each concentration of Test Compound assayed. The Development Reaction Interference was established by comparing the Test Compound Control wells that did not contain ATP versus the 0% Phosphorylation Control (which did not contain the Test Compound). The expected value for a non-interfering compound should be 100%. Any value outside of 90% to 1 10% was flagged. The Test Compound Fluorescence Interference was determined by comparing the Test Compound Control wells that did not contain the Kinase/Peptide Mixture (zero peptide control) versus the 0% Inhibition Control.

The expected value for a non-fluorescence compound should be 0%. Any value > 20% was flagged.

[0571] The data in Table A was calculated. XL fit from 1DBS was used. The dose response curve was curve fit to model number 205 (sigmoidal dose-response model). If the bottom of the curve did not fit between -20% & 20% inhibition, it was set to 0% inhibition. If the top of the curve did not fit between 70% and 130% inhibition, it was set to 100% inhibition.

Table A.

FI = Fltsoreseeace Intensity

Cyss_¾ = Average Casmann emission signal of fee 100% Pbos. Control

s_¾= Average Coimiarin emission signal of the 0% P os. Control

F_1¾Ki = Average Fluorescein emission signal of tire 100% Phos. Control

F:? = Average Fluorescein emission signs! of the 0% Ptios Control

DRI = Development Reaction erference

TCFI = Test Compound Fluorescence interference

[0572] Table 7 lists the MEK1 inhibition assay results of selected compounds according to the above procedure. A indicates an IC50 of less than or equal to 150 nM, B indicates an IC50 of greater than 150 nM and less than or equal to 1.5 mM, and C indicates an IC50 of greater than 1.5 |iM. Table 7: MEK Inhibition Assay Results

ND - not determined

Example 11: Cell-Based Assay-1

[0573] Preparation of cell lines useful for testing the soft MEK inhibitors in NF1 related cell- proliferation assays can be found in Basu et al. Nature 356: 713-715, 1992; and DeClue et al. Cell 69: 265-273, 1992. In addition, exemplary in vitro and in vivo models to determine efficacy of the soft MEK inhibitors described herein can be found in U.S. Patent Nos. 8,211 ,875 and 8,487,004, which are incorporated by reference in their entireties.

Example 12: Cell-Based Assay-2

[0574] Alternatively, the following procedure can be used to measure cell-based activity. Test compounds were dissolved in DMSO in 10 mM stock. Cell Titer-Glo® 2.0 Luminescent cell viability assay reagent was purchased from Promega (Madison, WI). A375 and HCT116 cell lines were purchased from American Type Culture Collection (Manassas, VA). For A375 cells, cell culture media was DMEM + 10%FBS. Cell culture media are listed in the following table. For HCT1 16 cells, cell culture media was McCoy's 5A + 10%FBS. All media were supplemented with 100 pg/mL of penicillin, and 100 pg/mL of streptomycin. Cultures were maintained at 37 °C in a humidified atmosphere of 5% CO2 and 95% air.

[0575] Test compounds were diluted in DMSO solution with 10-dose and 3-fold dilutions in a source plate starting at 10 mM. 25 nL of each test compound was delivered from the source plate to each well of the 384-well cell culture plates (T = Final) by Echo 550. 25 pL of culture medium containing 2000 of A375 or F1CT1 16 cells was added to each of the wells in duplicates of the cell culture plates (T = 0 and T = Final). 25 pL of Cell Titer Glo 2.0 reagent was added to each well of cell culture plate (T = 0). The contents were mixed on an orbital shaker for 2 min and incubated at room temperature for 15 min to stabilize luminescent signal. Luminescence was recorded by Envision 2104 Multilabel Reader (PerkinElmer, Santa Clara, CA). The number of viable cells in culture was determined based on quantitation of the ATP present in each culture well. The cells in cell culture plate (T = Final) were incubated with the compounds at 37 °C, 5% CO2 for 72 hours. 25 pL of Cell Titer Glo 2.0 reagent was added to each well. The contents were mixed on an orbital shaker for 2 min and incubated at room temperature for 15 min to stabilize luminescent signal. Luminescence was recorded by Envision 2104 Multilabel Reader (PerkinElmer, Santa Clara, CA). The number of viable cells in culture was determined based on quantitation of the ATP present in each culture well. The GI50 curves were plotted using the GraphPad Prism 4 program based on a sigmoidal dose-response equation Y=Bottom + (Top- Bottom)/(l+10^A((LogEC50-X)*HillSlope)). All parameters in the equation were calculated by GraphPad Prism 4 program. GI50 is the concentration of the compound calculated according to [(Ti - T_Z)/(C - T_z)] * 100 = 50 where Ti is the row data of cells with test compounds at T = Final; T_z is the row data of cells without compounds at T = 0 h; C is the row data of cells with control compound staurosporine (Sigma- Aldrich) at T = 72 h. Accordingly, GI50 is the value of 10^x, where X was calculated by the Curve Fitting Equation when Y = 50 using Excel.

Example 13: S9 Stability Assays

[0576] Compounds can be assessed for metabolic stability in human skin by assessing their rate of disappearance from human S9 skin fraction. Similarly, compounds can be assessed for metabolic stability in human liver by assessing their rate of disappearance from human S9 liver fraction. The protocol below is used to assess the difference between skin and hepatic metabolism.

[0577] The assay was carried out in 96-well microtiter plates at 37°C. Reaction mixtures (25 pL) contained a final concentration of 1 mM test compound, 2 mg/mL liver or skin protein, and 1 mM NADPH in buffer (100 mM potassium phosphate, pH 7.4 buffer with 1 mM EDTA, 3 mM MgCh). At each of the time points (0, 15, 30, and 60 minutes), 150 pL of quench solution (100% acetonitrile with 0.1% formic acid) with internal standard was transferred to each well. Besides the zero minute controls, mixtures containing the same components except the NADPH were also prepared as the negative control. Verapamil or testosterone was included as a positive control to verify assay performance. Plates were sealed and centrifuged at 4°C for 15 minutes at 4000 rpm. The supernatant was transferred to fresh plates for LC/MS/MS analysis.

[0578] All samples were analyzed on LC/MS/MS using an AB Sciex API 4000 instrument, coupled to a Shimadzu LC-20AD LC Pump system. Analytical samples were separated using a Waters Atlantis T3 dC18 reverse phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL/min. The mobile phase consisted of 0.1 % formic acid in water (solvent A) and 0.1 % formic acid in 100% acetonitrile (solvent B).

[0579] The extent of metabolism was calculated as the disappearance of the test compound, compared to the 0-min control reaction incubations. Initial rates were calculated for the compound concentration and used to determine ti/2 values and subsequently, the intrinsic clearance, CLin_t = (0.693) (1/ ti/2 (min)) (mL incubation/mg of S9 protein).

[0580] Data for known, clinical MEK1 compounds (C1-C7) in this assay are provided below. Data for compounds within the scope of Formula (II) and formula (111) are provided in the Results section below.

Example 14: Microsomal Stability Assay

[0581] Metabolic stability of testing compound can be evaluated using human liver microsomes to predict intrinsic clearance. Human liver microsomes are obtained from Coming Gentest.

[0582] The assay was carried out in 96-well microtiter plates at 37°C. Reaction mixtures (25 pL) contain a final concentration of 1 mM test compound, 0.5 mg/mL liver microsomes protein, and 1 mM NADPH in buffer (100 mM potassium phosphate, pH 7.4 buffer with 3 mM MgCh). At each of the time points (0, 15, 30, and 60 minutes), 150 pL of quench solution (100% acetonitrile with 0.1% formic acid) with internal standard was transferred to each well.

Verapamil was included as a positive control to verify assay performance. Plates were sealed and centrifuged at 4 °C for 15 minutes at 4000 rpm. The supernatant was transferred to fresh plates for LC/MS/MS analysis.

[0583] All samples were analyzed on LC/MS/MS using an AB Sciex API 4000 instrument, coupled to a Shimadzu LC-20AD LC Pump system. Analytical samples were separated using a Waters Atlantis T3 dCl 8 reverse phase HPLC column (20 mm x 2.1 mm) at a flow rate of 0.5 mL/min. The mobile phase consisted of 0.1 % formic acid in water (solvent A) and 0.1% formic acid in 100% acetonitrile (solvent B).

[0584] The extent of metabolism was calculated as the disappearance of the test compound, compared to the 0-min time incubation. Initial rates were calculated for the compound concentration and used to determine ti/2 values and subsequently, the intrinsic clearance, CLim = (0.693)(1/ ti/2 (min))(g of liver/kg of body weight)(mL incubation/mg of microsomal protein)(45mg of microsomal protein/g of liver weight).

Example 15: Assay Results of Tested Compounds

Tested Compounds of formula (1)

[0585] The following applies to Table 8 below for tested compounds of formula (I). [0586] Assay 1 is the biochemical MEK IC50 (nM) assay as described in Example 9. A1 indicates an IC50 of less than or equal to 150 nM, and B1 indicates an IC50 of greater than 150 nM and less than or equal to 1 .5 mM.

[0587] Assay 2 is the A375 (BRAF) GI50 (nM) cell-based assay as described in Example 12. A2 indicates an IC50 of less than or equal to 500 nM, and B2 indicates an IC50 of greater than 500 nM and less than or equal to 1 .5 mM.

[0588] Assay 3 is the HCT1 16 (Kras) GI50 (nM) assay as described in Example 12. A3 indicates an IC50 of less than or equal to 750 nM, and B3 indicates an IC50 of greater than 750 nM and less than or equal to 2 mM.

[0589] Assay 4 is the liver S9 half-life stability assay as described in Example 13. A4 indicates a half life of greater than 50 minutes and less than or equal to 200 minutes, and B4 indicates a half life of less than or equal to 50 minutes.

Table 8: Assay Results of Tested Compounds of formula (I)

Tested Compounds of formula (II)

[0590] The following applies to the table 9 below for tested compounds of formula (II). NT indicates that the compound was not tested in a particular assay. Assay 1 is the biochemical MEK IC50 (nM) assay as described in Example 9 and as used for all tested compounds except compounds 2.042, 2.044, 2.047, and 2.048 which were tested using Example 10. Assay 2 is the A375 (BRAF) GI50 (nM) cell-based assay as described in Example 12. Assay 3 is the HCT1 16 (Kras) GI50 (nM) assay as described in Example 12. Assay 4 is the human liver S9 half-life stability assay as described in Example 13. Assay 5 is the human liver S9 instrinsic clearance value (pL/min/mg protein) as described in Example 13.

Table 9: Assay Results of Tested Compounds of formula (II)

Tested Compounds of formula PIP

[0591] The following applies to the table 10 below for tested compounds of formula (111). NT indicates that the compound was not tested in a particular assay. Assay 1 is the biochemical MEK IC50 (nM) assay as described in Example 9 and as used for compounds 2 and 6;

compounds 1, 3, 5, and 7-8 were tested using Example 10. Assay 2 is the A375 (BRAF) GI50 (nM) cell-based assay as described in Example 12. Assay 3 is the HCT116 (Kras) GI50 (nM) assay as described in Example 12. Assay 4 is the human liver S9 half-life stability assay as described in Example 13. Assay 5 is the human liver S9 intrinsic clearance value (pL/min/mg protein) as described in Example 13. Table 10: Assay Results of Tested Compounds of formula (111)

Tested Compounds of formula (TV)

[0592] The following applies to Table 1 1 below for tested compounds of formula (IV).

[0593] Assay 1 is the biochemical MEK IC50 (nM) assay as described in Example 9. A1 indicates an IC50 of less than or equal to 500 nM; B1 indicates an IC50 of greater than 500 nM and less than or equal to 1 mM; Cl indicates an IC50 of greater than 1 mM and less than or equal to 5 mM; and D1 indicates an IC50 of greater than 5 mM and less than or equal to 10 mM.

[0594] Assay 2 is the A375 (BRAF) GI50 (nM) cell-based assay as described in Example 12. A2 indicates an IC50 of less than or equal to 1 mM, and B2 indicates an IC50 of greater than 1 mM and less than or equal to 2 mM.

[0595] Assay 3 is the HCT116 (Kras) GI50 (nM) assay as described in Example 12. A3 indicates an IC50 of less than or equal to 5 mM, and B3 indicates an IC50 of greater than 5 mM and less than or equal to 10 mM.

[0596] Assay 4 is the liver S9 half-life stability assay as described in Example 13. A4 indicates a half life of greater than 50 minutes and less than or equal to 100 minutes, and B4 indicates a half life of less than or equal to 50 minutes. [0597] Assay 5 is the skin S9 half-life stability assay as described in Example 13. A5 indicates a half life of greater than or equal to 400 minutes.

[0598] Assay 6 is the liver microsomes half-life stability assay as described in Example 14. A6 indicates a half life of greater than 50 minutes and less than or equal to 100 minutes, and B6 indicates a half life of less than or equal to 50 minutes.

Table 11 : Assay Results of Tested Compounds

Example 16: In Vivo Model

[0599] Study Procedures: A topical formulation of a compound described herein along with a topical formulation of vehicle are applied to the skin of nude mice in duplicate. Skin is biopsied at discrete time intervals and bisected with half snap frozen in liquid nitrogen and half formalin fixed and paraffin embedded. Protein is isolated for Western blot analysis for p-ERK levels. p-ERK immunostaining is performed of FFPE sections for cell-specific analysis of p-ERK levels. Additional analysis includes H&E staining to investigate skin integrity.

[0600] A compound is assessed in suppressing p-ERK, a downstream biomarker of

RAS/MAPK signaling in murine skin. In addition, proliferation of murine skin, apoptosis in murine skin, and histologic integrity of murine skin are also assessed.

[0601] Mice: 8 week old 129 mice obtained from Jackson laboratories are shaved prior to start of study. Approximately 21 mice were used for study. A compound is applied to the hairless dorsal skin of the mouse and at 12 hour intervals and skin biopsies are obtained prior to treatment, 24 hours, 72 hours and at 96 hours using 6mm punch biopsies.

[0602] Western Blot analysis: For immunoblotting, epidermal skin is snap frozen in liquid nitrogen immediately afterbiopsy. The epidermis is lysed in lysis buffer and run on Western blots. Antibodies used for immunoblotting include rabbit anti-phospho-p44/42 MAPK (1 :3000, Cell Signaling) and rabbit anti-p44/42 MAPK (1 :3000, Cell Signaling), mouse anti-actin (1 :5,000, Sigma-Aldrich), donkey anti-mouse IgG conjugated to horseradish peroxidase (HRP;

1 :40,000, Amersham Biosciences) and goat anti-rabbit IgG conjugated HRP (1 :40,000, Jackson ImmunoResearch) .

[0603] Immunohistochemistrv: Immunohistochemistry is performed on 5 pm paraffin sections. Antigen retrival is accomplished with enzyme treatment (1 : 1000) using standard protocols. Antibodies used are rabbit p-ERK (Cell Signaling, 4307S, 1 : 100). Bond Polymer Refine anti rabbit HRP Detection (Leica Biosystems) is used according to manufacturer’s protocol. Sections are then counterstained with hematoxylin, dehydrated and film coverslipped using a TissueTek- Prisma and Coverslipper (Sakura).

[0604] Histologic analysis: H&E is performed on 5 pM paraffin sections and tissue is examined to assess for cellular toxicity, inflammation or other changes in the integrity of murine skin.

[0605] Exogenous RAS activation in murine skin: The experiments are to be conducted in untreated murine skin. Alternatively, skin is pre-treated with TPA to enhance p-ERK levels. TPA-induced RAS/MAPK activation is performed with 96 hours of 12.5uG TPA in 100 pL acetone to the skin of nude mice. Studies are performed 48 hours after TPA exposure. [0606] T-test is used to assess differences in p-ERK and Ki-67 in samples treated with topical MEK1 inhibitors compared to vehicle control.

Example 17: In Vivo Mouse Model

[0607] This study was designed to assess the skin toxicity and gross systemic toxicity of twice daily topical administration of a compound disclosed herein, as well as to evaluate the effect of metabolic lability on systemic toxicity .

[0608] Study Objective: The primary objective of this study was to characterize the skin and systemic toxicity of twice daily topical application of a compound disclosed herein, applied for 25 days in mice. Secondary objectives included determination of the 25-day skin and plasma compound levels of formulations containing three dosages of compound No. 2.003 after application to 10% body surface area (BSA) murine skin; assessment of gross systemic toxicity from the application of compound No. 2.003 after twice daily application to 10% BSA murine skin for 25 days; and determination of the correlation of skin and plasma compound levels with associated toxicity.

[0609] Duration: 25 days

[0610] Mice: 8 week old male C57BL/6J mice (Jackson Laboratories) were shaved prior to start of study and weekly. All experiments were approved by the Stanford University Animal Care and Use Committee.

[0611] Intervention arms:

[0612] Compound application: Compounds were dissolved in a 50% DMSO/50% propyelene glycol vehicle. 0.125 mL of the following compounds were applied to the shaved dorsal back of mice (10% BSA) twice daily for 5 days per week for a total of 24 days. The second dose was applied 8 hours after first morning dose. All mice were shaved once per week at application site.

[0613] Oral trametinib was dissolved in 0.5% hydroxypropyl methylcellulose (Sigma-Aldrich) and 0.2% Tween-80 (Sigma-Aldrich) and administered by oral gavage (0.2 mL bolus or 10 mg/kg) once daily 5 days per week. These mice were also shaved weekly.

[0614] Weekly (Weeks 0-4): body weight measurements weekly, starting week 0 until experiment end; photographs of dorsal back and face of each mouse weekly, starting week 0 until experiment end; skin; and gross stool analysis assessed weekly for heme color, starting week 0 until experiment end.

[0615] Week 4 (Experiment end): Skin and blood were collected right before the last morning dose (N=3), 1 hour (N=3 mice), and 2 hours (N=3 mice) after final application; Blood draw: Plasma compound levels (LCMS); Skin biopsy: formalin fixed for histology and p-ERK staining, flash frozen for Western analysis and skin compound levels (LCMS).

[0616] Oversight: The study was conducted with oversight from Stanford IACUC committee.

[0617] Skin biopsy and GI tract sampling: Skin was wiped down with 100% ethanol and a lcm² biopsy was obtained from compound application site each mouse at the 25 day end of experiment (except as noted below). The skin was biopsied prior to final dose from 3 mice, 1 hour after last compound application from 3 mice, 2 hours after last compound application from 3 mice. Half of the specimen were immediately flash frozen for LCMS analysis and Western Blot Analysis. Half of the specimen was fixed for 24 hours in 10% formalin and then transferred to ethanol for immunohistochemistry. Gastrointestinal tract was also formalin fixed overnight then transferred to 70% ETOH for storage.

[0618] Western Blot analysis: For immunoblotting, total skin biopies were lysed in lysis buffer and run on Western blots. Antibodies used for immunoblotting included rabbit anti- phospho-p44/42 MAPK (1 :3000, Cell Signaling) and rabbit anti-p44/42 MAPK (1 :3000, Cell Signaling), rabbit anti -phospho-Mek 1/2 (1 : 3000, Cell Signaling), mouse anti-actin (1 :5000, Sigma-Aldrich), donkey anti-mouse IgG conjugated to horseradish peroxidase (HRP; 1 :40,000, Amersham Biosciences) and goat anti-rabbit IgG conjugated HRP (1 :40,000, Jackson

ImmunoResearch). [0619] Immunohistochemistry: Immunohistochemistry was performed on 5pm paraffin sections.

[0620] Antigen retrieval was accomplished with enzymatic treatment. Sections were blocked with 10% normal goat serum and subsequently incubated in phospho-p44/42 MAPK (Erkl/2) rabbit monoclonal antibody (Cell Signaling) or mouse anti-Ki-67 (Pharmingen) at 1 : 100 dilution for 60 minutes at room temperature. Detection was achieved with a peroxidase-conjugated anti rabbit system (Leica Biosystem).

[0621] Histologic analysis: H&E was performed on 5 mM paraffin sections and tissue was examined to assess for cellular toxicity, inflammation or other changes in the integrity of murine skin.

[0622] Compound level analysis: Liquid chromatography with mass spectrometry method (LCMS) was used to detect compound levels in the skin and plasma. Tissues were preprocessed prior to LCMS as follows. Tissues were minced and incubated with collagenase and then finally homogenized using the stainless steel beads prior to LCMS analysis. Calibration curves and a QC test were run with each assay.

[0623] The study planned for the mice to be sacrificed at Day 25. However, at Day 18, several mice which were treated with topically-applied, 1% Trametinib were found dead, or had to be sacrificed due to unacceptable weight loss. The study was allowed to continue for the mice treated with Compound 2.003 and for the mice treated with oral trametinib.

Results

[0624] Kaplan Meier curves were analyzed to determine progression to skin toxicity for each arm as compared with vehicle. T-test were used to compare compound levels at each dosage. KΪ-67+ cells and p-ERK expression were also assessed on a cellular level via immunostaining. Western blots informed semi-quantitative changes in p-ERK expression.

[0625] See Table 12 which shows that topical application of compound 2.003 demonstrated less systemic toxicity when compared to a topical application of Trametinib. All mice survived in the oral vehicle and skin vehicle arms. All mice survived in the following arms: topically applied 0.1%, 0.5%, and 1% formulations of compound 2.003. Table 12: Survival Rates

[0626] Provided below are plasma and skin levels of the compounds administered in this example. In the table below h refers to hours.

Table 13: Plasma LCMS Compound Levels (ng/mL)

Table 14: Compound Levels (pg/mL) in Neck/Back Skin

Example 18: hERG Screening Assay

[0627] hERG screening was conducted using a procedure similar to the procedure described by Piper et al. (Piper, D.R. et al., Assay Drug Dev. Technol. 2008,6(2):213-223). The Predictor hERG FP assay (available from ThermoFisher, cat. no. PV5365) is a homogenous, fluorescence polarization biochemical-based format utilizing a membrane fraction containing hERG channel protein (Predictor hERG Membrane) and a high affinity, red-fluorescent hERG channel ligand (Predictor hERG Tracer Red). When the Predictor hERG Tracer ligand is bound to the hERG channel it produces high fluorescence polarization values. Compounds that bind to the hERG channel protein (competitors) displace the Predictor hERG Tracer Red resulting in decreased fluorescence polarization values.

[0628] Test compounds were solubilized in DMSO at 100X (or greater) of the desired starting concentration. Screening was conducted with a final concentration of 1% DMSO. For 10-point titrations, 3-fold serial dilutions were performed from the starting concentrations. The assay buffer used was 25 mM HEPES (pH 7.5), 15 mM KC1, 1 mM MgCl2, and 0.05% Pluronic F-127 (available from Sigma-Aldrich).

[0629] Predictor hERG membranes were stored as a 2X stock at -80 °C. Each membrane lot was titrated to identify the concentration of membranes required to obtain -70% bound tracer. Before setting up the assay the membranes were thawed in a 37°C water bath and stored at room temperature. To avoid light scatter caused by large membrane particulates the membranes were sonicated until a homogeneous solution free of particulates is obtained. Thawed membranes were sonicated with a Branson Sonifer (R) 450 for 10 pulses (Duty cycle: 20%, Output Control: 3 out of 10, Timer: hold). The sample was returned to ice for 30 seconds followed by another 5-10 pulses until homogeneous. After sonication the membranes were stored at room temperature.

[0630] The tracer (E-4031), selectively blocks hERG K+ channels, and is available from

Sigma Aldrich. E-4031 was stored as a 250X stock at -20 °C. Prior to the assay, the tracer was thawed and stored at room temperature. The tracer was diluted in Assay Buffer to 4X with a final assay concentration of 1 nM. [0631] 384 well untreated low-volume polystyrene microplates (Coming Cat. #451 1) were used for the assay. To each well was added 5 mΐ. of 4X test compound diluted in Assay Buffer (4% DMSO), or 200 nL 100X test compound in 100% DMSO. An additional 4.8 pL of Assay Buffer was added to the assay plate. Each compound titration was performed in the absence and presence of E-4031. 10 pL of 2X Predictor hERG Membranes was added to the appropriate wells of the assay plate. 5 pL of 4X Predictor hERG Tracer Red was added to the appropriate assay wells. The assay plate was shaken on an orbital shaker for 20-30 seconds. The assay plate was covered and incubated for 3 hours at room temperature. The assay plate was read on a fluorescence plate reader (Tecan Safire²) and the data was analyzed.

[0632] Each plate was run with a control representing 100% tracer displacement (the minimum polarization value) as identified by 30 pM E-4031 displacement of Predictor hERG Tracer Red from Predictor hERG Membranes. Assay wells consisted of 30 pM E-4031 , Predictor hERG Membranes and Predictor hERG Tracer Red with ] % DMSO.

[0633] Each plate also comprised a control representing 0% tracer displacement from the Predictor hERG Membranes (the maximum polarization value). Assay wells consisted of Assay Buffer, Predictor hERG Membranes, and Predictor hERG Tracer Red with 1% DMSO.

[0634] Assay blank control wells consisted of Predictor hERG Membranes and Assay Buffer. The blank wells were used for background subtraction of raw parallel and perpendicular fluorescence values prior to the calculation of polarization values.

[0635] An 8-point titration of the known inhibitor, E-4031 , in duplicate was included on each assay plate to ensure that the assay was performing within an expected IC50 range.

[0636] The following controls were monitored for each concentration of test compound:

[0637] Test Compound Polarization Interference (TCPI). At higher concentrations some test compounds may exhibit an additional non-hERG specific reduction in polarization values producing data that appears to be affecting a one-site binding model. This phenomenon is observed with membranes lacking the hERG channel protein suggesting the presence of a non- hERG component in the membrane prep that is binding the tracer. This non-specific interaction is displaced by certain compounds at higher concentrations resulting in a reduction in polarization values. The effect of the test compound on this non- specific interaction was tested in the presence of saturating concentrations of E-4031. Assay wells utilized to test for Test Compound Polarization Interference contained test compound, 30 mM E- 4031, Predictor hERG Membranes, and Predictor hERG Tracer Red with 1% DMSO. Calculated TCPI values outside ± 25% were flagged. [0638] Test Compound Fluorescence Interference (TCFI): Test Compound Fluorescence

Interference was determined by comparing the total fluorescence for test compound wells with the total fluorescence values from the 0% and 100% inhibition control wells. TCFI values outside ± 20% the controls were flagged. The following equations were used for each set of data points:

[0639] Graphing Software: XLfit from IDBS was used for graphing. The dose response curve was curve fit to model number 205 (sigmoidal dose-response model). If the bottom of the curve did not fit between -20% and 20% inhibition, it was set to 0% inhibition. If the top of the curve did not fit between 70% and 130% inhibition, it was set to 100% inhibition.

[0640] The compound No. 2.003 demonstrated an activity of > 30 mM in this assay. The compound No. 3.022 demonstrated an activity of 11.8 pM in this assay. Compound C9 demonstrated an activity of 7.3 pM in this assay. Compound C8 demonstrated an activity of 1.8 pM in this assay.

Example 19: Calculated pKa

[0641] pKa was calculated using Instant JChem, available from from Chemaxon. The pyridine nitrogen of the compound No. 2.003 provided a pKa value of 3.65. The pyridine nitrogen of compound C8:

provided a calculated pKa of 7.46. The difference in the calculated values is close to three log units, or almost 1000 fold.

Example 20: MDCK-MDR1 Bi-Directional Transport Assay

[0642] MDCK-MDR1 is a stable-transfected cell line originating from MDCK cells, with over-expression of human MDR1 gene. The cell line is widely used for the identification and characterization of P-gp substrates and inhibitors.

[0643] MDCK-MDR1 cells were plated into 96-well Millipore Millicell-96 plates at 7,500 cells/75 pL/well and incubated for three days at 37 °C with 5% CO2. Cells were washed with Hank’s Balanced Salt Solution (HBSS) with 5mM HEPES for 30 minutes before starting the experiment. Test compound solutions were prepared by diluting DMSO stock into HBSS buffer, resulting in a final DMSO concentration of 0.1%. Prior to the experiment, cell monolayer integrity was verified by transendothelial electrical resistance (TEER). Transport experiment was initiated by adding test compounds to the apical (75 pL) or basal (250 pL) side. Transport plates were incubated at 37°C in a humidified incubator with 5% CO2. Samples were taken from the donor and acceptor compartments after one hour and analyzed by liquid chromatography with tandem mass spectrometry (LC/MS/MS).

[0644] Digoxin was used as reference control.

[0645] Apparent permeability (Papp) values were calculated using the following equation: Papp = (dQ/dt)/A/Co; where dQ/dt is the initial rate of amount of test compound transported across cell monolayer, A is the surface area of the filter membrane, and Co is the initial concentration of the test compound, calculated for each direction using a 4-point calibration curve by LC/MS/MS.

[0646] Net flux ratio between the two directional transports was calculated by the following equation: Ratio = Papp, B-A/Papp, A-B; where Papp, B-A and Papp, A-B represent the apparent permeability of test compound from the basal-to-apical and apical-to-basal side of the cellular monolayer, respectively.

[0647] Recovery was calculated based on the compound concentration at the end of the experiment, compared to that at the beginning of the experiment, adjusted for volumes. [0648] A net flux ratio greater than two was considered a positive result for substrate determination. To further confirm whether the efflux activity observed for any test compounds is due to P-gp mediated transport, similar bi-directional transport studies in the presence of a potent P-gp inhibitor, such as GF 120918, can be done. If the addition of a known P-gp inhibitor to the experiment reduces the net flux ratio by a significant amount (more than 50% reduction or reduces the ratio to close to unity), it is likely that the compound tested is a P-gp substrate.

Example 21: Metabolite Identification Study

[0649] Sample Processing: Compound was dissolved in dimethyl sulfoxide (DMSO) at 10 mM and tested at 20 mM.

[0650] Human Liver Microsomes (LM) Incubation: LM were thawed and diluted to 0.5 mg/mL with NADPH (1 mM), alamethicin (10 uM) and UDPGA (1 mM) solution before 0.5 mL was transferred to vials. 0 hr sample: the LM were incubated for 1 hr at 37 °C, before 1 mL of quench solution (100% acetonitrile) was added to the vial and mixed well. Then, 1 pL of the stock solution was added to the vials. 1 hr sample: 1 pL of the stock solution was added to the vials with 0.5 mL diluted LM. The sample was incubated at 37°C for 1 hr and quenched with 1 mL of 100% acetonitrile.

[0651] Samples were centrifuged and the supernatant was diluted with water and injected to LC-MS. [0652] Metabolites were characterized by their mass spectronomy fragmentation pattern.

[0653] Using the above conditions, at least masses of 368 and 457 were observed and are believed to correspond, respectively, to the following metabolites identified for Compound No.

2.003:

Example 22: 4-cyano-2-((2-fIuoro-4-iodophenyl)amino)benzoic acid

[0654] A solution of 4-cyano-2-fluorobenzoic acid (3.0 g, 18.1 mmol) in THF (30 mL) stirred under N2 at -78 C was treated with LDA (2.0 M in THF, 27.2 mL, 54.5 mmol) added dropwise. After 20 min a solution of 2-fluoro-4-iodoaniline (12.9 g, 54.5 mmol) in dry THF (15 mL) was added dropwise and the reaction mixture was further stirred allowing it to warm up to room temperature. After 16 h the reaction mixture was concentrated in vacuo, acidified with 1M HC1 and extracted twice with Et₂0. The combined organic phase was washed with brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The crude residue was purified by trituration in boiling DCM to give the product (1.57 g, 22.7%) as a yellow solid m/z 381.1 [M-H]\ 'H NMR (400 MHz, DMSO-cfe) d ppm 13.91 (s, 1H), 9.74 (s, 1H), 8.04 (d, .7=8.2 Hz, 1H), 7.77 (dd, .7=10.3, 2.0 Hz, 1H), 7.58 (dt, .7=8.5, 1.3 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.24 (dd, =8.2, 1.6 Hz,

1H)

Example 23: 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid

[0655] A microwave vial was charged with 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (80% pure) (0.19 g, 0.4 mmol), 3-hydroxyazetidine hydrochloride (0.07 g, 0.6 mmol), HATU (0.25 g, 0.6 mmol) and diisopropyl ethyl amine (140 pL, 0.8 mmol) and N,N- dimethylformamide (6 mL). The reaction mixture was stirred at room temperature overnight.

The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with water, brine and dried over sodium sulfate. The solvents were evaporated. The residue was purified by flash chromatography (12 g silica, 0-5% methanol in dichloromethane) and again by reverse phase HPLC (30-95% Acetonitrile/ water) to give the product as a light yellow solid (71 mg, 41%). m/z 438.1 [M+l]⁺. Ή NMR (300 MHz, DMSO-d6): S 8.97 (s, 1H), 7.69-7.65 (dd, J=1.2 Hz and 0.9Hz, 1H), 7.55-7.47 (m, 2H), 7.40 (s, 1H), 7.28-7.18 (m, 2H), 5.80 (s, 1H), 4.45 (s, 1H), 4.35 (t, J=7.6 Hz, 1H), 4.21 (t, J=8.9 Hz, 1H), 4.00-3.98 (m, 1H), 3.76-3.73 (m, 1H).

[0656] The following compounds are prepared as described in Example 23, replacing the 3- hydroxyazetidine hydrochloride with an appropriate amine which is commercially available or prepared using conditions known to one of ordinary skill in the art.

Example 37: N-(azetldin-3-ylmethoxy)-4-cyano-2-((2-fluoro-4- iodophenyl)amino)benzamide

Step 1 : tert-butyl 3-fff4-cvano-2- fluoro-4-iodophenyr)amino)benzamido)oxy)methyl)

azetidine-1 -carboxylate

[0657] A microwave vial was charged with 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (0.100 g, 0.3 mmol), tert-butyl 3-((aminooxy)methyl)azetidine-l -carboxylate, (60% pure) (0.13 g, 0.4 mmol), HATU (0.15 g, 0.4 mmol) and diisopropyl ethyl amine (135 pL, 0.8 mmol) in A/ZV-dimethylformamide (3 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with water, brine and dried over sodium sulfate. The solvents were evaporated.

The residue was purified by flash chromatography (12 g silica, 0-70% ethyl acetate in hexanes). The product fractions were collected and the solvent was removed to give a yellow oil (77 mg, 52%). m/z 565.2 [M-l]\ Ste^p 2: N-iazetidin-3-ylmethoxy)-4-cvano-2-((2-fluoro-4-iodophenyl)amino^’)benzamide

[0658] A round bottom flask was charged with tert-butyl 3-(((4-cyano-2-((2-fluoro-4- iodophenyl)amino)benzamido)oxy)methyl)azetidine-l-carboxylate (0.077 g, 0.1 mmol) in dichloromethane (6 mL) and hydrogen chloride (4.0 M in 1 ,4-dioxane, 0.510 ml, 2.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase HPLC ((10-95% Acetonitrile/water (0.1 %TFA)). The product fractions were collected, washed with sodium bicarbonate and dried in vacuo to give the product as a yellow solid m/z 461.7 [M+l]⁺.

'H NMR (300 MHz,CDC13): d 8.41 (s, 1 H), 7.67 (d, J=8.1 Hz, 1 H), 7.50-7.42 (m, 2H), 7.35 (s, 1H), 7.12-7.03 (m, 1H), 4.16-4.10 (m,lH), 4.06-4.00 (m,lH), 3.94-3.90 (m, 1H), 3.73-3.68 (m,

1H), 2.89-2.79 (m, 3H).

Example 38: 4-Cyano-2-((2-fluoro-4-iodophenyl)amino)-/V-hydroxybenzamide

[0659] A solution of hydroxylamine hydrochloride (333 mg, 0.52 mmol) in dry DMF (2.4 mL) and dry acetonitrile (2.4 mL) stirred at room temperature was treated with Et3N (1.33 mL, 9.6 mmol). After 1 h the suspension was diluted with DCM (2.4 mL), cooled down to 0°C and a solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoyl chloride (209 mg, 0.52 mmol) in dry THF (2.4 mL) was added. After 1 h the reaction mixture was diluted with EtOAc, quenched with a saturated NH₄CI aqueous solution, partitioned, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na₂S0₄, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC purification to give the product (37 mg, 17.8%) as a yellow solid m/z 396.1 [M-H] . 'H NMR (400 MHz, DMSO-flfc): d ppm 1 1.60 (s, 1H), 9.46 (s, 1H), 9.41 (s, 1H), 7.72 (dd, .7=10.5, 2.0 Hz, 1H), 7.64 (d, .7=8.0 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.46 (s, 1H), 7.37 - 7.28 (m, 2H). Example 39: 2-((4-Cyano-2-((2-fluoro-4-iodophenyl)amino)benzainido)oxy)ethan-l- a inium 2,2,2-trifluoroacetate

Step 1 : /ert-Butyl (2-(f4-cvano-2-((2-fluoro-4-iodophenyl)amino)benzamido~)oxy)ethvD carbamate

[0660] A solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (150 mg, 0.39 mmol) and HATU (298 mg, 0.78 mmol) in dry DMF (3.9 mL) was treated with dry D1PEA (0.13 mL, 0.78 mmol). The reaction mixture was stirred at 50°C for 30 min, cooled down to room temperature and a solution of tert- butyl (2-(aminooxy)ethyl)carbamate (103 mg, 0.58 mmol) in dry DMF (0.5 mL) was added. After 16 h the reaction mixture was diluted with EtOAc, quenched with H2O, partitioned, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude residue was purified by a flash column chromatography (Silica, 1-40% EtOAc in hexanes) to give the product (87 mg, 41%) as a yellow oil. UPLC-MS (Acidic Method, 2 min): rt 1.27 min. m/z 539.1 [M-H]\ 'H NMR (400 MHz, CDCb): d ppm 10.56 (s, 1H), 9.45 (s, 1H), 7.59 (d, .7=8.1 Hz, 1H), 7.57 - 7.46 (m, 2H), 7.32 (s, 1H), 7.16 - 7.07 (m, 2H), 5.06 (s, 1H), 4.01 (t, .7=4.9 Hz, 2H), 3.54 - 3.45 (m, 2H), 1.49 (s, 9H).

Step 2: 2-(Y4-Cvano-2-(Y2-fluoro-4-iodophenyl^')amino^')benzamido^')oxy^')ethan-l -aminium 2.2.2- trifluoroacetate

[0661] A solution of tert- butyl (2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy) ethyl) -carbamate (67 mg, 0.12 mmol) in dioxane (1.0 mL) stirred at room temperature was treated with 4N HC1 in dioxane (62 mΐ, 0.24 mmol). After 1 h an additional portion of 4N HC1 in dioxane (62 mΐ, 0.24 mmol) was added, similarly after 16 h. After 48 h a further portion of 4N HC1 in dioxane (0.25 mL, 1 mmol) was added. After 48 h the reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC purification to give the product (21.1 mg, 32%) as a yellow solid in a form of its trifluoroacetate salt m/z 441.1 [M+H]⁺ . 'H NMR (400 MHz, DMSO-<7₆): d ppm 7.79 - 7.69 (m, 2H), 7.54 (dd, 7=8.3, 1.9 Hz, 1H), 7.45 (d, =1.5 Hz, 1H), 7.35 (dd, .7=8.1 , 1.5 Hz, 1H), 7.29 (t, .7=8.6 Hz, 1H), 4.07 (t, 7=5.1 Hz, 2H), 3.08 (t, 7=5.2 Hz, 2H).

Example 40: Methyl 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)acetate

[0662] A solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (500 mg, 1.30 mmol) and HATU (995 mg, 2.61 mmol) in dry DMF (13.0 mL) was treated with dry DIPEA (0.45 mL, 2.61 mmol). The reaction mixture was stirred at 50°C for 30 min, cooled down to room temperature and a solution of methyl 2-(aminooxy)acetate hydrochloride (270 mg, 1.96 mmol) in dry DMF (1.0 mL) was added followed by dry DIPEA (0.34 mL, 2.0 mmol). After 48 h the reaction mixture was diluted with EtOAc, quenched with H2O, partitioned, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na₂S0₄, filtered and concentrated in vacuo. The crude residue was purified by a flash column chromatography (Silica, 10-41% EtOAc in hexanes) to give the product (373 mg, 61%) as a yellow solid m/z 468.1 [M-H]\ ‘H NMR (400 MHz, DMSO-cfe): d ppm 12.29 (s, 1H), 9.16 (s, 1H), 7.76 - 7.60 (m, 2H), 7.52 (dt, 7=8.4, 1.4 Hz, 1H), 7.41 (s, 1H), 7.35 - 7.19 (m, 2H), 4.72 - 4.55 (m, 2H), 3.70 (s, 3H). Example 41: 2-((4-Cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)acetic acid

[0663] A solution of methyl 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy) acetate (306 mg, 0.64 mmol) in THF (1.93 mL), MeOH (0.64 mL), and ¾0 (1.28 mL) stirred at room temperature was treated with 1M LiOH (0.64 mL, 0.64 mmol). After 24 h an additional portion of 1M LiOH (0.64 mL, 0.64 mmol) was added and stirring continued. After 24 h the reaction mixture was diluted with a saturated NaHC03 aqueous solution, partitioned with EtOAc, and the aqueous phase was acidified with 1M HC1 and extracted with EtOAc. The organic phase was washed with 1M HC1 and brine, dried over NaHCOa, filtered and concentrated in vacuo to give the product (238 mg, 81%) as a yellow solid m/z 454.0 [M-H]\ 'H NMR (400 MHz, DMSO-i/e): d ppm 13.00 (s, 1 H), 12.30 (s, 1 H), 9.21 (s, l H), 7.72 (dd, .7=10.4, 1.9 Hz, 1H), 7.68 (s, 1H), 7.53 (dt, .7=8.5, 1.4 Hz, 1H), 7.40 (d, .7=1.6 Hz, 1H), 7.34 - 7.24 (m, 2H), 4.52 (s, 2H).

Example 42 : 7V-(2- Amino-2-oxoethoxy)-4-cyano-2-((2-fluoro-4-iodophenyI)amino) benzamide

Step 1 : 2-(Y4-Cvano-2-(Y2-fluoro-4-iodophenyllamino')benzamido')oxy')acetyl chloride

[0664] A solution of 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)acetic acid (181 mg, 0.39 mmol) in dioxane (1.5 mL) stirred at room temperature under N2 was treated with SOCh (0.3 mL, 3.9 mmol). After 24 h the reaction mixture was concentrated in vacuo and azeotroped with dry toluene (3 x 5 mL). The resultant orange solid was used in the subsequent reaction without further purification m/z 468.1 [M+H] (detected as the corresponding methyl ester after quenching an aliquot of the mixture with 10% pyridine in MeOH).

Step 2: jV-(2-Amino-2-oxoethoxy)-4-cyano-2-((2-fluoro-4-iodophenvDamino)benzamide

[0665] A solution of 2-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)acetyl chloride (188 mg, 0.39 mmol) in dry dioxane (0.9 mL) stirred at 0°C under N2 was treated with 0.5 M NH3 in dioxane (0.91 mL). After 48 h the reaction mixture was diluted with EtOAc, quenched with 1M HC1, partitioned and the organic phase was washed with brine, dried over Na₂S0₄, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC purification to give the product (49.7 mg, 28%) as a yellow solid m/z 453.0 [M-H]\ 'H NMR (400 MHz, DMSO-de): d ppm 12.29 (br s, 1H), 9.40 (br s, 1 H), 7.74 - 7.69 (m, 2H), 7.54 - 7.48 (m, 1H), 7.40 (s, 1H), 7.34 - 7.24 (m, 2H), 4.34 (s, 2H).

Example 43: Methyl 3-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy) propanoate

[0666] A solution of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (500 mg, 1.30 mmol) and HATU (995 mg, 2.61 mmol) in dry DMF (13.0 mL) stirred at room temperature was treated with dry DLPEA (0.45 mL, 2.61 mmol). The reaction mixture was stirred at 50°C for 30 min, cooled down to room temperature and a suspension of methyl 3-(aminooxy)propanoate hydrochloride (305 mg, 1.96 mmol) in dry acetonitrile (2.9 mL) and dry THF (2.9 mL) was added, followed by dry DIPEA (0.45 mL, 2.6 mmol). After 16 h the reaction mixture was diluted with EtOAc, quenched with H2O, partitioned, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na₂S0₄, filtered and concentrated in vacuo. The crude residue was purified by a flash column chromatography (Silica, 20-50% EtOAc in hexanes) to give the product (369 mg, 59%) as a yellow solid m/z 482.0 [M-H] . Ή NMR (400 MHz, DMSO-7₆): d ppm 12.05 (s, 1 H), 9.29 (s, 1 H), 7.72 (dd, .7=10.5, 1.9 Hz, 1H), 7.66 (s, 1H), 7.53 (d, 7=8.6 Hz, 1H), 7.42 (d, 7=1.7 Hz, 1H), 7.36 - 7.25 (m, 2H), 4.14 (m, 2H), 3.61 (s, 3H), 2.70 (t, 7=6.6 Hz, 2H).

Example 44: 3-((4-Cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)propanoic acid

[0667] A solution of methyl 3-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy) propanoate (321 mg, 0.66 mmol) in THF (4.0 mL), MeOH (1.33 mL), and ¾0 (2.65 mL) stirred at room temperature was treated with 1 M LiOH (1.33 mL, 1.33 mmol). After 3 days an additional portion of 1 M LiOH (0.32 mL, 0.32 mmol) was added and stirring continued. After 3 h the reaction mixture was diluted with a saturated NaHC0₃ aqueous solution, partitioned with EtOAc, and the aqueous phase was acidified and extracted with EtOAc. The first EtOAc extract was washed with 1 M HC1 and brine sequentially, dried over NaHC0₃, filtered and concentrated in vacuo to give the product (203 mg, 65.5% yield, 79% pure) as a yellow solid. The second EtOAc extract was washed with brine, dried over NaHC0₃, filtered and concentrated in vacuo to give the product (46 mg, 14.8% yield, 100% pure) as a yellow solid m/z 468.1 [M-H] . 'H NMR (400 MHz, DMSO-7₆): d ppm 12.37 (m, 2H), 9.29 (s, 1 H), 7.76 - 7.62 (m, 2H), 7.53 (dd , 7 = 8.1, 1.9 Hz, 1H), 7.42 (d, 7 = 1.7 Hz, 1H), 7.35 - 7.24 (m, 2H), 4.12 (s, 2H), 2.61 (t, .7= 6.1 Hz, 2H).

Example 45: 3-((2-Fluoro-4-iodophenyl)amino)-4-(3-oxoisoxazolidine-2- carbonyl)benzonitrile

[0668] A solution of 3-((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)propanoic acid (203 mg, 0.43 mmol) in dioxane (1.7 mL) stirred at room temperature under N2 was treated with SOCb (0.32 mL, 4.3 mmol). After 24 h the reaction mixture was concentrated in vacuo and azeotroped with dry toluene (3 x 5 mL). The resulting orange solid was used in the next step without further purification m/z 450.0 [M+H] .

Example 46: /V-(3-Amino-3-oxopropoxy)-4-cyano-2-((2-fluoro-4-iodophenyl)amino) benzamide

[0669] A solution of 3-((2-fluoro-4-iodophenyl)amino)-4-(3-oxoisoxazolidine-2- carbonyl)benzonitrile (195 mg, 0.43 mmol) in dry dioxane (1.03 mL) stirred at 0°C under N2 was treated with 0.5 M NH3 in dioxane (0.99 mL, 0.49 mmol). After 30 min the reaction mixture was diluted with EtOAc, quenched with 1M HC1, partitioned and the organic phase was washed with brine, dried over Na2SC>4, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC purification to give the product (22.2 mg, 11%) as a yellow solid. m/z 467.1 [M-H]\ 'H NMR (400 MHz, DMSO-ck): d ppm 12.04 (br s, 1H), 9.47 (br s, 1H), 7.71 (dd, .7=10.4, 2.0 Hz, 2H), 7.52 (d, .7=8.0 Hz, 1H), 7.41 (s, 1H), 7.33 - 7.26 (m, 2H), 6.90 (br s, 2H), 4.09 (t, .7=5.1 Hz, 2H), 2.44 (t, .7=6.3 Hz, 2H).

Example 47: 3-Hydroxycyclobutyl 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoate

Step 1 : 4-Cvano-2-((2-fluoro-4-iodophenyl)amino)benzoyl chloride /General preparation)

[0670] A suspension of 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (200 mg, 0.52 mmol) in dioxane (1.61 mL) stirred at room temperature was treated with SOCh (0.38 mL, 5.23 mmol). The reaction mixture was further stirred at 50°C under N2. After 48 h the reaction mixture was concentrated in vacuo and azeotroped with dry toluene (2 x 5 mL). The resultant crude material in residual toluene was used in the next step without further purification.

Step 2: 3-Hvdroxycvclobutyl 4-cvano-2- fluoro-4-iodophenvf)amino)benzoate

[0671] To a solution of cyclobutane- 1 , 3 -diol (159 mg, 1.8 mmol) and Et3N (0.16 mL, 1.1 mmol) in dry THF (1.0 mL) stirred at 0°C under N2 atmosphere a solution of 4-cyano-2-((2- fluoro-4-iodophenyl)amino)benzoyl chloride (157 mg, 0.39 mmol) in dry THF (1.3 mL) was added. After 1 h the reaction mixture was diluted with EtOAc, quenched with a saturated NH₄CI aqueous solution, partitioned, and the aqueous phase re-extracted with EtOAc. The combined organic phases were washed with brine, dried over Na₂S0₄, filtered, and concentrated in vacuo. The crude residue was purified by a flash column chromatography (Silica, 5-31% EtOAc in hexanes) to give the product (43.7 mg, 24.7%) as a yellow solid m/z 451.1 [M-H] . 'H NMR (400 MHz, DMSO-7₆): d ppm 9.36 (s, 1H), 8.06 (d, 7=8.2 Hz, 1H), 7.76 (dd, 7=10.3, 1.9 Hz, 1H), 7.58 (dt, .7=8.4, 1.3 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.27 (dd, =8.2, 1.6 Hz, 1H), 5.26 (d, 7=6.5 Hz, 1H), 4.74 (p, 7=7.3 Hz, 1H), 3.88 (h, 7=6.9 Hz, 1H), 2.86 - 2.70 (m, 2H), 2.12 - 1.98 (m, 2H). Example 48: 3-Hydroxy-2,2,4,4-tetramethyIcyclobutyl 4-cyano-2-((2-fIuoro-4- iodophenyl)amino)benzoate

[0672] To a solution of 2,2,4,4-tetramethylcyclobutane-l ,3-diol (520 mg, 3.6 mmol) and Et3N (0.32 mL, 2.3 mmol) in dry THF (2.0 mL) stirred at 0°C under N2 atmosphere a solution of 4- cyano-2-((2-fluoro-4-iodophenyl)amino)benzoyl chloride (314 mg, 0.78 mmol) in dry THF (2.7 mL) was added. After 48 h the reaction mixture was diluted with EtOAc, quenched with a saturated NH4CI aqueous solution, partitioned, and the aqueous phase re-extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The crude residue was purified by a flash column chromatography (Silica, 0-50% EtOAc in hexanes) to give the product (26.6 mg, 6.7%) as a yellow solid m/z 506.9 [M-H]\ 'H NMR (400 MHz, DMSO-7₆): d ppm {Note: a mixture of diastereoisomers 2: 1) 9.31 (s, 0.35H), 9.29 (s, 0.67H), 8.10 (d, 7=8.2 Hz, 0.37H), 8.06 (d, 7=8.2 Hz, 0.63H), 7.77 (dd, 7=10.3, 1.9 Hz, 1H), 7.59 (dd, 7=7.8, 1.9 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.34 - 7.27 (m, 1H), 5.01 (t, 7=4.8 Hz, 1H), 4.52 (s, 0.35H), 4.41 (d, 7=0.9 Hz, 0.67H), 3.53 (d, 7=4.8 Hz, 0.36 H), 3.37 (d, 7=4.8 Hz, 0.66 H), 1.18 (s, 4H), 1.09 (s, 2H), 1.07 (s, 2H), 1.00 (s, 4H). Example 49: 2,3-Dihydroxypropyl 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoate

[0673] To a solution of 1 ,2,3-propanetriol (332 mg, 3.6 mmol) and Et3N (0.32 mL, 2.3 mmol) in dry THF (2.7 mL) stirred at 0°C under N2 atmosphere a solution of 4-cyano-2-((2-fluoro-4- iodophenyl)amino)benzoyl chloride (314 mg, 0.78 mmol) in dry THF (2.0 mL) was added. After 16 h the reaction mixture was diluted with EtOAc, quenched with a saturated NH₄CI aqueous solution, partitioned, and the aqueous phase re-extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. A portion of the crude material (198 mg) was purified by preparative HPLC purification to give the product (34 mg, 9.5%) as a glassy yellow solid m/z 455.0 [M-H]\ 'H NMR (400 MHz, DMSO- d )\ d ppm 9.33 (s, 1H), 8.12 (d, =8.2 Hz, 1H), 7.77 (dd, 7=10.3, 1.9 Hz, 1H), 7.59 (dt, =8.4,

1.4 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.29 (dd, 7=8.2, 1.6 Hz, 1H), 5.12 (d, 7=5.3 Hz, 1H), 4.75 (t, 7=5.7 Hz, 1H), 4.37 (dd, 7=1 1.1, 3.9 Hz, 1H), 4.23 (dd, 7=11.1, 6.2 Hz, 1H), 3.88 - 3.76 (m,

1H), 3.53 - 3.38 (m, 2H). Example 50: 4-cyano-3-fluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid

Step 1 : 2-fluoro-4-ftrimethylsiIv0aniline

[0674] A round bottom flask was charged with 4-bromo-2-fluoroaniline (1.00 g, 5.3 mmol) and anhydrous tetrahydrofuran (8 mL), cooled to-78°C and a 2.5M solution of nBuLi in hexanes (8 ml, 20 mmol) was added dropwise keeping the internal temperature below -60°C. The reaction mixture was treated dropwise with chlorotrimethylsilane (2.26 ml, 17.4 mmol.), keeping the internal temperature below -60°C. The reaction mixture was allowed to warm to 0°C over one hour period. The reaction mixture was poured into ice-cold 2M hydrochloric acid and was vigorously stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate and evaporated to dryness to give the product as colorless oil (0.58g, 54%). m/z 184.2 [M+l]⁺.

Step 2: 4-bromo-3-fluoro-2- fluoro-4-(^'trimethylsilvQphenyr)amino^')benzoic acid

[0675] To a stirred solution comprised of 2-fluoro-4-(trimethylsilyl)aniline (1.0 g, 5.1 mmol) in tetrahydrofuran (6 mL) at -78°C was added lithium diisopropylamide (2.0 M in

THF/heptane/ethylbenzene, 2.5 ml, 5.1 mmol). The resulting suspension was stirred vigorously for 10 minutes, after which time a solution of 4-bromo-2,3-difluorobenzoic acid (0.400 g, 1.7 mmol) in tetrahydrofuran (5 mL) was added. The cold bath was subsequently removed, and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the concentrate was treated with 3M hydrochloric acid (10 mL). The resulting suspension was extracted with ethyl ether. The combined organics were dried over sodium sulfate. The solvents were removed in vacuo. Hexanes was added into the residue. The precipitated beige solid (382 mg) was washed using hexane and a few drop of ethyl acetate and isolated by filtration m/z 400.1 [M⁺] Ή NMR (300 MHz, DMSO-d6): d 9.06 (s, 1H), 7.70-7.66 (m, 1H), 7.38-7.33 (m, 1H), 7.27 (d, J=1 1.7 Hz, 1H), 7.20-7.17 (m, 1H), 6.93-6.86 (m, 1H), 0.22 (s, 9H).

Step 3: 4-cvano-3-fluoro-2-(Y2-fluoro-4-ftrimethylsilvDphenyDamino^')benzoic acid

[0676] A microwave vial was charged with4-bromo-3-fluoro-2-((2-fluoro-4- (trimethylsilyl)phenyl)amino)benzoic acid (0.180 g, 0.4 mmol), zinc cyanide (0.05 g, 0.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.05 g, 0.05 mmol) in A/A-dimethyl formamide (3 mL) under argon. The reaction mixture was stirred at 90°C overnight. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with water, brine and dried over sodium sulfate. The solvents were evaporated. The residue was purified by flash chromatography (12 g silica, 0-70% ethyl acetate in hexanes) to give the product as a yellow solid (50 mg, 32%). Ή NMR (300 MHz, CDC13): d 8.95 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.24-7.21 (m, 2H), 7.19-7.08 (m, 1H), 7.00-6.93 (m, 1H), 0.28 (s, 9H). Step 4: 4-cvano-3-fluoro-2-(Y2-fluoro-4-iodophenyl~)amino~)benzoic acid

[0677] A round bottom flask was charged with4-cyano-3-fluoro-2-((2-fluoro-4- (trimethylsilyl)phenyl)amino)benzoic acid (0.49 g, 1.4 mmol) in anhydrous methanol (6 mL) and anhydrous dichloromethane (6 mL). Silver trifluoroacetate (0.66 g, 3.0 mmol) was added. The reaction mixture was cooled to 0°C. Iodine (0.72 g, 2.8 mmol) was then added in one portion. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was filtered through celite and the solvents were removed. The residue was treated with saturated sodium thiosulfate and extracted with ethyl acetate. The combined organics were dried over sodium sulfate. The solvents were removed in vacuo. Dichloromethane was added to the residue whereby a solid precipitated out. The solid was collected by filtration and dried to give the product as beige colored solid (200 mg, 35%). Ή NMR (300 MHz, DMSO-d6): d 7.83-7.81 (m, 1H), 7.59-7.54 (dd, J=1.8 and 1.8 Hz, 1H), 7.39-7.36 (m, 2H), 6.74-6.66 (m, 1H).

Example 51 : 4-cyano-3-fluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy) benzamide

[0678] A microwave vial was charged with 4-cyano-3-fluoro-2-((2-fluoro-4- iodophenyl)amino)benzoic acid (0.100 g, 0.2 mmol), 2-(aminooxy)ethanol (0.03 g, 0.4 mmol), HATU (0.14 g, 0.4 mmol) and diisopropyl ethyl amine (86 pL, 0.5 mmol.) and N,N- dimethylformamide (3 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with water, brine and dried over sodium sulfate. The solvents were evaporated. The residue was purified by flash chromatography (12 g silica, 0-5% methanol in dichloromethane). The product fractions were collected and the solvent was removed. The residue was purified again by reverse phase HPLC (20-80% Acetonitrile/water) to give the product as a light yellow solid m/z 458.0 [M-l]\ Ή NMR (300 MHz, DMSO-d6): d 1 1.93 (s, 1H), 8.44 (s, 1H), 7.67- 7.62 (m, 1H), 7.56 (d, J=9.6 Hz, 1H), 7.47-7.44 (m, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.70-6.63 (m, 1H), 3.79 (t, J=4.4 Hz, 2H), 3.55-3.53 (m, 2H).

[0679] The following compounds are prepared as described in Example 51 , replacing the 2- (aminooxy)ethanol with an appropriate amine which is commercially available or prepared using conditions known to one of ordinary skill in the art.

Example 53: Methyl 6-cyano-2-((2-fluoro-4-iodophenyl)amino)nicotinate

Step 1 : 6-Chloro-2- fluoro-4-(^,trimethylsilvnphenyl^')aminolmcotinic acid

[0680] To a solution of 2-fluoro-4-(trimethylsilyl)aniline (9.2 g, 50 mmol) in dry THF (40 mL) stirred at -78°C was added LiHMDS (1 M in THF, 100 mL, 100 mmol). The reaction mixture was stirred for 1 h at -78°C followed by an addition of a solution of 2,6-dichloroisonicotinic acid (8 g, 41.7 mmol) in dry THF (31 mL). The reaction mixture was stirred at -78°C for 1 h and then gradually warmed up to room temperature. The reaction mixture was quenched with a saturated NH4CI aqueous solution (100 mL) at 0°C, diluted with EtOAc (200 mL), acidified with 1M HC1 to pH 3 and partitioned. The aqueous phase was extracted with EtOAc (2x 100 mL), the organic phase was washed with brine (100 mL), dried over Na2S04 and concentrated in vacuo. The crude material was purified by trituration with methanol to give the product (10.6 g, 75%) as a yellow solid m/z 339.1/341.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-7₆): d ppm 13.94 (s, 1H), 10.79 (d, 7=2.9 Hz, 1H), 8.41 (t, .7=8.1 Hz, 1H), 8.27 (d, .7=8.1 Hz, 1H), 7.37 (m, 2H), 7.00 (d, .7=8.1 Hz, 1H), 0.26 (s, 9H).

Step 2: Methyl 6-chloro-2-((2-fluoro-4-(trimethylsilyl)phenyl)amino)nicotinate

[0681] A solution of 6-chloro-2-((2-fluoro-4-(trimethylsilyl)phenyl)amino)nicotinic acid (0.5 g, 1.476 mmol) in DCM (7.4 mL) stirred at room temperature was treated with DIPEA (0.26 mmol, 1.476 mmol). After 10 min the reaction mixture was cooled down to 0°C and was treated with DMF (0.03 mL) and oxalyl chloride (0.12 mL, 1.476 mmol) with subsequent warm up to room temperature. The reaction mixture was stirred for 30 minutes, then slowly added to the solution of DIPEA (0.26 mL, 1.476 mmol) in MeOH (7.4 mL) stirred at 0°C with a subsequent warm up to room temperature. After 15 minutes the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (20 mL), washed with a saturated NaHC0₃ aqueous solution (10 mL), H2O (10 mL), brine (10 mL), dried over Na₂S0₄ and concentrated in vacuo to give the product (0.45 g, 87%) as a brown solid m/z 353.1/355.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-r/e): d ppm 10.48 (d, 7=3.0 Hz, 1H), 8.36 (t, 7=7.9 Hz, 1H), 8.29 (d, 7=8.2 Hz, 1H), 7.43 - 7.33 (m, 2H), 7.02 (d, 7=8.2 Hz, 1H), 3.91 (s, 3H), 0.26 (s, 9H).

Step 3: Methyl 6-cvano-2- fluoro-4-itrimethylsilvnphenvnamino)nicotinate

[0682] A degassed solution of methyl 6-chloro-2-((2-fluoro-4-(trimethylsilyl)phenyl)amino) nicotinate (0.4 g, 1.13 mmol), zinc cyanide (0.1 1 g, 0.96 mmol) and tetrakis(triphenylphosphine) palladium(O) (0.13 g, 0.11 mmol) in NMP (3.5 L) was heated in a microwave oven at 190°C for 15 min. The reaction mixture was filtered, diluted with EtOAc (20 mL), washed with a saturated NaHCCL aqueous solution (10 mL), LhO (10 mL), brine (10 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-15% EtOAc in hexanes) to give the product (0.133 g, 43%) as a yellow solid m/z 344.1 [M+H]⁺. Ή NMR (400 MHz, DMSO-rf₆): d 10.43 (d, .7=2.8 Hz, 1H), 8.46 (d, .7=7.8 Hz, 1H), 8.32 (t, .7=8.0 Hz, 1H), 7.54 (d, .7=7.8 Hz, 1H), 7.45 - 7.36 (m, 2H), 3.94 (s, 3H), 0.26 (s, 9H).

Step 4: Methyl 6-cvano-2-((2-fluoro-4-iodophenyl)amino)nicotinate

[0683] A suspension of silver tetrafluoroborate (85 mg, 0.437 mmol) in DCM (0.5 mL) was stirred at -50°C for 5 min in the dark, then a solution of methyl 6-cyano-2-((2-fluoro-4- (trimethylsilyl)phenyl)amino)-nicotinate (50 mg, 0.146 mmol) in DCM (1 mL) was added dropwise. After 15 min the reaction mixture was treated with iodine monochloride (26 mg, 0.161 mmol) in DCM (0.3 mL). The reaction mixture was stirred for 15 min and an additional portion of iodine monochloride (7 mg, 0.044 mmol) in DCM (0.1 mL) was added. After 15 min the reaction mixture was quenched with a saturated Na SaCL aqueous solution (1 mL), extracted with EtOAc (3 ^c 5 mL), the organic phase was washed with brine (5 mL), dried over Na₂S0₄ and the solvent was removed in vacuo to give the product (53 mg, 91%) as a yellow solid m/z 398.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-< ₆): d ppm 10.37 (d, .7=2.8 Hz, 1H), 8.46 (d, .7=7.8 Hz, 1H), 8.11 (t, .7=8.6 Hz, 1H), 7.76 (dd, .7=10.6, 2.0 Hz, 1H), 7.64 (dd, .7=8.6, 1.7 Hz, 1H), 7.55 (d, .7=7.8 Hz, 1H), 3.94 (s, 3H). Example 54: 6-Cyano-2-((2-fluoro-4-iodophenyl)amino)nicotinic acid

[0684] To a suspension of methyl 6-cyano-2-((2-fluoro-4-iodophenyl)amino)nicotinate (0.42 g, 1.06 mmol) in THF (3.2 mL), MeOH (1.05 mL) and H2O (2.1 mL) stirred at room temperature was treated with 1M LiOH aqueous solution (1.06 mL, 1.06 mmol). After 30 min an additional portion of 1M LiOH aqueous solution (1.06 mL, 1.06 mmol) was added. After 30 min the reaction mixture was concentrated in vacuo , the residue was partitioned between EtOAc (10 mL) and H2O (10 mL). The aqueous phase was acidified to pH 3 with 1M HC1 aqueous solution and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2S04 and concentrated in vacuo to give the product (0.40 g, quant.) as a yellow solid m/z 382.0 [M-H]\ Ή NMR (400 MHz, DMSO-7₆): d ppm 8.42 (d, 7=7.7 Hz, 1H), 8.21 (t, .7=8.5 Hz, 1H), 7.73 (dd, .7=10.8, 1.9 Hz, 1H), 7.62 (d, 7=8.6 Hz, 1H), 7.52 (d, 7=7.7 Hz, 1H).

Example 55 : 6-Cyano-/V-ethoxy-2-((2-fluoro-4-iodophenyl)amino)nicotinamide

[0685] To a suspension of 6-cyano-2-((2-fluoro-4-iodophenyl)amino)nicotinic acid (100 mg, 0.26 mmol) in dry DMF (2.5 mL) were added HATU (200 mg, 0.52 mmol) and DIPEA (0.13 mL, 0.65 mmol) and the reaction mixture was heated at 50°C for 30 min. The reaction mixture was then cooled down to room temperature and a solution of ethoxyamine hydrochloride (38 mg, 0.39 mmol) in dry DMF (0.5 mL) was pre-treated with DIPEA (0.05 mL, 0.39 mmol) for 5 min was added. After 1 h the reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc (5 mL), washed with H2O (5 mL) and brine (5 mL). The organic phase was dried over Na2S0₄ and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-37% EtOAc in hexanes) followed by a trituration with diethyl ether to give the product (7 mg, 6%) as a yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.26 min, m/z 425.1 [M-H]-. Ή NMR (400 MHz, DMSO-7₆): d ppm 12.18 (s, 1 H), 10.89 (s, 1 H), 8.16 (d, 7=7.7 Hz, 2H), 7.71 (dd, 7=10.7, 2.0 Hz, 1H), 7.60 (dt, 7=8.6, 1.5 Hz, 1H), 7.55 (d, 7=7.8 Hz, 1H), 4.00 (d, 7=7.1 Hz, 2H), 1.24 (t, 7=7.0 Hz, 3H).

Example 56: 6-Cyano-2-((2-fluoro-4-iodophenyl)amino)-./V-(2-hydroxyethoxy) nicotinamide

[0686] To a solution of 6-cyano-2-((2-fluoro-4-iodophenyl)amino)nicotinic acid (100 mg, 0.261 mmol) and HATU (198.5 mg, 0.522 mmol) in DMF (3 mL) stirred at room temperature

DIPEA (91 mΐ, 0.522 mmol) was added dropwise and the reaction was monitored towards completion of HATU-activation of the acid. After 2 h 2-(aminooxy)ethan-l-ol (30.2 mg, 0.395 mmol) was added to the reaction mixture and it was stirred at room temperature for 45 min. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (4 * 20 mL). The combined organic phase was washed with brine (2 * 20 mL), dried over Na2SC>4, and concentrated in vacuo. The crude was purified by preparative HPLC to give the product (55.2 mg, 48%) as a yellow solid m/z 443.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-cfo): d ppm 12.29 (br s, 1H), 10.73 (s, 1H), 8.16 (d, .7=7.8 Hz, 1H), 8.14 (t, .7=8.5 Hz, 1H), 7.71 (dd, .7=10.7, 2.0 Hz, 1H), 7.60 (dt, .7=8.6, 1.3 Hz, 1H), 7.55 (d, 7= 7.8 Hz, 1H), 4.79 (br s, 1H), 4.00 (t, 7=4.8 Hz, 2H), 3.66 (t, 7=4.9 Hz, 2H).

Example 57: Methyl 6-cyano-5-fluoro-2-((2-fluoro-4-iodophenyl)amino)nicotinate

Step 1 : 6-Chloro-5-fluoro-2-(f2-fluoro-4-(trimethylsilyl)phenyl)amino)nicotinic acid

[0687] A solution of 2-fluoro-4-(trimethylsilyl)aniline (8.4 g, 45.7 mmol) in dry THF (34 mL) stirred at -78°C was treated with LiHMDS (1M in THF, 91.2 mL, 91.2 mmol). The reaction mixture was stirred for 1 h at -78°C and then a solution of 2,6-dichloro-5-fluoroisonicotinic acid (8 g, 38 mmol) in dry THF (30 mL). The reaction mixture was stirred at -78°C for 1 h, then gradually warmed up to room temperature and stirred for 1 h. The reaction mixture was cooled down to 0°C and was quenched with a saturated NH4CI aqueous solution, then diluted with EtOAc (200 mL), acidified with 1M HC1 to pH 3, partitioned and the aqueous phase was extracted with EtOAc (2 x 100 mL). The organic phase was washed with brine (100 mL), dried over Na₂S0₄ and concentrated in vacuo. The crude material was purified by trituration with methanol to the product (7.5 g, 55%) as a yellow solid m/z 357.0/359.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-7₆) d ppm 10.69 (s, 1H), 8.36 (t, 7=8.0 Hz, 1H), 8.28 (d, 7=8.5 Hz, 1H), 7.41 - 7.32 (m, 2H), 0.25 (s, 9H). Step 2: Methyl 6-chloro-5-fluoro-2-((2-fluoro-4-(trimethylsilyl)phenyl)amino)nicotinate

[0688] A suspension of 6-chloro-5-fluoro-2-((2-fluoro-4-(trimethylsilyl)phenyl)amino) nicotinic acid (2.4 g, 6.726 mmol) and DMF (0.32 mL) in DCM (32 mL) stirred at 0°C was treated with oxalyl chloride (2.85 mL, 33.63 mmol), then stirred at reflux for 1 h. The reaction mixture was concentrated in vacuo, azeotroped with toluene (3 x 25 mL) and then the residue was treated with ice-cold methanol (32 mL). The resulted suspension was stirred at reflux. After 2 h the reaction mixture was cooled down and formed precipitate was filtered under reduced pressure. The collected precipitate was washed with ice-cold methanol (3 x 5 mL) and dried in vacuo to give the product (2.18 g, 88%) as a yellow solid m/z 371.1/373.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-7₆) d ppm 10.33 (d, 7=3.0 Hz, 1H), 8.37 - 8.25 (m, 2H), 7.44 - 7.33 (m, 2H), 3.92 (s, 3H), 0.26 (s, 9H).

Step 3: Methyl 6-cvano-5-fluoro-2-((2-fluoro-4-(trimethylsilyl)phenyl)amino)nicotinate

[0689] A degassed solution of methyl 6-chloro-5-fluoro-2-((2-fluoro-4-

(trimethylsilyl)phenyl)amino)nicotinate (0.5 g, 1.35 mmol), zinc cyanide (0.14 g, 1.215 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol) in NMP (4 mL) was heated in a microwave oven at 150°C for 15 min. The reaction mixture was filtered, diluted with EtOAc (20 mL), washed with a saturated NaHCCL aqueous solution (20 mL) and partitioned. The aqueous phase was extracted with EtOAc (3 x 10 mL) and the combined organic phase was washed with H2O (20 mL), brine (20 mL), dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-15% EtOAc in hexanes) to give the product (0.425 g, 87%) as a yellow solid m/z 362.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-cfe) d ppm 10.29 (d, 7=2.8 Hz, 1H), 8.51 (d, 7=8.7 Hz, 1H), 8.28 (t, 7=8.0 Hz, 1H), 7.46 - 7.37 (m, 2H), 3.96 (s, 3H), 0.27 (s, 9H).

Step 4: Methyl 6-cyano-5-fluoro-2-((2-fluoro-4-iodophenyl)ainino)nicotinate

[0690] A suspension of silver tetrafluoroborate (0.69 g, 3.531 mmol) in DCM (4.2 mL) was stirred at - 50°C for 10 min in the dark, then a solution of methyl 6-cyano-5-fluoro-2-((2-fluoro- 4-(trimethylsilyl)phenyl)-amino)nicotinate (0.425 g, 1.177 mmol) in DCM (8.5 mL) was added dropwise. After 30 min the reaction mixture was treated with iodine monochloride (0.21 g,

1.295 mmol) in DCM (2.5 mL). The reaction mixture was stirred for 30 min and an additional portion of iodine monochloride (0.21 g, 1.295 mmol) in DCM (2.5 mL) was added. After 30 min the reaction mixture was quenched with a saturated Na2S2C>3 aqueous solution (10 mL), extracted with EtOAc (3 * 25 mL), the organic phase was washed with brine (25 mL), dried over Na2SC>4 and the solvent was removed in vacuo to give the product (0.36 g, 76%) as a yellow solid m/z 416.4 [M+H]⁺ . Ή NMR (400 MHz, DMSO-<fc): d ppm 10.22 (s, 1H), 8.50 (d, .7=8.8 Hz, 1H), 8.05 (t, J= 8.6 Hz, 1H), 7.76 (dd, .7=10.6, 2.0 Hz, 1H), 7.66 - 7.60 (m, 1H), 3.95 (s, 3H).

Example 58: 6-Cyano-5-fluoro-2-((2-fluoro-4-iodophenyl)amino)nicotinic acid

[0691] To a suspension of methyl 6-cyano-5-fluoro-2-((2-fluoro-4- iodophenyl)amino)nicotinate (0.36 g, 0.898 mmol) in THF (2.7 mL), MeOH (0.9 mL) and ¾0 (1.8 mL) stirred at room temperature was treated with 1M LiOH aqueous solution (0.9 mL, 0.898 mmol). After 30 min the reaction mixture was concentrated in vacuo, the residue was partitioned between EtOAc (10 mL) and H2O (10 mL). The aqueous phase was acidified to pH 3 with 1M HC1 aqueous solution and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na₂S0₄ and concentrated in vacuo to give the product (0.30 g, 86%) as a brown solid m/z 400.0 [M-H] . 'H NMR (400 MHz, DMSO-i¾): d ppm 10.70 (s, 1H), 8.43 (d, .7=8.7 Hz, 1H), 8.13 (t, .7=8.7 Hz, 1H), 7.72 (dd, .7=10.7, 1.9 Hz, 1H), 7.61 (dt, = 8.6, 1.6 Hz, 1H).

Example 59: tert- Butyl 2-((2-fluoro-4-iodophenyl)amino)-l-methyl-l//-pyrrolo[2,3- b\ pyridine-3-carboxylate

Alternative A for Preparation of l -Methyl-177-pyrrolor2.3-Zflpyridine-3-carboxylic acid

Step 1 of Alternative A: l-Methyl-177-nyrrolor2.3-blpyridine-3-carbonitrile

[0692] A solution of 7-azaindole-3-carbonitrile (9.0 g, 62.8 mmol) in dry DMF (80 mL) was cooled to 0 °C in an ice bath and treated with sodium hydride (5.0 g, 125.7 mmol, 60% in mineral oil) in a portion-wise manner. The resulting mixture was stirred for 45 min at 0 °C, then treated with iodomethane (7.8 mL, 125.7 mmol) and gradually warmed up to a room temperature over 1 h. The mixture was then cautiously poured into H2O (450 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed sequentially with water (3 x 50 mL) and brine, dried over Na2SC>₄, filtered, and concentrated in vacuo. The crude was purified by flash column chromatography (Silica 120 g, 10-50% EtOAC in hexane) to give the product (7.3 g, 74%) as an off-white solid. UPLC-MS (Acidic Method, 4 min): rt 2.30 min, m/z 158.2

[M+H]⁺. Ή NMR (400 MHz, CDCI3): d ppm 8.48 (dd, J = 4.7, 1.5 Hz, 1H), 8.09 (dd, J = 7.9, 1.6 Hz, 1H), 7.75 (s, 1H), 7.25-7.30 (m, 1H), 3.98 (s, 3H).

Step 2 of Alternative A: 1 -Methyl- rrolor2,3-61pyridine-3-carboxylic acid

[0693] A suspension of l -methyl-l//-pyrrolo[2,3-/i]pyridine-3-carbonitrile (7.3 g, 46.5 mmol) in concentrated hydrochloric acid (12 M, 73 mL, 876 mmol) was heated at 100°C with stirring for 10 h, resulting in a clear solution. The reaction mixture was then cooled to 5°C (ice bath) and cautiously treated with 40% NaOH aqueous solution until the pH reached 2 leading to a formation of a white precipitate. The resulting mixture was stirred for 1 h, filtered, and the solid was washed with H2O until the filtrate became pH neutral before being dried in vacuo to give the product (6.9 g, 84%) as a white solid. UPLC-MS (Basic Method, 2 min): rt 0.17 min, m/z 175.2 [M+H]⁺. Ή NMR (400 MHz, DMSO-rfe): d ppm 8.28 -8.37 (m, 2H), 8.22 (s, 1 H), 7.25 {Ad, J = 7.8, 4.7 Hz, 1H), 3.86 (s, 3H).

Alternative B for Preparation of l-Methyl-l/ -pyrrolor2.3-61pyridine-3-carboxylic acid

Step 1 of Alternative B: 1 -methyl-

[0694] To a suspension of sodium hydride, 60% dispersion in mineral oil (36.5 g, 914 mmol), in anhydrous DMF (300 mL) cooled in an ice bath was added a solution of 7-azaindole (90.0 g, 762 mmol) in DMF (200 mL) via addition funnel over 3 h. The reaction mixture was stirred for 30 minutes and cooled in an ice bath before methyl iodide (52 mL, 838 mmol) was added via dropping funnel over 30 minutes. After stirring the reaction mixture at r.t. over the weekend, UPLC analysis showed the reaction was incomplete. Additional methyl iodide (5 mL, 80.3 mmol) was added and the reaction monitored by UPLC until completion. The reaction mixture was cooled in an ice bath and quenched with H2O, extracted into EtOAc (3 x 800 mL) and the combined organic layers were washed with brine, dried over Na2SC>4, and the solvent removed in vacuo to give the desired product (130.7 g (89.4 g, 89% active compound)) as a dark brown biphasic oil. UPLC-MS (Acidic Method, 2 min): rt 0.75 min, m/z 133.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-i/e) d ppm 8.25 (dd, .7 = 4.6, 1.5 Hz, 1H), 7.94 (dd, = 7.8, 1.5 Hz, 1H), 7.50 (d , J = 3.4 Hz, 1H), 7.07 (dd, J = 7.8, 4.7 Hz, 1H), 6.45 (d, J = 3.4 Hz, 1H), 3.82 (s, 3H).

Ste^p 2 of Alternative B: 2.2.2-trifluoro- rrolor2.3-61pyridin-3-yl)ethanone

[0695] To a solution of l-methyl-l//-pyrrolo[2,3-/>]pyridine (89.4 g, 676 mmol) in DMF (450 mL) cooled in an ice bath, was added TFAA (141 mL, 1.01 mol) dropwise via addition funnel 3 h. The reaction was stirred at r.t. overnight before dilution with FhO (1 L) over 1 h. Addition of H2O resulted in precipitate formation, which was stirred for 30 minutes before filtration. The solid was washed with H2O and dried to give the desired product (121 g, 79%) as a white solid. UPLC-MS (Acidic Method, 2 min): rt 1.05 min, m/z 229.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-r e) d ppm: 8.80 (d , J = 1.5 Hz, 1H), 8.52 (q, J= 1.5 Hz, 1H), 8.50 (s, 1H), 7.40 - 7.49 (m, 1H), 3.97 (s, 3H); ^{l 9}F NMR (376 MHz, DMSO-< ) d ppm: -71 .6 (s, I F).

Step 3 of Alternative B: l-methyl- pyrrolor2.3-61pyridine-3-carboxylic acid

[0696] To a flask containing solid 2,2,2-trifluoro-l-(l-methyl-l//-pyrrolo[2,3-6]pyridine-3- yl)ethenone (89.9 g, 394 mmol) was added 5 M NaOH (788 mL, 3.94 mol), the resultant mixture was heated to 50 °C overnight. The reaction mixture was diluted by 50% with H2O and washed with TBME (800 mL). The resultant aqueous layer was acidified to pH 1 with concentrated HC1 (330 mL), resulting in formation of a white precipitate. The precipitate was filtered, washed with H2O (1.2 L) and dried under vacuum at 40 °C, to a constant weight giving the desired product (69.9 g, 99%) as a white solid. UPLC-MS (Basic Method, 2 min): rt 0.17 min, m/z 175.2 [M+H . Ή NMR (400 MHz, DMSO-<¾) d ppm 8.28 -8.37 (m, 2H), 8.22 (s, 1H), 7.25 (dd, J = 7.8, 4.7 Hz, 1H), 3.86 (s, 3H

Alternative 1 for the Preparation of /ert-Butyl l -methyl-l//-pyrrolor2.3-61pyridine-3-carboxylate

[0697] To a suspension of l-methyl-l//-pyrrolo[2,3-6]pyridine-3-carboxylic acid (10.0 g, 56.8 mmol), prepared as described above in Alternative A or B, in anhydrous DCM (390 mL) cooled on ice, oxalyl chloride (14.4 mL, 170.4 mmol) was added dropwise over 15 min and the mixture was stirred at room temperature for 2 h. The mixture was then concentrated in vacuo to give a yellow solid, which was treated with ZerZ-butanol (300 mL, 3.14 mol), followed by an addition of potassium te/7-butoxide (10.2 g, 91 mmol). The resulting mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude was purified by flash column chromatography (Silica 120 g, 0-10% MeOH in DCM) to give the product (12.6 g, 86%) as a light brown solid. UPLC-MS (Acidic Method, 2 min): rt 1.10 min, m/z 233.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-rfe) d ppm 8.35 (dd, ,7 = 4.6, 1.6 Hz, 1H), 8.27 (dd, J= 7.8, 1.6 Hz, 1H), 8.20 (s, 1H), 7.27 (dd, J = 7.9, 4.6 Hz, 1H), 3.86 (s, 3H), 1.56 (s, 9H).

Alternative 2 for the Preparation of tert-Butyl l -methyl-17/-pyrrolor2.3-61pyridine-3-carboxylate

[0698] 1 -Methyl- l/7-pyrrolo[2,3-6]pyridine-3-carboxylic acid (68.7 g, 390 mmol), prepared as described above in Alternative A or B, was added to thionyl chloride (700 mL, 9.67 mol) under stirring at room temperature, and the resulting mixture was stirred overnight. The thionyl chloride was then removed under vacuum to give a thick suspension, which was co-distilled from toluene (3 x 200 mL) to give an off-white solid. This material was subsequently suspended in ZerZ-butanol (500 mL). Solid potassium fe/7-butoxide (70 g, 624 mmol) was added to the suspension in a portion-wise manner, and the resulting mixture was stirred overnight. The solvent was removed under vacuum to give a thick solid, which was partitioned between EtOAc (1.5 L) and a saturated solution of aqueous NaHCCE (1 L). The organic phase was collected and washed with a saturated solution of aqueous NaHCC>3 (1 L), before being dried over Na2SC>4, filtered and evaporated to dryness to give the desired product (66.7 g, 74%) as a green solid. /ert-Butyl 2-chloro-l-methyl-l/ -pyrrolor2.3-blpyridine-3-carboxylate

[0699] A solution of tert- butyl 1 -methyl- l//-pyrrolo[2,3-b]pyridine-3-carboxylate (4.8 g, 21.0 mmol) in dry THF (90 mL), prepared as described in Alternative 1 or Alternative 2 above, was flushed with N2, cooled to -78°C and then treated with a solution of LDA (2 M in THF, 21 mL, 42 mmol). The mixture was stirred at -78 °C for 0.5 h. A solution of hexachloroethane (9.9 g, 42.0 mmol) in dry THF (30 mL) was added and the mixture was gradually warmed up to a room temperature and stirred for 1.5 h. The mixture was treated with saturated NH4CI aqueous solution and extracted with EtOAc (3 ^c 50 mL). The combined organic phases were dried over Na₂S0₄, filtered and concentrated in vacuo. The crude was purified by flash column chromatography (Silica 80 g, 0-12% EtOAc in hexanes) to give the product (4.5 g, 81 %) as a pale-yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.21 min, m/z 267.1/269.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-c/e) d ppm 8.37 (dd, 7 = 4.8, 1.6 Hz, 1H), 8.27 (dd, 7= 7.9, 1.6 Hz, 1H), 7.32 (dd, 7= 7.9, 4.7 Hz, 1H), 3.83 (s, 3H), 1.58 (s, 9H)

/er/-Butyl 2-(Y2-fluoro-4-iodophenvPamino~)-l-methyl- pyrrolor2.3-b1pyridine-3-carboxylate

[0700] A suspension of tert- butyl 2-chloro-l -methyl-l//-pyrrolo[2,3-/>]pyridine-3-carboxylate (1.0 g, 3.8 mmol) and 2-fluoro-4-iodoaniline (0.8 g, 3.6 mmol) in dry THF (20 mL) was flushed with N2, cooled to -78 °C and treated with a solution of LiHMDS (1 M in THF, 7.5 mL, 7.5 mmol). The mixture was gradually warmed up to room temperature and stirred for 3 h. The mixture was quenched with saturated NH4CI aqueous solution and then extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na₂S0₄, filtered, and concentrated in vacuo. The crude was purified by flash column chromatography (Silica 40 g, 0-12% EtOAc in hexanes) to give the product (1.5 g, 87%) as a yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.42 min, m/z 468.1 [M+H]⁺. Ή NMR (400 MHz, DMSO-i/e) d ppm 8.57 (s, 1H), 8.24 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (dd, J= 7.8, 1.6 Hz, 1H), 7.63 (dd, J = 10.8, 2.0 Hz, 1H), 7.37 (dt, J = 8.5, 0.9 Hz, 1H), 7.23 (dd, J = 7.8, 4.8 Hz, 1H), 6.68 (t, J = 8.8 Hz, 1H), 3.55 (s, 3H), 1.41 (s, 9 H)

Example 60: 2-((2-Fluoro-4-iodophenyl)amino)-lV-(2-hydroxyethoxy)-l-methyl-l/T- pyrrolo[2,3-6]pyridine-3-carboxamide

2-(T2-Fluoro-4-iodophenyl^')amino)-l-methyl- pyrrolor2.3-61pyridine-3-carbonyl chloride

[0701] To tert- butyl 2-((2-fluoro-4-iodophenyl)amino)-l -methyl- l//-pyrrolo[2,3-6]pyridine-3- carboxylate (0.6 g, 1.3 mmol), thionyl chloride (0.9 mL, 12.8 mmol) was added followed by H2O (23 pL). The flask was sealed with a rubber septum and the mixture was stirred at room temperature for 18 h. The mixture was concentrated to dryness in vacuo to give the product (0.5 g, 94%) as a beige solid. UPLC-MS (Acidic Method, 2 min): rt 1.28 min, m/z 426.0 [M+H]⁺ (detected as the corresponding methyl ester after quenching an aliquot of the mixture with MeOH).

[0702] Alternative preparation: A stirred solution of ie/7-butyl 2-((2-fluoro-4- iodophenyl)amino)-l -methyl-l//-pyrrolo[2,3-6]pyridine-3-carboxylate (5.00 g, 10.7 mmol) in anhydrous 1 ,4-dioxane (28 mL) was treated with thionyl chloride (7.7 mL, 107 mmol) at ambient temperature, followed by a 4 N solution of hydrogen chloride in 1 ,4-dioxane (14 mL, 5.35 mmol), and the resulting mixture was heated to 50 °C for 48 h. The reaction mixture was cooled to 40 °C and subjected to a continuous distillation process under vacuum from anhydrous toluene (maintaining the total volume of the batch around 30 mL) to remove the thionyl chloride and 1 ,4- dioxane. The resulting dark grey suspension of 2-((2-fluoro-4-iodophenyl)amino)-l -methyl- 177- pyrrolo[2,3-Z>]pyridine-3-carbonyl chloride was used in subsequent steps without further purification. UPLC-MS (Acidic Method, 2 min): rt 1.29 min, m/z 426.0 [M+H]+ (following the quenching of an aliquot of the batch into methanol to give the corresponding methyl ester). Altemtaive 1 for the preparation of 2-((2-Fluoro-4-iodophenyl)amino)-7V-(2-hvdroxyethoxy)-l - methyl-177-pyrrolor2.3-61pyridine-3-carboxamide

[0703] A solution of 2-((2-fluoro-4-iodophenyl)amino)-l-methyl-l//-pyrrolo[2,3-6]pyridine-3- carbonyl chloride (460 mg, 1.07 mmol) in dry DCM (27 mL) was cooled to 0°C in an ice bath and then treated with dry pyridine (970 pL, 1 1 .98 mmol) and the mixture was stirred for 15 min followed by an addition of (2-aminooxy)ethanol (124 mg, 1.61 mmol) in dry DCM (2 mL). The mixture was stirred for 15 min, then diluted with DCM and acidified with 1 M citric acid aqueous solution to pH 3. The organic phase was washed with H2O, brine, dried over Na2SC>4 and concentrated in vacuo. The crude was purified by preparative HPLC to give the product (181 mg, 36%) as a white solid. UPLC-MS (Acidic Method, 4 min): rt 2.67 min, m/z 471.2

[M+H]⁺ . Ή NMR (400 MHz, DMSO-rfe): d ppm 10.84 (br s, 1 H), 8.69 (br s, 1 H), 8.25 (dd, J = 4.8, 1.4 Hz, 1H), 8.13 (dd, 7 = 7.9, 1.5 Hz, 1H), 7.63 (dd, J= 10.8, 1.9 Hz, 1H), 7.33 (dd, .7 = 8.5, 1.1 Hz, 1H), 7.21 (dd, J = 7.8, 4.8 Hz, 1H), 6.52 (t, .7 = 8.8 Hz, 1H), 4.74 (br s, 1H), 3.79 (t , J = 4.9 Hz, 2H), 3.48 -3.54 (m, 5 H).

Altemtaive 2 for the preparation of 2-((2-Fluoro-4-iodophenyl)amino)-A/-(2-hvdroxyethoxy)-l- methyl- pyrrolor2.3-61pyridine-3-carboxamide

[0704] To a solution of 2-(aminooxy)ethanol (8.41 g, 109 mmol) in anhydrous THF (20 mL) at 0 °C was added a suspension of 2-((2-fluoro-4-iodophenyl)amino)-l -methyl-l//-pyrrolo[2,3- Z>]pyridine-3 -carbonyl chloride (9.37 g, 21.8 mmol) in anhydrous THF (80 mL) and residual toluene via syringe. After 40 minutes UPLC analysis showed complete conversion. The reaction mixture was partitioned between EtOAc (300 mL) and H2O (300 mL), the biphasic mixture was filtered and the organic layer separated. The aqueous layer was extracted with EtOAc (200 mL) and the organics combined, washed with brine, dried over Na₂S0₄ and the solvent removed in vacuo. The crude solid was suspended in EtOAc (40 mL, 4 volumes), stirred over the weekend and filtered to give the desired product (7.45g, 73%) as a dark beige solid which can be recrystallized from anisole. UPLC-MS (Acidic Method, 2 min): rt 1.01 min, m/z 471.2 [M+H]⁺. 'H NMR (400 MHz, DMSO-7₆) d ppm 10.84 (br s, 1H), 8.69 (br s, 1H), 8.25 (dd, = 4.8, 1.4 Hz, 1H), 8.13 (dd, 7 = 7.9, 1.5 Hz, 1H), 7.63 (dd, 7 = 10.8, 1.9 Hz, 1H), 7.33 (dd, 7= 8.5, 1.1 Hz, 1H), 7.21 (dd, 7= 7.8, 4.8 Hz, 1H), 6.52 (t, 7 = 8.8 Hz, 1H), 4.74 (br s, 1H), 3.79 (t, 7= 4.9 Hz, 2H), 3.48 -3.54 (m, 5 H).

Example 61 : 2-((4-Ethynyl-2-fluorophenyl)amino)-./V-(2-hydroxyethoxy)-l-methyl-l /- pyrrolo[2,3-6]pyridine-3-carboxamide

2-((2-Fluoro-4-((trimethylsily0ethvnv0phenv0amino~)- (2-hvdroxyethoxy^,)-l-methyl-

pyrrolol2.3-blpyridine-3-carboxamide

[0705] A solution of 2-((2-fluoro-4-iodopheny l)amino)- V-(2-hydroxyethoxy)- 1 -methyl- 1//- pyrrolo[2,3-6]pyridine-3-carboxamide (100 mg, 0.21 mmol, 71% pure by UPLC-MS), copper(I) iodide (1 mg, 0.004 mmol), PdCh(PPh3)2 (3 mg, 0.004 mmol) in dry THF (0.5 mL) flushed with N2, trimethylsilylacetylene (32 pL, 0.23 mmol) in Et3N (21 pL, 1.49 mmol) was added. The mixture was stirred at room temperature for 3 h. The mixture was diluted with Et₂0, filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The crude was purified by flash column chromatography (Silica 4 g, 20-70% EtOAc in hexanes) to give the product (25 mg, 38%) as a colorless oil. UPLC-MS (Acidic Method, 2 min): rt 1.20 min, m/z 441.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-t/e) d ppm 10.83 (s, 1H), 8.75 (s, 1H), 8.27 (dd, .7 = 4.7, 1.6 Hz, 1H), 8.15 (dd, .7 = 7.9, 1.5 Hz, 1H), 7.51-7.63 (m, 1H), 7.33 (dd, J = 12.1, 1.8 Hz, 1H), 7.22 (dd, J = 7.9, 4.8 Hz, 1H), 7.09 (dd, J = 8.3, 1.6 Hz, 1H), 6.60 (t, /= 8.7 Hz, 1H), 4.70 (t, /= 5.8 Hz, 1H), 3.78 (t, J = 4.9 Hz, 2H), 3.47-3.57 (m, 5 H), 0.19 (s, 9H)

2-(Y4-Ethvnyl-2-fluorophenyl)amino)-./V-(2-hvdroxyethoxy)-l -methyl- rnito1oG2.3-

61pyridine-3-carboxamide

[0706] A solution of 2-((2-fluoro-4-((trimethylsilyl)ethynyl)phenyl)amino)-/V-(2- hydroxyethoxy)-l-methyl-l//-pyrrolo[2,3-/>]pyridine-3-carboxamide (100 mg, 0.23 mmol, 80% pure by UPLC-MS) in MeOH (2.1 mL) was treated with K2CO3 (35 mg, 0.25 mmol). The mixture was stirred for 18 h at room temperature. The mixture was purified by preparative HPLC to give the product (15 mg, 22%) as a white solid. UPLC-MS (Acidic Method, 2 min): rt 0.93 min, m/z 369.1 [M+Hf. Ή NMR (400 MHz, DMSO-*) d ppm 8.25 (br d, J = 3.5 Hz, 1H), 8.14 (d, J= 7.8 Hz, 1H), 7.35 (br d, J = 11.8 Hz, 1H), 7.21 (dd, J = 7.7, 4.8 Hz, 1H), 7.1 1 (dd , J

= 8.3, 1.4 Hz, 1H), 6.63 (t, J= 8.7 Hz, 1H), 4.09 (s, 1H), 3.78 (t, = 4.7 Hz, 2H), 3.37-3.55 (m, 5 H).

Example 62: 2-((2-Fluoro-4-iodophenyl)amino)-7V-hydroxy-l-inethyl-l -pyrrolo[2,3- 6]pyridine-3-carboxamide

Perfluorophenyl 2-(Y2-fluoro-4-iodophenvDamino)-l -methyl- pyrrolor2.3-61pyridine-3-

carboxylate

[0707] A solution of 2-((2-fluoro-4-iodophenyl)amino)-l-methyl-l//-pyrrolo[2,3-6]pyridine-3- carbonyl chloride (0.9 g, 2.1 mmol) in dry DCM (50 mL) was cooled to 0 °C in an ice bath and then treated with Et3N (0.8 mL, 5.4 mmol) and pentafluorophenol (0.6 g, 3.2 mmol) and stirred for 1 h. The mixture was diluted with 1 : 1 DCM/thO solution. The organic phase was washed with brine, dried over Na₂S0₄, and concentrated in vacuo to give the product (1.56 g, quantitative) that was used in the next step without further purification. UPLC-MS (Acidic Method, 2 min): rt 1.43 min, m/z 577.8 [M+H]⁺. Ή NMR (400 MHz, DMSCWe) d ppm 9.13 (s, 1H), 8.29 (dd, = 4.8, 1.6 Hz, 1H), 8.13-8.17 (m, 1H), 7.59-7.64 (m, 1H), 7.42 (dt, J= 8.4, 1.0 Hz, 1H), 7.20-7.31 (m, 1H), 6.95 (t, J= 8.7 Hz, 1H), 3.65 (s, 3H).

2-((2-Fluoro-4-iodophenyl)amino)-A/-hvdroxy- 1 -methyl- lH-pyrrolof 2 ,3 -blpyridine-3 - carboxamide

[0708] A suspension of perfluorophenyl 2-((2-fluoro-4-iodophenyl)amino)-l-methyl-l//- pyrrolo[2,3-6]-pyridine-3-carboxylate (400 mg, 0.69 mmol, 85% pure by UPLC-MS) in dry DMF (2.4 mL) was treated with hydroxylamine hydrochloride (58 mg, 0.83 mmol) and DIPEA (43 pL, 2.43 mmol). The mixture was stirred for lh at room temperature. The mixture was concentrated in vacuo, then the residue was diluted with 1 : 1 EtOAc/H₂0 solution. The organic phase was washed with water, brine, dried over Na SCL, and concentrated in vacuo. The crude was purified by preparative HPLC to give the product (104 mg, 39%) as an off-white solid. UPLC-MS (Acidic Method, 2 min): rt 1.03 min, m/z 427.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-fife) d ppm 10.34 (br s, 1H), 8.83 (br s, 1H), 8.72 (br s, 1H), 8.26 (dd, 7 = 4.8, 1.5 Hz, 1H), 8.18 (dd, J = 7.8, 1.6 Hz, 1H), 7.64 (dd, 7 = 10.8, 2.0 Hz, 1H), 7.34 (dt, 7= 8.4, 0.9 Hz, 1H), 7.21 (dd, 7 = 7.9, 4.8 Hz, 1H), 6.45 (t, 7= 8.9 Hz, 1H), 3.52 (s, 3H).

Example 63: ( ?)-./V-(2,3-Dihydroxypropoxy)-2-((2-fluoro-4-iodophenyl)aniino)-l-methyl- l/f-pyrrolo[2,3-6]pyridine-3-carboxamide

(7?~)-2-((2.2-Dimethyl-L3-dioxolan-4-yl)methoxy)isoindoline-1.3-dione

[0709] To a suspension ofTV-hydroxyphthalimide (6.6 g, 40.5 mmol) in THF (135 mL) at 0 °C was added triphenylphosphine (10.6 g, 40.5 mmol) and (S)-(2,2-dimethyl-[l ,3]dioxolan-4-yl)- methanol (5 mL, 40.5 mmol). Diisopropyl azodicarboxylate (10.3 mL, 52.7 mmol) was added dropwise whilst keeping the internal temperature below 15 °C. Upon completion of the addition, the mixture was warmed to room temperature and stirred under N2 for 2 h. The solvent was removed in vacuo and the residue was diluted with DCM (50 mL). The resulting precipitate was filtered and the filtrate was concentrated in vacuo. The crude was purified by flash column chromatography (Silica 340 g, 10-100% EtOAc in hexane) to give the product (11.1 g, 99%) as a white solid. UPLC-MS (Acidic Method, 2 min): rt 1.06 min, m/z 278.1 [M+H]⁺. 'H NMR (400 MHz, CDCb) d ppm 7.85-7.82 (m, 2H), 7.76-7.75 (m, 2H), 4.52-4.46 (m, 1H), 4.31 (dd, 7 =

10.0, 5.5 Hz, 1H), 4.17 (dd, 7 = 8.5, 6.0 Hz, 1H), 4.13 (dd, 7 = 10.0, 6.0 Hz, 1H), 3.96 (dd, 7 = 8.5, 5.5 Hz, 1H), 1.39 (s, 3H), 1.33 (s, 3H). -0-(^'(^'2.2-Dimethyl-1.3-dioxolan-4-vDmethvDhvdroxylamine

[0710] To a suspension of (R)-2-((2, 2-dimethyl- l ,3-dioxolan-4-yl)methoxy)isoindoline- 1 ,3- dione (3.0 g, 10.8 mmol) in DCM (22 mL) at 0°C was added methyl hydrazine (0.62 mL, 1 1.9 mmol) drop wise. The resultant mixture was warmed to room temperature and stirred under N2 for lh. The solvent was removed in vacuo and the residue was diluted with diethyl ether (20 mL). The mixture was stirred for 0.5 h before filtering and washing with diethyl ether (2 ^c 20 mL). The filtrate was concentrated to dryness in vacuo to give the product (0.85 g, 46%) as a pale-yellow oil. Ή NMR (400 MHz, CDCI3) d ppm 5.00-4.94 (m, 1H), 4.38-4.32 (m, 1H), 4.06 (dd, J = 8.5, 6.5 Hz, 1H), 3.74 (dd, J = 6.0, 5.0 Hz, 1H), 3.69 (dd, J = 8.5, 6.5 Hz, 1H), 1.43 (s, 3H), 1.37 (s, 3H).

(Y2.2-Dimethyl- 1.3 -dioxolan-4-vnmethoxy~)-2-(^'(^'2-fluoro-4-iodophenyl~)amino)- 1 -methyl- rrolor2.3-61pyridine-3-carboxamide

[0711] To a solution of perfluorophenyl 2-((2-fluoro-4-iodophenyl)amino)-l-methyl-l//- pyrrolo[2,3— 6]pyridine-3-carboxylate, prepared as described in Example 4, (390 mg, 0.676 mmol) in DMF (2 mL) was added a solution of (/?)-0-((2,2-dimethyl-l ,3-dioxolan-4- yl)methyl)hydroxylamine (149 mg, 1.010 mmol) in DMF (0.5 mL) and DIPEA (24 pL, 1.350 mmol). The resultant mixture was stirred at room temperature under N2 for 18 h. The reaction mixture was diluted with ice-cold H2O (50 mL) and then extracted with EtOAc (2 ^c 25 mL). The combined organic phases were washed with brine (2 ^c 100 mL), dried over Na2SC>4, and concentrated in vacuo to give the product (300 mg, 82%) as a dark red solid that was used in the next step without further purification. UPLC-MS (Acidic Method, 2 min): rt 1.15 min, m/z 541.1 [M+H]⁺. 'H NMR (400 MHz, CDCb) d ppm 8.82 (s, 1 H), 8.75 (s, 1 H), 8.26 (dd, 7 = 5.0, 1.5 Hz, 1H), 7.87 (d, 7 = 7.5 Hz, 1H), 7.50 (dd, 7 = 10.0, 1.5 Hz, 1H), 7.40-7.37 (m, 1H), 7.20 (dd, 7 = 7.5, 5.0 Hz, 1H), 6.66 (app t, 7 = 8.5 Hz, 1H), 5.00-4.95 (m, 1H), 4.51 -4.45 (m, 1H), 4.18-4.05 (m, 2H), 3.85 (dd, 7 = 9.0, 6.5 Hz, 1H), 3.52 (s, 3H), 1.46 (s, 3H), 1.40 (s, 3H)

Example 64: (R)-/V-(2,3-Dihydroxypropoxy)-2-((2-fluoro-4-iodophenyl)amino)-l-methyl- l//-pyrrolo[2,3-6]pyridine-3-carboxamide

[0712] To a solution of (R)-N-((2, 2-dimethyl- 1, 3-dioxolan-4-yl)methoxy)-2-((2-fluoro-4- iodophenyl)amino)-l -methyl-l//-pyrrolo[2,3-6]pyridine-3-carboxamide (220 mg, 0.40 mmol) in MeOH (5 mL) was added ^-toluene sulfonic acid monohydrate (39 mg, 0.20 mmol) and ethylene glycol (13 pL, 2.40 mmol). The resultant mixture was stirred at room temperature under N2 for 0.5h. A few drops of Et3N were added to the reaction mixture and the solvent was removed in vacuo. The crude product was purified by preparatory HPLC to give the product (47 mg, 24%) as an off-white solid. UPLC-MS (Acidic Method, 2 min): rt 0.96 min, m/z 501.0 [M+H]⁺.'H NMR (400 MHz, DMSO-y₆) 5 ppm 10.89 (s, 1 H), 8.71 (s, 1 H), 8.27 (dd, .7 = 5.0, 1.5 Hz, lH), 8.16 (dd, .7 = 7.5, 1.5 Hz, 1H), 7.64 (dd, 7 = 10.5, 1.5 Hz, 1H), 7.37-7.35 (m, 1H), 7.23 (dd, 7 = 7.5, 5.0 Hz, 1H), 6.55 (app t, 7 = 8.5 Hz, 1H), 4.93 (s, 1H), 4.60 (s, 1H), 3.87-3.82 (m, 1H), 3.72-3.66 (m, 2H), 3.54 (s, 3H), 3.39-3.35 (m, 2H). Example 65: /V-(Cyclopropylmethoxy)-2-((2-fluoro-4-iodophenyl)amino)-l-methyl-17f- pyrrolo[2,3-6]pyridine-3-carboxamide

[0713] To a solution of perfluorophenyl 2-((2-fluoro-4-iodophenyl)amino)-l-methyl-l//- pyrrolo[2,3-6]pyridine-3-carboxylate, prepared as described in Example 4, (400 mg, 0.69 mmol) in DMF (2.5 mL) was added a solution of 0-(cyclopropylmethyl)hydroxylamine hydrochloride (100 mg, 0.83 mmol) in DMF (0.5 mL) and DIPEA (24 pL, 1 .35 mmol). The resultant mixture was stirred at room temperature under N2 for 18 h. The reaction mixture was diluted with ice- cold H2O (50 mL) and then extracted with EtOAc (2 * 25 mL). The combined organic phases were washed with brine (2 ^c 100 mL), dried over Na2SC>4, and concentrated in vacuo. The crude product was purified by preparative HPLC (Reach Separations, UK) to give the product (135 mg, 36%) as a white solid. UPLC-MS (Acidic Method, 4 min): rt 1.95 min, m/z 481.0 [M+H]⁺. 'H NMR (400 MHz, CDCI3) d ppm 1 1.42 (s, 1 H), 10.75 (s, 1 H), 8.67 (s, 1 H), 8.25 (dd, J = 5.0, 1.5 Hz, 1H), 8.14 (dd, .7 = 8.0, 1.5 Hz, 1H), 7.63 (dd, 7 = 10.5, 2.0 Hz, 1H), 7.36-7.33 (m, 1H), 7.22 (dd, = 7.5, 5.0 Hz, 1H), 3.56 (d , J= 7.0 Hz, 1H), 3.55 (s, 3H), 1.04-0.97 (m, 1H), 0.50-0.45 (m, 2H), 0.22-0.18 (m, 2H).

Example 66: 2-((2-Fluoro-4-iodophenyl)amino)-/V-(2-hydroxyethoxy)-5-methoxy-l-methyl- 1/7-pyrrolo [2,3-6] pyridine-3-carboxamide

5-Methoxy-l -methyl- pyrroloi2.3-61pyridine

[0714] A solution of 5-methoxy-7-azaindole (5.0 g, 33.7 mmol) in dry DMF (25 mL) was cooled to 0 °C in an ice bath and treated with sodium hydride (1.6 g, 40.5 mmol, 60% in mineral oil) in a portion-wise manner. The resulting mixture was stirred for 1 h at 0 °C, then treated with iodomethane (2.3 mL, 37.1 mmol) and was stirred at 0 °C for 1 h. The mixture was then cautiously poured into H2O (200 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed sequentially with water (3 x 30 mL) and brine, dried over Na2SC>4, filtered, and concentrated under vacuum to give the product (5.8 g, quantitative) as a light-brown solid. UPLC-MS (Acidic Method, 4 min): rt 0.91 min, m/z 161.1 [M+H]⁺. Ή NMR (400 MHz, CDCI3) d ppm 8.12 (d, J= 2.6 Hz, 1H), 7.42 (d, .7=2.8 Hz, 1H), 7.27 (s, 1H), 7.16 (d, .7=3.4 Hz, 1H), 6.37 (d, .7=3.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H).

5-Methoxy-l-methyl- pyrrolor2.3-hlDyridine-3-carboxylic acid

[0715] A solution of 5-methoxy-l-methyl-177-pyrrolo[2,3-h]pyridine (5.5 g, 46.5 mmol) in dry DMF (7 mL) was cooled to 0 °C in an ice bath and treated with trifluoroacetic anhydride (10.6 g, 50.7 mmol). The reaction mixture was then gradually warmed up to room temperature and left stirring for 1 h. The resulting mixture was cooled to 0 °C in an ice bath and treated with water (200 mL) and extracted with DCM (3 x 30 mL). The combined organic phases were dried over

Na₂S0₄, filtered, and concentrated under vacuum. The residue was suspended in 5M NaOH aqueous solution (68 mL) and heated at 50°C for 18 h. The reaction mixture was washed with Et₂0 (1 x 30 mL) and cautiously treated with 1M HC1 aqueous solution until pH = 1 leading to a formation of a beige precipitate. The solid was collected by filtration, washed with H2O until the filtrate became pH neutral, and dried to give the product (5.9 g, 85%) as a beige solid. UPLC- MS (Acidic Method, 2 min): rt 0.80 min, m/z 207.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-ck) d ppm 8.18 (s, 1H), 8.10 (d, .7=2.9 Hz, 1H), 7.81 (d, .7=2.9 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H). tert-Butyl 5-methoxy-l -methyl- pyrroloi2,3-¾lpyridine-3-carboxylate

[0716J To a suspension of 5-methoxy-l -methyl-l -pyrrolo[2,3-6]pyridine-3-carboxylic acid (5.9 g, 28.6 mmol) in anhydrous DCM (200 mL) cooled on ice, oxalyl chloride (7.3 mL, 85.8 mmol) was added dropwise over 15 min and the mixture was stirred at room temperature for 1.5 h. The mixture was then concentrated under vacuum to give a yellow solid, which was cooled on ice, then treated with /erf-butanol (150 mL, 1.6 mol), followed by an addition of potassium fe/7-butoxide (5.1 g, 45.8 mmol). The resulting mixture was gradually warmed up to room temperature and left stirring for 18 h. The reaction mixture was concentrated under vacuum, distributed between EtOAc (50 mL) and H2O (50 mL) and extracted with EtOAc (3 ^c 50 mL). The combined organic phases were dried over Na₂S0₄, filtered, and concentrated under vacuum. The crude material was purified by flash column chromatography (Silica 120 g, 0-3% MeOH in DCM) to give the product (3.9 g, 53%) as a yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.15 min, m/z 263.2 [M+H]⁺. Ή NMR (400 MHz, DMSO-*) d ppm 8.08 - 8.14 (m, 2H), 7.76 - 7.81 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 1.57 (s, 9H).

tert-Butyl 2-chloro-5-methoxy-l -methyl- Dyrrolor2.3-61pyridine-3-carboxylate

[0717] A solution of tert-butyl 5-methoxy-l -methyl-l//-pyrrolo[2,3-6]pyridine-3-carboxylate (2.2 g, 8.6 mmol) in dry THF (36 mL) was flushed with N2, cooled to -78°C and then treated with a solution of LDA (2M in THE, 8.55 mL, 17.1 mmol). The mixture was stirred at -78 °C for 30 min. A solution of hexachloroethane (4.1 g, 17.1 mmol) in dry THF (12 mL) was added and the mixture was gradually warmed up to a room temperature and stirred for 2 h. The mixture was treated with saturated NH4CI aqueous solution and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over Na2S04, filtered and concentrated under vacuum. The crude was purified by flash column chromatography (Silica 120 g, 0-10% EtOAc in hexanes) to give the product (2.4 g, 95%) as a beige solid. UPLC-MS (Acidic Method, 2 min): rt 1.27 min, m/z 297.1/299.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-<¾ d ppm 8.12 (br d, .7=2.6 Hz, 1H), 7.78 (br d, .7=2.5 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 1.59 (s, 9H). Butyl 2-((2-fluoro-4-iodophenyl^’)aminol-5-methoxy-l -methyl- pyrrolor2.3-/ilpyridine-3-

carboxylate

[0718] A suspension of tert-b\xiy\ 2-chloro-5-methoxy-l -methyl-l//-pyrrolo[2,3-b]pyridine-3- carboxylate (2.4 g, 8.1 mmol) and 2-fluoro-4-iodoaniline (1.8 g, 7.7 mmol) in dry THF (44 mL) was flushed with N2, cooled to -78 °C and treated with a solution of LiHMDS (1M in THF, 16.2 mL, 16.2 mmol). The mixture was gradually warmed up to room temperature and stirred for 1.5 h. The mixture was quenched with saturated NH4CI aqueous solution and then extracted with EtOAc (3 x 25 mL). The combined organic phases were dried over Na2SC>4, filtered, and concentrated under vacuum. The crude material was purified by flash column chromatography (Silica 120 g, 0-10% EtOAc in hexanes) to give the product (3.5 g, 91 %) as a pale yellow solid. UPLC-MS (Acidic Method, 4 min): rt 2.59 min, m/z 498.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-A) d ppm 8.56 (s, 1H), 7.98 - 8.03 (m, 1H), 7.74 (d, .7=2.8 Hz, 1H), 7.64 (dd, 7=10.8, 1.9 Hz, 1H), 7.37 (d, 7=8.5 Hz, 1H), 6.65 (t, 7=8.8 Hz, 1H), 3.86 (s, 3H), 3.56 (s, 3H), 1.41 (s, 9H) 2-((2-Fluoro-4-iodoDhenvnaminoV5-methoxy- l -methyl- Dyrrolor2.3-hlpyridine-3 -carbonyl

chloride

[0719] Thionyl chloride (5.1 mL, 69.8 mmol) was added to tert- butyl 2-((2-fluoro-4- iodophenyl)amino)-5-ethoxy-l -methyl-177-pyrrolo[2,3-b]pyridine-3-carboxylate (3.5 g, 7.0 mmol) followed by H2O (130 pL, 7.0 mmol). The flask was sealed with a rubber septum and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated to dryness under vacuum to give the product (3.6 g, 55%) as a beige solid and was used in the next step without further purification. UPLC-MS (Acidic Method, 2 min): rt 1.31 min, m/z 456.0 [M+H]⁺ (detected as the corresponding methyl ester after quenching an aliquot of the mixture with MeOH).

2-((2-Fluoro-4-iodophenyl)aminoVA-(2-hvdroxyethoxy^,)-5-methoxy-l-methyl-

pyrrolor2.3-61pyridine-3-carboxamide

[0720] A solution of 2-((2-fluoro-4-iodophenyl)amino)-5-methoxy-l -methyl-l//-pyrrolo[2,3- 6]pyridine-3-carbonyl chloride (1.0 g, 2.2 mmol) in dry DCM (57 mL) was cooled to 0 °C in an ice bath and then treated with dry pyridine (2 mL, 24.4 mmol) and the mixture was stirred for 5 min followed by an addition of (2-aminooxy)ethanol (0.4 g, 5.4 mmol) in dry DCM (5 mL). The mixture was stirred for 15 min, then concentrated under vacuum. The crude material was purified by preparative HPLC to give the product (85 mg, 13%) as a beige-yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.07 min, m/z 501.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-C&) d ppm 10.79 (s, 1H), 8.70 (br s, 1H), 8.02 (d, .7=2.6 Hz, 1H), 7.75 (d, 7= 2.6 Hz, 1H), 7.64 (dd, 7=10.9,

1.8 Hz, 1H), 7.35 (d, 7=8.6 Hz, 1H), 6.52 (t, 7=8.8 Hz, 1H), 4.75 (br t, 7=5.8 Hz, 1H), 3.80 - 3.89 (m, 5H), 3.48 - 3.56 (m, 5H).

Example 67: (5)-A-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-2-((2-fluoro-4- iodophenyl)amino)-l-methyl-l//-pyrrolo[2,3-Z>]pyridine-3-carboxamide

[0721] A solution of 2-((2-fluoro-4-iodophenyl)amino)-l -methyl-l//-pyrrolo[2,3-b]pyridine-3- carbonyl chloride (937 mg, 2.18 mmol) in dry THF (4 mL) under N2 was cooled in an ice-water bath while stirring. The reaction mixture was treated with a solution of (S)-(+)-(2,2-dimethyl- 1 ,3-dioxolan-4-yl)methanamine (256 mg, 1.95 mmol) and diisopropylethylamine (0.33 mL, 1.95 mmol) in dry THF (5 mL) and stirred for 18 h. Reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (Silica 40 g, 20-80% EtOAc in hexane) to give the product (512 mg, 44.4%) as an off-white solid which was used in subsequent steps without further purification. UPLC-MS (Acidic Method, 2 min): rt 1.10 min, m/z 525.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-7₆) d ppm 8.84 (s, 1 H), 8.34 (dd, 7= 7.9, 1.6 Hz, 1H), 8.29 (dd, 7=4.8, 1.6 Hz, 1H), 7.65 (dd, =10.7, 1.9 Hz, 1H), 7.59 (s, 1H), 7.32 - 7.36 (m, 1H), 7.24 (dd, 7=7.8, 4.8 Hz, 1H), 6.44 (t, 7=8.8 Hz, 1H), 4.05 - 4.10 (m, 1H), 3.86 (dd, 7=8.3, 6.27 Hz, 1H), 3.56 - 3.62 (m, 1H), 3.54 (s, 3H), 3.36 (td, 7=5.8, 2.0 Hz, 2H), 1.26 (s, 3H), 1.22 (s, 3H).

Example 68: (5')-./V-(2,3-dihydroxypropyl)-2-((2-fluoro-4-iodophenyl)amino)-l-methyl-l//- pyrrolo[2,3-6]pyridine-3-carboxamide

[0722] A solution of (5 -A-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-2-((2-fluoro-4- iodophenyl)-amino)-l -methyl- l//-pyrrolo[2,3-6]pyridine-3-carboxamide (512 mg, 0.97 mmol) in 1,4-dioxane (5.1 mL) was treated with 4 N HC1 in 1 ,4-dioxane (0.61 mL, 2.42 mmol) and stirred at room temperature for 72 h. The reaction mixture was concentrated, the residue was re suspended in 1 ,4-dioxane (5.1 mL) with addition of 4 N HC1 in 1 ,4-dioxane (0.61 mL, 2.42 mmol) and stirred for 16 h until completion. The reaction mixture was concentrated and the crude residue was purified by preparatory HPLC to give the product (172 mg, 36.6%) as a flocculant white solid. UPLC -MS (Acidic Method, 2 min): rt 0.89 min, m/z 485.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-rfe) d ppm 8.89 (s, 1 H), 8.33 (dd, 7=7.9, 1.5 Hz, 1H), 8.29 (dd, 7=4.8, 1.5 Hz, 1H), 7.65 (dd, 7=10.7, 1.9 Hz, 1H), 7.52 (t, 7=5.5 Hz, 1H), 7.35 (d, 7=8.6 Hz, 1H), 7.24 (dd, 7=7.9, 4.8 Hz, 1H), 6.46 (t, 7=8.8 Hz, 1H), 4.79 (d, 7= 4.8 Hz, 1H), 4.57 (t, 7= 5.8 Hz, 1H), 3.52 (m, 4H), 3.39 (m, 1H), 3.15 - 3.31 (m, 3H).

Example 69: ((/?)-7V-((2,2-dimethyI-l,3-dioxolan-4-yl)methyl)-2-((2-fluoro-4- iodophenyl)amino)-l-methyl-l -pyrrolo[2,3-6]pyridine-3-carboxamide

[0723] A solution of 2-((2-fluoro-4-iodophenyl)amino)-l-methyl-l//-pyrrolo[2,3-/>]pyridine-3- carbonyl chloride (937 mg, 2.18 mmol) in dry THF (4 mL) under N2 was cooled in an ice-water bath while stirring. The reaction mixture was treated with a solution of (R)-(-)-(2,2-dimethyl- l ,3-dioxolan-4-yl)methanamine (256 mg, 1.95 mmol) and diisopropylethylamine (0.33 mL, 1.95 mmol) in dry THF (5 mL) and stirred for 18 h. Reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (Silica 40 g, 20-80% EtOAc in hexane) to give the product (442 mg, 38.5%) as an off-white solid which was used in subsequent steps without further purification. UPLC -MS (Acidic Method, 2 min): rt 1.10 min, m/z 525.0

[M+Hj⁺. Ή NMR (400 MHz, DMSO-cfe) d ppm 8.83 (s, 1H), 8.32 - 8.36 (m, 1H), 8.27 - 8.32 (m, 1H), 7.62 - 7.68 (m, 1H), 7.55 - 7.62 (m, 1H), 7.31 - 7.37 (m, 1H), 7.21 - 7.27 (m, 1H), 6.40 - 6.47 (m, 1H), 4.05 - 4.09 (m, 1H), 3.84 - 3.89 (m, 1H), 3.57 - 3.62 (m, 1H), 3.54 (s, 3H), 3.37 - 3.38 (m, 2H), 1.26 (s, 3H), 1.22 (s, 3H). Example 70: (/?)-7V-(2,3-dihydroxypropyl)-2-((2-fliioro-4-iodophenyI)amino)-l-methyl-l//- pyrrolo[2,3-6]pyridine-3-carboxamide

[0724] A solution of (7?)-/V-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-2-((2-fluoro-4- iodophenyl)-amino)-l -methyl-l -pyrrolo[2,3-6]pyridine-3-carboxamide (442 mg, 0.84 mmol) in 1 ,4-dioxane (4.4 mL) was treated with 4 N HC1 in 1 ,4-dioxane (0.52 mL, 2.1 mmol) and stirred at room temperature for 72 h. The reaction mixture was concentrated, the residue was re suspended in 1 ,4-dioxane (4.4 mL) with addition of 4 N HC1 in 1 ,4-dioxane (0.52 mL, 2.1 mmol) and stirred for 16 h until completion. The reaction mixture was concentrated and the crude residue was purified by preparatory HPLC to give the product (156 mg, 38%) as a flocculant white solid. UPLC-MS (Acidic Method, 2 min): rt 0.89 min, m/z 485.0 [M+H]⁺. 'H NMR: (400 MHz, DMSO-cfe) d ppm 8.89 (s, 1 H), 8.33 (dd, 7=7.9, 1.5 Hz, 1H), 8.29 (dd, 7=4.8, 1.5 Hz, 1H), 7.64 (dd, .7=10.8, 1.9 Hz, 1H), 7.48 - 7.56 (m, 1H), 7.35 (dd, 7=8.5, 1.1 Hz, 1H), 7.24 (dd, 7=7.8, 4.8 Hz, 1H), 6.46 (t, 7=8.8 Hz, 1H), 4.79 (d, 7=4.8 Hz, 1H), 4.57 (t, 7=5.8 Hz, 1H), 3.50 - 3.57 (m, 4H), 3.41 (dt, 7=13.2, 5.6 Hz, 1H), 3.14 - 3.31 (m, 3H).

Example 71: 2-(2-Fluoro-4-iodoanilino)-l-methyl-l/f-pyrroIo[2,3-Z>]pyridine-3- carboxamide

[0725] A suspension of 2-((2-fluoro-4-iodophenyl)amino)-l-methyl-l/ -pyrrolo[2,3- Z?]pyridine-3-carbonyl chloride (0.50 g, 1.16 mmol) in 1,4-dioxane (2.3 mL) was stirred under N2 on an ice/water bath and 0.5 M NH3 in 1,4-dioxane (2.7 mL, 1.33 mmol) was added dropwise over 5 min. An additional portion of 1 ,4-dioxane (2.3 mL) was added and the reaction mixture was stirred for the next 18 h while warming up to room temperature. Then the reaction mixture was concentrated to dryness in vacuo and the crude was purified by flash column

chromatography (Silica 20 g, 20-100% EtOAC in hexane) to give the product (39.1 mg, 9%) as an off-white solid. UPLC-MS (Acidic Method, 2 min): rt 0.97 min, m/z 411.0 [M+H]⁺.

Ή NMR (400 MHz, DMSC s) d ppm 9.07 (s, 1 H), 8.34 (dd, J = 7.9, 1.5 Hz, 1H), 8.27 (dd , J = 4.8, 1.5 Hz, 1H), 7.67 (dd , J= 10.7, 1.9 Hz, 1H), 7.38 (dd, 7 = 8.4, 1.1 Hz, 1H), 7.22 (dd, 7 = 7.9, 4.8 Hz, 1H), 7.13 (br s, 2H), 6.52 (t, 7 = 8.8 Hz, 1H), 3.50 (s, 3H).

Example 72: 2-((4-ethynyl-2-fluorophenyl)amino)-N-(2-hydroxyethoxy)thieno[2,3- b] pyridine-3-carboxamide

Step 1 : 2-fluoro-4-iodo-l-isothiocvanatobenzene

[0726] Thiophosgene (8.0 g, 69.6 mmol) was added to a rapidly stirred mixture of 2-fluoro-4- iodoaniline (15.00 g, 63.3 mmol) in dichloromethane (200 mL) and water (150 mL). The reaction mixture was stirred at room temperature overnight. The organic phase was separated, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and filtered. The solvents were removed under vacuum to give the title compound as a beige colored solid ( 17.1 g, 96.8%). 'HNMR (300 MHz, DMSO-d6): d 7.87 (dd, J=1.8Hz and 1.8Hz, 1H), 7.60 (d, J=8.1Hz, 1H), 7.24 (t, J=8.3Hz, 1H).

Step 2: 2-(2-chloropyridin-3-yl)acetic acid

[0727] A solution of 15% w/w sodium hydroxide (150 mL) was added to 2-(2-chloropyridin-3- yl)acetonitrile (10.0 g, 62.3 mmol). The mixture was heated at reflux for 1 hour then cooled to room temperature. The mixture was further cooled to 0~5 °C and then acidified with con. HC1 (~60 mL) to pH 1. The suspension was left to stand for 1 hour in an ice bath. The precipitate formed was collected by filtration and washed with cold water, then cold 2-propanol (100 mL x 2). The solid was dried in a vacuo to get the title compound as an off-white solid (10.6 g, 99%). 'HNMR (300 MHz, d⁶-DMSO): d 12.63 (s, 1 H), 8.32 (dd, J = 4.8 and 1.9 Hz, 1 H), 7.86 (dd, J = 7.6 and 1.9 Hz, 1H), 7.41 (dd, J = 7.5 and 4.5 Hz, 1H), 3.75 (s, 2H).

Step 3: 2-((2-fluoro-4-iodophenvDaminolthienor2,3-blpyridine-3-carboxylic acid

[0728] To a stirred solution of diisopropyl amine (0.82 mL, 5.8 mmol) in anhydrous THF (5 mL) cooled to -15°C was added n-butyl lithium (2.5 M in hexanes, 2.3 mL, 5.8 mmol) slowly, maintaining the temperature of the flask between -10°C and 0°C. The resultant mixture was stirred at room temperature for 15 minutes before being cooling to 0°C. The LDA thus formed was added to a rapidly stirred suspension of 2-(2-chloropyridin-3-yl)acetic acid (500 mg, 2.9 mmol) in anhydrous THF (10 mL) at 0°C. The resultant bright yellow suspension was stirred at 0°C for 15 min. A solution of 2-fluoro-4-iodo-l -isothiocyanatobenzene (814 mg, 2.9 mmol) in anhydrous THF (10 mL) was then added to the reaction mixture (brown suspension) and heated to 65°C for 18 hours. The reaction mixture was cooled and the volatiles removed in vacuo. The resultant crude product was redissolved in THF, cooled to 0°C and 10% aqueous acetic acid in water (10 mL) was added slowly. Acetonitrile (5 mL) was added slowly until a brown solid developed, the solid was isolated by filtration and washed with ether and acetonitrile to give the title compound. LC/MS: [M+l]⁺ 415; Ή NMR (300 MHz, DMSO-d6): d 10.74 (s, 1H), 9.21 (s, 1H), 8.36-8.25 (m, 2H), 7.79 (d, J = 1.8 Hz, 1H), 7.68-7.61 (m, 1H), 7.51 (t, J=8.5 Hz, 1H), 7.42- 7.31 (m, 1H). Step 4: 2-((2-fluoro-4-(YtrimethylsilyDethvnvDphenyr)amino~)thienor2.3-b1pyridine-3-carboxylic acid

[0729] A round bottom flask was charged with 2-((2-fluoro-4-iodophenyl)amino)thieno[2,3- b]pyridine-3 -carboxylic acid (0.150 g, 0.4 mmol), copper iodide (3 mg, 0.02 mmol) bis(triphenyl)palladium(II)dichloride (12 mg, 0.02 mmol) in dry THF (10 mL) under nitrogen. The flask was degassed and flushed with nitrogen 3 times. Then trimethyl silyl acetylene (0.040 g, 0.4 mmol) dissolved in 0.4 mL of triethylamine was added very slowly over a period of 10 minutes. The suspension was stirred for 15 hours. The reaction mixture was then poured into ethyl acetate (150 mL) and washed with water (3X50 mL), brine (50 mL) and dried over Na2S04. The solvents were removed under reduced pressure and the residue purified by flash chromatography (12 g silica, 0-10% MeOH in DCM) to get the product as a pale brown oil (90 mg, 65%). LC/MS: [M+l] 385.1.

Step 5: 2-((4-ethvnyl-2-fluorophenyl^')amino^')thienor2.3-blpyridine-3-carboxylic acid

[0730] A round bottom flask was charged with 2-((2-fluoro-4-

((trimethylsilyl)ethynyl)phenyl)amino)thieno[2,3-b]pyridine-3-carboxylic acid (0.090 g, 0.2 mmol), methanol (5 mL) and THF (1 mL) and potassium carbonate (0.065 g, 0.5 mmol) wasadded to the resulting suspension. The reaction mixture was stirred at room temperature for 3 hours at which point both TLC and LC/MS indicated completion of the reaction. Water was added to the reaction mixture and extracted with ethyl acetate (3X25 mL) and the combined organics were washed with brine and dried over MgS04. The solvents were evaporated to dryness to give the compound as brown solid (60 mg, 82%). This was used in the next reaction without further purification. LC/MS: 312.3 [M+l].

Step 6: 2-((4-ethvnyl-2-fluorophenyl)amino~)-N-(2-(vinyloxy^')ethoxy^')thienor2.3-blpyridine-3- carboxamide

[0731] A microwave vial was charged with 2-((4-ethynyl-2-fluorophenyl)amino)thieno[2,3- b]pyridine-3 -carboxylic acid (0.060 g, 0.2 mmol), 0-(2-(vinyloxy)ethyl)hydroxylamine (0.03 g, 0.3 mmol), HATU (0.11 g, 0.3 mmol) and diisopropyl ethyl amine (66 ul, 0.4 mmol) in DMF(4 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3X25 mL). The solvents were removed under reduced pressure and the residue purified by flash chromatography (4g silica, 0- 5% MeOH in DCM) to get the product as yellow solid (35 mg, 46%). LC/MS: 398.2 [M+l]

Step 7: 2-(Y4-ethvnyl-2-fluorophenyl)amino)-N-f2-hvdroxyethoxy)thienor2.3-blpyridine-3- carboxamide

[0732] A round bottom flask was charged with 2-((4-ethynyl-2-fluorophenyl)amino)-N-(2- (vinyloxy)ethoxy)thieno[2,3-b]pyridine-3-carboxamide (0.03 g, 0.1 mmol), ethanol (3 mL) and 2N HC1 ( 1 mL) and the reaction mixture stirred at room temperature for 1 hour. The solvents were removed and the aqueous residue was neutralized to pH 7 with IN NaOH solution and extracted with ethyl acetate (3X25 mL). The combined organics were washed with water, brine and dried over MgS04. The solvents were removed under reduced pressure and the residue was purified by flash chromatography (4g, 0- 10% methanol in dichloromethane) to get the product as pale yellow solid (13 mg, 43%). LC/MS: [M+l]⁺ 372.0; Ή NMR (300 MHz, CDC13): d 8.47 (s, 1H), 8.36 (dd, J=4.5 and 1.2 Hz, 1H), 7.90 (dd, J=8.1 and 1.2 Hz, 1H), 7.1 (t, J=8.4 Hz, 1H), 7.37-7.30 (m, 3H), 4.17-4.15 (m, 2H), 3.85 (t, J=4.5 Hz, 2H).

Example 73: 2-((2-fluoro-4-(methylthio)phenyl)amino)-N-(2-hydroxyethoxy)thieno[2,3- b]pyridine-3-carboxamide

Step 1 : (3-fluoro-4-isothiocvanatophenyl)(methyl)sulfane

[0733] Thiophosgene (5.48 g, 47.7 mmol) was added to a rapidly stirred mixture of 2-Fluoro- 4-(methylsulphanyl)aniline (5.00 g, 31.8 mmol) in DCM (60 mL) and water(40 mL). The reaction mixture was stirred at room temperature overnight. The organic phase was separated, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and filtered. The solvents were removed in vacuo to give the title compound as a yellow solid (5 g,

78.9%). 'HNMR (300 MHz, DMSO-d6): d 7.41 -7.31 (m, 2H), 7.09 (d, J=8.4 Hz, 1 H), 2.49 (s,3H).

Step 2: 2-(2-fluoro-4-(methylthio henylamino~Khienor2.3-blpyridine-3-carboxylic acid

[0734J To a stirred solution of diisopropyl amine (1.65 mL, 1 1.7 mmol) in anthydrous THF (10 mL) cooled to -15°C was added n-butyl lithium (2.5 M in hexanes, 4.80 mL, 12.0 mmol) slowly between -10°C and 0°C. The resultant mixture was stirred at room temperature for 15 minutes before being cooled to 0°C. The solution of LDA thus formed was added to a rapidly stirred suspension of 2-(2-chloropyridin-3-yl)acetic acid (1.00 g, 5.8 mmol) in anhydrous THF( 20 mL ) at 0°C. Upon complete addition of the LDA solution the resultant bright yellow suspension was stirred at 0°C for 15 minutes. A solution of (3-fluoro-4- isothiocyanatophenyl)(methyl)sulfane (1.63 g, 8.2 mmol) in anhydrous THF (10 mL) was then added to the reaction mixture and heated to 65°C for 18 hours. The reaction mixture was cooled to room temperature and the volatiles removed in vacuo. The resultant brown gum was redissolved in THF, cooled to 0°C and 10% aq acetic acid 10 mL added slowly. Acetonitrile (5 mL) was added slowly until a yellow solid developed, the solid was isolated by filtration and washed with ether and acetonitrile to give the title compound as a yellow solid (546mg, 20%). LC/MS: [M+l] 335. 'HNMR ( 300 MHz, DMSO-d6): d 8.34 ( d, J=8.1 Hz, 1 H ), 7.85-8.20 ( m, 1H ), 7.61 ( t, J = 8.6 Hz, 1H ), 7.39-7.30 ( m, 2H ), 7.21 (d, J = 9.2 Hz, 1H ), 2.52 (s, 3H).

Step 3: N-(2-(vinyloxy~)ethoxy~)-2-(2-fluoro-4-(methylthio~)phenylamino^')thienor2.3-blpyridine-3- carboxamide

[0735] A vial was charged with 2-(2-fluoro-4-(methylthio)phenylamino)thieno[2,3-b]pyridine- 3-carboxylic acid (0.100 g, 0.1 mmol), 0-(2-(vinyloxy)ethyl)hydroxylamine (25 mg, 0.2 mmol), HATU (0.085 g, 0.2 mmol) and diisopropyl ethyl amine (52 ul, 0.3 mmol) and DMF (4 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with water, brine and dried over sodium sulfate. The solvents were evaporated to give a light yellow solid (88 mg) which was used without further purification. LC/MS: [M+l] 420.0. Step 4: 2-(2-fluoro-4-(methylthio >henylaminoVN-(2-hydroxyethoxy)thienor2.3-blpyridine-3- carboxamide

[0736] A microwave reaction vial was charged with N-(2-(vinyloxy)ethoxy)-2-(2-fluoro-4- (methylthio)phenylamino)thieno[2,3-b]pyridine-3-carboxamide (0.088 g), ethanol (2 mL), and 2N HC1 (2mL). The reaction mixture was stirred at room temperature for one hour. The reaction was quenched with water and adjusted to pH to 8 - 10, then extracted with ethyl acetate. The organics were washed with water, brine and dried over sodium sulfate. The solvents were evaporated. The residue was purified by flash chromatography (4 g silica, 0-5% MeOH/DCM). The product fractions were collected and the solvents were removed in vacuo. The residue was purified again by preparative TLC (5% MeOH/DCM) and dried to give a light yellow solid (12 mg, 24%). LC/MS: [M+l ]: 394.19. ’HNMR ( 300 MHz, CDC13 ): 510.70 (s, 1H), 8.37 ( s, 1H ), 8.33-7.84 ( m, 1H ), 7.88-7.81 ( m, 1H ), 7.52 ( t, J = 8.4Hz, 1H ), 7.32-7.25 ( m, 1H ), 7.12-7.06 ( m, 1H ), 4.15 ( t, J = 4.38Hz, 2H), 3.85 ( m, 2H ), 2.46 ( s, 3H).

Example 74: Synthesis of 2-((2-Fluoro-4-iodophenyl)amino)-A-(2- hydroxyethoxy)thieno[2,3-6]pyridine-3-carboxamide

Step 1 : f2-Chloropyridin-3-yl)methanol

[0737] To a stirred solution of methyl 2-chloronicotinate (25 g, 145.71 mmol) in anhydrous THF (250 mL) at 0 °C under an atmosphere of nitrogen was added solid lithium aluminium hydride (11.06 g, 291.41 mmol) in small portions over a period of 20 min, maintaining the internal temperature below 5 °C. The resulting grey suspension was heated to 50 °C for 2 h, before being allowed to cool to room temperature with stirring over 16 h. The reaction mixture was then cooled to 0 °C and quenched by the cautious addition of a saturated solution of aqueous sodium sulphate, resulting in the formation of a suspension. The mixture was passed through a pad of celite, and the pad was subsequently washed with ethyl acetate (2 x 50 mL). The combined filtrates were diluted with ethyl acetate (500 mL) and washed water (250 mL), before being dried over sodium sulphate, filtered and evaporated to dryness to give the crude product as a brown oil. Purification by silica gel chromatography eluting with a gradient of ethyl acetate (10 to 40%) in hexane afforded the desired compound as a pale brown solid (7.13 g, 34.1%). UPLC-MS (Acidic Method, 2 min): rt = 0.60 min, m/z 144.0 [M+H]⁺. 'H NMR (400 MHz, CDCb) d ppm 8.28 (dd, J = 4.77Hz, 1.76Hz, 1H), 7.93 (dt , J = 7.59Hz, 0.97Hz, 0.97Hz, 1H), 7.29 (dd, 7 = 7.40Hz, 5.14Hz, 1H), 4.79 (s, 2H), 3.23 (br, s, 1H).

Step 2: (^'2-Chloropyridin-3-vnmethyl methanesulfonate

[0738] Methanesulfonyl chloride (7.70 mL, 99.380 mmol) was added dropwise to a stirred solution of (2-chlorop yri din-3 -yl)methanol (7.134 g, 49.960 mmol) and Et N (13.85 mL, 99.380 mmol) in dichloromethane (50 mL) at 0 °C, taking care to maintain the internal temperature below 5 °C. Upon completion of the addition, the reaction mixture was warmed to ambient temperature with stirring for 2 h. The reaction mixture was quenched with water (200 mL) and extracted with dichloromethane (2 * 200 mL). The combined organics were dried over Na SC> , filtered and evaporated to dryness to afford the desired product as a brown oil (12.02 g, 100%). This material was taken in to the next step without any further purification. UPLC-MS (Acidic Method, 2 min): rt = 0.79 min, m/z 222.0 [M+H]⁺. Ή NMR (400 MHz, CDC1₃) d ppm 8.43-8.36 (m, 1H), 7.88-7.84 (m, 1H), 7.35-7.28 (m, 1H), 5.33 (s, 2H), 3.69 (s, 1H), 3.1 1 (s, 3H)

Step 3: 2-(^'2-Chloropyridin-3-yl~)acetonitrile

[0739] Sodium cyanide (7.98 g, 162.77 mmol) was added in a single portion to a solution of (2-chloropyridin-3-yl)methyl methanesulfonate (12.02 g, 54.24 mmol) in DMF (50 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 2 h. The reaction was then poured into water (200 mL), and the resulting mixture was extracted with ethyl acetate (2 x 300 mL). The combined organics were dried over NaaSCb, filtered and evaporated to dryness to give the crude product, which was purified by column chromatography eluting with a gradient of ethyl acetate (10 to 30%) in hexane to afford the desired product as a pale brown solid (5.34 g, 64.5%). UPLC-MS (Acidic Method, 2 min): rt = 0.73 min, m/z 153.0 [M+H]⁺. ^]H NMR (400 MHz, CDCb) d 8.40 (dd, J = 4.77Hz, 1.76Hz, 1H), 7.89 (ddt, J = 7.62Hz, 1.79Hz, 0.82Hz, 0.82Hz, 1H), 7.34 (dd, J = 7.53Hz, 4.77Hz, 1H), 3.87 (s, 2H). Step 4: 2- Chloropyridin-3-yl^')acetic acid

[0740] 2-(2-Chloropyridin-3-yl)acetonitrile (5.34 g, 34.97 mmol) was dissolved in a 15% (w/w) aqueous NaOH solution (50 mL), and the resulting solution was stirred at ambient temperature for 60 min. The reaction was then acidified to pH = 1 with concentrated hydrochloric acid, forming a beige precipitate, which was collected by filtration, washed with water (2 ^c 25 mL) and dried in an oven under vacuum at 40 °C to afford the desired product as a beige solid (5.57 g, 92.8%). UPLC-MS (Acidic Method, 2 min): rt = 0.66 min, m/z 172.0

[M+H]⁺. Ή NMR (400 MHz, DMSO-d6) d ppm 12.64 (br, s, 1 H), 8.33 (dd, J = 4.77Hz, 2.01Hz, 1H), 7.86 (dd, y = 7.53Hz, 2.01Hz, 1H), 7.41 (dd, J= 7.53Hz, 4.77Hz, 1H), 3.76 (s, 2H).

Step 5: Butyl 2-i2-chloropyridin-3-vDacetate

[0741] To a cooled solution of /V,7V-dicyclohexylcarbodiimide (7.36 g, 35.69 mmol, ) in dichloromethane (120 mL) was added DMAP (3.17 g, 25.96 mmol) at 0 °C, followed by 2-(2- chloropyridin-3-yl)acetic acid (5.57 g, 32.45 mmol), and the resulting mixture was stirred at 0 °C for 5 min. teri-Butanol (9.3 mL, 97.337 mmol) was then added to the reaction, and the resulting mixture was allowed to warm to room temperature with stirring for 12 h. The reaction was then evaporated to dryness to give a residue, which was dissolved in diethyl ether (400 mL). The ether solution was then filtered through a pad of celite, which was washed with diethyl ether (2 ^c 200 mL). The combined filtrates were washed sequentially with 1 M aqueous NaOH (300 mL),

2 N aqueous HC1 (300 mL), water (300 mL) and brine (200 mL). The organic layer was then dried over Na2S04, filtered and evaporated to dryness to give the crude product as a residue. Purification by flash column chromatography eluting with a gradient of ethyl acetate (5-20%) in hexane to afford the desired product as beige solid (5.25 g, 71.0%). UPLC-MS (Acidic Method, 2 min): rt = 1.08 min, m/z 228.1 [M+H]⁺. 'H NMR (400 MHz, CDCb) d ppm 8.31 (dd, J=4.77Hz, 2.01Hz, 1H), 7.63 (dd, J=7.53Hz, 2.01Hz, 1H), 7.22 (dd, J=7.53Hz, 4.77Hz, 1H), 3.68 (s, 2H), 1.46 (s, 9H).

Step 6 : Butyl-2-((2 -fluoro-4-iodophenyl)amino)thienor2.3 - ?lpyridine-3 -carboxylate

[0742] To a solution of tert-butyl 2-(2-chloropyridin-3-yl)acetate (5.05 g, 22.16 mmol, 1 eq) in tetrahydrofuran (200 mL) was added sodium tert-butoxide (2.24 g, 23.27 mmol, 1.05 eq), and the resulting mixture was stirred at room temperature for 15 min. 2-Fluoro-4-iodo-l - isothiocyanatobenzene (6.18 g, 22.16 mmol, 1 eq) was then added to the reaction, and the resulting solution was stirred for 30 min. The mixture was then stirred at reflux for 16 h, before being cooled to room temperature and partitioned between ethyl acetate (300 mL) and water (300 mL). The aqueous layer was collected and extracted with ethyl acetate (300 mL), and the combined organics were dried over Na2SC>4, filtered and concentrated. The crude material was purified by column chromatography eluting with dichloromethane to afford the desired product as a beige solid (8.49 g, 78.3%). UPLC-MS (Acidic Method, 2 min): rt = 1.54 min, m/z 471.0 [M+H]⁺. Ή NMR (400 MHz, CDCI3) d ppm 10.70 (br, s, 1 H), 8.25 (q, J=1.67Hz, 1H), 8.23 (s,

1H), 7.46-7.43 ( , 2H), 7.40-7.35 (m, 1H), 7.19 (dd, y=4.52Hz, 3.01Hz, 1H), 1.61 (s, 9H).

Step 7: 2- Fluoro-4-iodophenvI)amino)thienor2.3-/flpyridine-3-carboxylic acid

[0743] A solution of iert-butyl 2-((2-fluoro-4-iodophenyl)amino)thieno[2,3-Z>]pyridine-3- carboxylate (1.00 g, 2.13 mmol) in dichloromethane (20 mL) was treated with 4 N HC1 in dioxane (20 mL), and the resulting mixture was stirred at room temperature for 48 h. The solution was then concentrated to dryness to afford an oil, which was co-distilled with dichloromethane (2 x 25 mL) to afford the desired product as a yellow solid (1.04 g, 100%). UPLC-MS (Acidic Method, 2 min): rt = 1.24 min, m/z 414.9 [M+H]⁺. 'H NMR (400 MHz, DMSO-d₆) d ppm 10.73 (s, 1H), 8.42 (dd, J=8.16Hz, 1.63Hz, 1H), 8.38 (dd, J = 4.77Hz, 1.51Hz, 1H), 7.90 (dd, J = 10.16Hz, 1.88Hz, 1H), 7.76-7.73 (m, 1H), 7.60 (t , J = 8.53Hz, 8.53Hz, 1H),

7.48 (dd J = 8.28Hz, 4.77Hz, 1H), 3.63 (s, 1H).

Step 8: 2-(Y2-Fluoro-4-iodophenyl~)aminoV.V-(2-hvdroxyethoxy~)thienor2.3-61pyridine-3- carboxamide

[0744] To a stirred solution of 2-((2-fluoro-4-iodophenyl)amino)thieno[2,3-b]pyridine-3- carboxylic acid (1.5 g, 3.62 mmol, 1 eq), HATU (1.9 g, 5.07 mmol, 1.4 eq) and pyridine (0.59 mL, 7.24 mmol, 2 eq) in a mixture of DMF (15 mL) and DMSO (15 mL) was added 2- aminooxyethanol (0.56 g, 7.24 mmol, 2 eq), and the resulting mixture was stirred at room temperature for 16 h. The reaction was poured into water (100 mL), and the resulting mixture was extracted with ethyl acetate (3 * 50 mL). The combined organics were washed with brine (3 x 50 mL), dried over NaaSCL, filtered and concentrated to give the crude as a residue.

Purification by prep-HPLC to afford the desired product (209 mg, 12%) as a pale yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.1 1 min, m/z 473.9 [M+H]⁺. Ή NMR (400 MHz, DMSO-C?₆) d ppm 1 1.29 (br s, 1H), 10.36 (br s, 1H), 8.30-8.41 (m, 1H), 8.02-8.19 (m, 1H), 7.70- 7.87 (m, 1H), 7.61 (d, J= 8.7 Hz, 1H), 7.42 (br t, .7=8.7 Hz, 2H), 4.63-4.86 (m, 1H), 3.94 (br d,

.7=4.4 Hz, 2H), 3.65 (br d, .7=4.6 Hz, 2H). Example 75: Synthesis of (/?)-A-(2,3-Dihydroxypropoxy)-2-((2-iluoro-4- iodophenyl)amino)thieno|2,3-/>]pyridine-3-carboxamide

Step 1 : (7?)-A-((2.2-Dimethyl-1.3-dioxolan-4-yl)methoxy)-2-((2-fluoro-4- iodophenyl)amino)thienor2.3-b1pyridine-3-carboxamide

[0745] To a magnetically stirred mixture of 2-((2-fluoro-4-iodophenyl)amino)thieno[2,3- b]pyridine-3 -carboxylic acid in DMF was added HATU and TEA, and the resulting mixture was agitated for 15 min. (R)-<9-((2,2-Dimethyl-l,3-dioxolan-4-yl)methyl)hydroxylamine was then added to the reaction, and the resulting mixture was agitated at room temperature for 15 h. The reaction mixture was poured into water (30 mL), affording a yellow precipitate, which was collected by filtration. The resulting solid was washed with water (2 ^c 25 mL) and dried under vacuum at 40 °C to give the crude product as a yellow solid (0.27 g), which was used directly in the next step. UPLC-MS (Acidic Method, 2 min): rt 1.17 min, m/z 544.0 [M+H]⁺

Step 2: (/?V./V-(2.3-Dihvdroxypropoxy^')-2-((2-fluoro-4-iodophenvOamino^')thienor2.3-61pyridine- 3-carboxamide

[0746] A solution of (7?)-7V-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)-2-((2-fluoro-4- iodophenyl)amino)thieno[2,3-6]pyridine-3-carboxamide (270 mg, 0.50 mmol) in MeOH (10 mL) and ethylene glycol (140 JL) was treated with -toluene sulfonic acid monohydrate (41 mg, 0.21 mmol), and the resulting mixture was agitated for 15 h. The mixture was evaporated to dryness to give the crude product as a gum, which was purified by preparative HPLC, affording the desired product as an off-white solid (70 mg). UPLC-MS (Acidic Method, 2 min): rt 0.96 min, m/z 503.9 [M+H]⁺. Ή NMR (400 MHz, DMSO-76) d ppm 10.94-1 1.70 (m, 1H), 10.06-10.79 (m, 1 H), 8.29 (br s, 1H), 8.13 (br d, 7=4.39 Hz, 1H). 7.76 (br d, 7=10.04 Hz, 1H), 7.55-7.64 (m, 1H) 7.31-7.46 (m, 2H), 4.82-5.12 (m, 1H), 4.51 -4.72 (m, 1H), 3.93-4.05 (m, 1H), 3.72-3.86 (m, 2H), 3.42 (br d, 7=4.77 Hz, 2H).

Example 76: 2-((2-Fluoro-4-iodophenyl)amino)-./V-(2-hydroxyethoxy)-6-methylthieno[2,3- 6]pyridine-3-carboxamide

Step 1 : 2-Chloro-6-methylpyridin-3-yQmethanol

[0747] A cooled solution of methyl 2-chloro-6-methylpyridine-3-carboxylate (10 g, 53.88 mmol) in anhydrous tetrahydrofuran (120 mL) was treated with Lithium aluminium hydride (4.09 g, 107.75 mmol), which was added in a portion-wise over 20 min, taking care to maintain the internal temperature below 10 °C. Upon completion of the addition, the reaction mixture was stirred at 50 °C for 12 h. The reaction was then chilled in an ice-water bath and quenched by the addition of a saturated aqueous solution of Na2SC>₄ (100 mL), resulting in the formation of a suspension, which was filtered through a pad of celite, washing with ethyl acetate (2 x 300 mL). The combined filtrate was evaporated to dryness to give a light orange oil, which was purified by column chromatography eluting with a gradient of ethyl acetate (0 to 40%) in hexane to afford the desired product as a pale yellow oil (5.5 g, 65%). UPLC-MS (Acidic Method, 2 min): rt = 0.70 min, m/z 158.0 [M+H]⁺. Ή NMR (400 MHz, CDCh) d ppm 7.74 (d, 7=7.7 Hz, 1H), 7.1 1 (d, 7=7.8 Hz, 1H), 4.74 (s, 2H), 2.52 (s, 3H), 2.46 (br s, 1 H)

Step 2: (2-Chloro-6-methylpyridin-3-yl)methyl methanesulfonate

[0748] Methanesulfonyl chloride (5.4 mL, 69.8 mmol) was added dropwise to a solution of (2- chloro-6-methylpyridin-3-yl)methanol (5.5 g, 34.9 mmol) and Et3N (9.7 mL, 69.8 mmol) in dichloromethane (52 mL) at 0 °C, taking care to maintain the internal temperature below 5°C. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature with stirring for 2 h, before being quenched with water (200 mL) and extracted with

dichloromethane (2 * 250 mL). The combined organics were dried over Na₂S0₄, filtered and concentrated to afford the desired product as a brown oil (7.9 g, 96%), which was used directly in the next step without any further purification. UPLC-MS (Acidic Method, 2 min): rt = 0.86 min, m/z 236.0 [M+H]⁺. Ή NMR (400 MHz, CDCb) d ppm 7.71 (t, .7=7.5 Hz, 1 H), 7.14 (dd, .7=7.7, 14.62 Hz, 1H), 5.29 (s, 1H), 4.65 (s, 1H), 3.03-3.16 (m, 3H), 2.54 (d, 7=6.2 Hz, 3H)

Step 3 : 2-(2-Chloro-6-methylpyridin-3-yl)acetonitrile

[0749] To a solution of (2-chloro-6-methylpyridin-3-yl)methyl methanesulfonate (7.9 g, 33.5 mmol) in DMF (48 mL) was added sodium cyanide (4.9 g, 100.5 mmol), and the resulting mixture was stirred for 2 h at room temperature. The reaction was then poured into water (250 mL), and the resulting mixture was extracted with ethyl acetate (3 ^x 250 mL). The combined organics were dried over Na2SC>4, filtered and concentrated to afford the crude as a residue, which was purified by column chromatography eluting with a gradient of ethyl acetate (0 to 30%) in hexane to afford the desired product as a pale yellow solid (3.2 g, 58%). UPLC-MS (Acidic Method, 2 min): rt = 0.84 min, m/z 167.0 [M+H]⁺. 'H NMR (400 MHz, CDCb) d ppm 7.76 (d, .7=7.8 Hz, 1H), 7.17 (d, 7=7.8 Hz, 1H), 3.82 (s, 2H), 2.56 (s, 3H)

Step 4: 2-i2-Chloro-6-methylpyridin-3-yr)acetic acid

[0750] A stirred solution of 2-(2-chloro-6-methylpyridin-3-yl)acetonitrile (3.2 g, 19.2 mmol) in 15% (w/w) aqueous NaOH solution (32 mL) was heated at reflux for 30 min. The mixture was then cooled to room temperature and acidified to pH = 1 with concentrated HC1, affording a beige precipitate, which was collected by filtration, washed with water (2 ^c 50 mL) and dried under vacuum to afford the desired product as a beige solid (3.2 g, 90%). UPLC-MS (Acidic Method, 2 min): rt = 0.76 min, m/z 186.1 [M+H]⁺. Ή NMR (400 MHz, CDCb) d ppm 7.53 (d, 7=7.7 Hz, 1H), 7.09 (d, 7=7.7 Hz, 1H), 3.79 (s, 2H), 2.53 (s, 3H)

Step 5: te/7-Butyl 2-(2-chloro-6-methylpyridin-3-yl~)acetate

[0751] To a stirred solution of 7V,7V-dicyclohexylcarbodiimide (3.9 g, 18.92 mmol) in dichloromethane (72 mL) at 0 °C was added DMAP (1.7 g 13.76 mmol), followed by 2-(2- chloro-6-methylpyridin-3-yl)acetic acid (3.2 g, 17.2 mmol), and the resulting mixture was stirred at 0 °C for 5 min. ieri-Butanol (4.9 mL, 51.6 mmol) was then added to the reaction, and the resulting mixture was allowed to warm to room temperature with stirring over 16 h. The reaction was then evaporated to dryness to give a residue, was dissolved in diethyl ether (400 mL) and passed through a pad of celite, washing with diethyl ether (2 x 200 mL). The combined filtrate was washed sequentially with 1 M aqueous NaOH (300 mL), 2 N aqueous HC1 (300 mL), water (300 mL) and brine (200 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated. The crude material was purified by column chromatography eluting with a gradient of ethyl acetate (0 to 30%) in hexane to afford the desired product as a pale yellow oil (3.03 g, 73%). UPLC-MS (Acidic Method, 2 min): rt 1.14 min, m/z 242.1 [M+H]⁺. 'H NMR (400 MHz, CDCb) d ppm 7.50 (d, .7=7.7 Hz, 1H), 7.05 (d, =7.7 Hz, 1H), 3.62 (s, 2H), 2.51 (s, 3H), 1.44 (s, 9H)

Step 6: /ert-Butyl 2-(T2-fluoro-4-iodophenvDaminoV6-methylthienor2.3-blpyridine-3- carboxylate

[0752] To a solution of tert-butyl 2-(2-chloro-6-methylpyridin-3-yl)acetate (3.03 g, 12.5 mmol) in tetrahydrofuran (250 mL) was added sodium /ert-butoxide (1.26 g, 13.13 mmol) under nitrogen atmosphere. A yellow solution was formed which was stirred at room temperature for 15 min. Then 2-fluoro-4-iodo-l-isothiocyanatobenzene (3.5 g, 12.5 mmol) was added and the solution was stirred for 30 min. The solution turned light brown. Finally the mixture was stirred at reflux overnight. The reaction was cooled to room temperature and partitioned between ethyl acetate (300 mL) and water (300 mL). The organic phase was collected and the aqueous layer was extracted with ethyl acetate (300 mL). Combined organics were dried over NazSCU, filtered and concentrated. The crude material was purified by column chromatography eluting with dichloromethane to afford the desired product as a yellow solid (2.5 g, 42%). UPLC-MS (Acidic Method, 2 min): rt = 1.56 min, m/z 484.9 [M+H]⁺. 'H NMR (400 MHz, CDCh) d ppm 10.70 (br s, 1H), 8.21 (d, 7=8.3 Hz, 1H), 7.49-7.54 (m, 2H), 7.42-7.48 (m, 1H), 7.13 (d, 7=8.5 Hz, 1H), 2.59 (s, 3H), 1.68 (s, 9H).

Step 7: 2-((2-Fluoro-4-iodophenyl~)aminoT6-methylthienor2.3-61pyridine-3-carboxylic acid

[0753] To a solution of tert-butyl 2-((2-fluoro-4-iodophenyl)amino)-6-methylthieno[2,3- Z>]pyridine-3-carboxylate (0.26 g, 0.54 mmol) in dichloromethane (5.5 mL) was added trifluoroacetic acid (0.55 mL, 7.18 mmol), and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was then concentrated to afford a residue, which was co-distilled from toluene (3 x 50 mL) to afford the desired product as a yellow solid (0.24 g, 100%). UPLC-MS (Acidic Method, 4 min): rt = 2.15 min, m/z 428.9 [M+H]⁺. Ή NMR (400 MHz, DMSO-d₆) d ppm 10.63 (s, 1H), 8.24 (d, 7=8.3 Hz, 1H), 7.83 (dd, 7=1.9, 10.2 Hz, 1H), 7.65-7.70 (m, 1H), 7.52 (t, 7=8.6 Hz, 1H), 7.28 (d, 7=8.2 Hz, 1H)

Step 8: 2-((2-Fluoro-4-iodophenv0amino)-./V-(2-hvdroxyethoxyV6-methylthienor2.3-61pyridine- 3 -carboxamide

[0754] To a solution of 2-((2-fluoro-4-iodophenyl)amino)-6-methylthieno[2,3-b]pyridine-3- carboxylic acid (0.24 g, 0.56 mmol) in anhydrous tetrahydrofuran (14 mL) was added PyBOP (0.41 mg, 0.78 mmol), followed by Et3N (0.23 mL, 1.68 mmol), and the resulting solution was stirred at room temperature for 30 min. 2-(Aminooxy)ethan-l-ol (65 mg, 0.84 mmol) was then added to the reaction, and the resulting mixture was stirred at room temperature for 12 h. Water (50 mL) was added to the reaction, forming a biphasic mixture. The aqueous phase was collected and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with brine, dried over Na₂SC>₄, filtered and concentrated. The crude material was purified by prep-HPLC to afford the desired product as a pale yellow solid (1 15 mg, 42%). UPLC-MS (Acidic Method, 4 min): rt = 1.84 min, m/z 487.9 [M+H]⁺. 'H NMR (400 MHz, DMSO-d₆) d ppm 11.24 (br s, 1H), 10.11-10.38 (br s, 1H), 7.93-8.06 (m, 1H), 7.67-7.80 (m, 1H), 7.58 (br d, .7=7.7 Hz, 1H), 7.36 (br t, .7=8.6 Hz, 1H), 7.28 (br dd, =4.1, 7.2 Hz, 1H), 4.59-4.84 (br s, 1H), 3.92 (t, 7=4.9 Hz, 3H), 3.63 (br d, 7=3.8 Hz, 3H). Example 77 : 2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-6-methoxythieno[2,3- bjpyridine-3-carboxamide

Step 1 : (^'2-Chloro-6-methoxypyridin-3-yl)methanol

[0755] To a solution of methyl 2-chloro-6-methoxynicotinate (5.0 g, 24.8 mmol) in THF (50 mL) at 0 °C was added lithium aluminium hydride (1.88 g, 49.6 mmol) in a portion wise manner, taking care to keep the temperature below 10 °C. Upon completion of the addition, the reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was then cooled to 0 °C, before being quenched by the careful addition of a saturated solution of aqueous sodium sulphate (50 mL).

The resulting suspension was stirred for 20 min, before being filtered through a pad of celite, washing with ethyl acetate (2 ^c 50 mL). The combined organics were dried over anhydrous sodium sulphate, filtered and evaporated to dryness to give the desired product as a yellow- orange oil (3.82 g, 89%). UPLC-MS (Acidic Method, 2 mins): rt = 0.83 min, m/z 174.0 [M+H]⁺. Ή NMR (400 MHz, CDCb) d ppm 7.69 (d, .7=8.2 Hz, 1 H) 6.69 (d, .7=8.2 Hz, 1 H) 4.70 (s, 2 H) 3.88 (s, 3 H)

Step 2: C2-Chloro-6-methoxypyridin-3-yl)methyl methanesulfonate

[0756] Methanesulfonyl chloride (3.4 mL, 44.0 mmol) was added to a stirred solution of (2- chloro-6-methoxypyridin-3-yl)methanol (3.82 g, 22.0 mmol) in dichloromethane (90 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water (100 mL), affording a biphasic solution. The organic phase was collected and the aqueous phase extracted with dichloromethane (2 x 50 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give the desired product as an orange solid (4.26 g, 77%). UPLC-MS (Acidic Method, 2 mins): rt = 1.13 min, m/z 252.1 [M+H]⁺. Ή NMR (400 MHz, CDC ) d ppm 7.65 (d, .7=8.2 Hz, 1 H) 6.69 (d, .7=8.2 Hz, 1 H) 4.64 (s, 2 H) 3.94 (s, 3 H) 3.14 (s, 3 H) Step 3: 2-(^'2-Chloro-6-methoxypyridin-3-vDacetonitrile

[0757] To a solution of (2-chloro-6-methoxypyridin-3-yl)methyl methanesulfonate (4.26 g, 16.9 mmol) in DMF (17 mL) was added sodium cyanide (2.48 g, 50.7 mmol) in a portion wise manner over 5 min, and the resulting mixture was stirred at room temperature for 24 h. The reaction was poured into water (100 mL), and the resulting mixture was extracted with ethyl acetate (3 * 50 mL). The combined organics were washed with brine (2 * 200 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude was purified by flash column chromatography eluting with a gradient of methanol (0-5%) in DICHLOROMETHANE to give the desired product as a white solid (1.75 g, 57%). UPLC-MS (Acidic Method, 2 mins): rt 0.96 min, m/z 183.0 [M+H]⁺. Ή NMR (400 MHZ,CHC1 ) d ppm 7.69 (d, J= 8.2 Hz, 1H), 6.73 (d, J= 8.2 Hz, 1H), 3.94 (s, 3H), 3.75 (s, 2H).

Step 4: 2- Chloro-6-methoxypyridin-3-vDacetic acid

[0758] A suspension of 2-(2-chloro-6-methoxypyridin-3-yl)acetonitrile (1.75 g, 9.5 mmol) in an aqueous solution of 15% w/w NaOH (16 mL) was stirred at 60 °C for 24 h. The reaction mixture was then cooled to room temperature and acidified of pH=l with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and washed with water (2 x 20 mL), before being dried under vacuum at 40 °C to give the desired product as a white solid (1.50 g, 78%). UPLC-MS (Acidic Method, 2 mins): rt = 0.84 min, m/z 202.0 [M+H]⁺. 'H NMR

(400 MHz, DMSO-rfe) d ppm 12.51 (br s, 1H), 7.76 (d, ,7=8.2 Hz, 1H), 6.84 (d, .7=8.2 Hz, 1H), 3.85 (s, 3H), 3.66 (s, 2H).

Step 5: tert- Butyl 2-(2-chloro-6-methoxypyridin-3-yl)acetate

[0759] To a suspension of 2-(2-chloro-6-methoxypyridin-3-yl)acetic acid (1.34 g, 6.65 mmol) in teH-butanol (15 mL) was added di-tert-butyl dicarbonate (2.3 mL, 9.97 mmol), followed by DMAP (0.082 g, 0.67 mmol), and the resulting mixture was stirred at 50 °C for 18 h. The reaction mixture was cooled to room temperature and evaporated to dryness to give a residue, which was diluted with water (20 mL) and extracted with ethyl acetate (2 ^c 20 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude, which was purified by flash column chromatography eluting with a gradient of ethyl acetate (20-80%) in hexane to give the desired product as a pale yellow oil (1.27 g, 69%). UPLC-MS (Acidic Method, 2 mins): rt = 1.21 min, m/z 258.1 [M+H]⁺. Ή NMR (400 MHz, CDCI3) d ppm 7.49 (d, .7=8.2 Hz, 1H), 6.65 (d, .7=8.2 Hz, 1H), 3.92 (s, 3H), 3.58 (s, 2H), 1.45 (s, 9H).

Step 6: /er/-Butyl 2- fluoro-4-iodophenyr)amino~)-6-methoxythienor2.3-/?1pyridine-3-

carboxylate

[0760] /eH-Butyl 2-(2-chloro-6-methoxypyridin-3-yl)acetate (1.0 g, 3.88 mmol) and sodium tert-butoxide (0.41 g, 4.27 mmol) were added to a microwave vial, followed by THF (35 mL), and the resulting mixture was agitated for 5 min. A solution of 2-fluoro-4-iodo-l- isothiocyanatobenzene (1.1 1 g, 3.88 mmol) in THF (5 mL) was then added to the microwave vial, and the resulting mixture was stirred at room temperature for 1 h. Caesium fluoride (0.295 g, 1.94 mmol) was then added to the vial, and the reaction mixture was heated at 90 °C under microwave irradiation for 1 h. The mixture was cooled to room temperature and evaporated to dryness to afford the crude product, which was purified by flash column chromatography eluting with dichloromethane to give the desired product as a yellow solid (0.564 g, 30%). UPLC-MS (Acidic Method, 4 mins): rt = 2.95 min, m/z 500.9 [M+H]⁺. 'H NMR (400 MHz, CDCI3) d ppm 10.56 (s, 1H), 8.25 (d, .7=8.8 Hz, 1H), 7.43-7.53 (m, 3H), 6.76 (d, .7=8.8 Hz, 1H), 3.96 (s, 3H), 1.78 (s, 9H).

Step 7: 2-((2-fluoro-4-iodophenyDamino^')-6-methoxythienor2,3-blpyridine-3-carboxylic acid

[0761] To a solution of tert-butyl 2-((2-fluoro-4-iodophenyl)amino)-6-methoxythieno[2,3- b]pyridine-3-carboxylate (0.050 g, 0.10 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.3 mL). The resultant mixture was stirred at room temperature under a N2 atmosphere for 6h. The solvent was removed in vacuo and co-distilled with toluene (2 x 10 mL) to give the desired product as a yellow solid (0.44 g, 100%), which was used in the next step without further purification. UPLC-MS (Acidic Method, 2 mins): rt = 1.35 min, m/z 445.0 [M+H]⁺

Step 8: 2-(^'(2-fluoro-4-iodophenv0aminoVN-f2-hvdroxyethoxy~)-6-methoxythienor2.3- blpyridine-3-carboxamide

[0762] To a suspension of 2-((2-fluoro-4-iodophenyl)amino)-6-methoxythieno[2,3-b]pyridine-

3-carboxylic acid (0.050 g, 0.1 1 mmol) in THF (2 mL) was added PyBOP (0.078g, 0.15 mmol) and triethylamine (0.05 mL, 0.33 mmol). The resultant mixture was stirred at room temperature under a N2 atmosphere for 30 min. A solution of 2-(aminooxy)ethanol (0.011 mL, 0.15 mmol) in THF (0.1 mL) was added and the reaction mixture was stirred at room temperature under a N2 atmosphere for lh. The reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (2 x 10 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give the crude product, which was purified by preparatory HPLC to give the desired product as an off-white solid (0.023 g, 22%). UPLC-MS (Acidic Method, 4 mins): it = 2.10 min, m/z 503.9 [M+H]⁺. 'H NMR (400 MHz, DMSO-7₆) d ppm 1 1.30 (br s, 1H), 9.77 (br s, 1H), 8.1 1 (br s, 1H), 7.70 (br s, 1H), 7.53 (br d, .7=8.2 Hz, 1H), 7.26 (br d, .7=8.2 Hz, 1H), 6.91 (br d, 7=7.0 Hz, 1H), 4.77 (br s, 1H), 3.90 (s, 3H), 3.89 (br s, 2H),

3.62 (br s, 2H).

Example 78: 2-((2-FIuoro-4-iodophenyl)amino)-/V-(2-hydroxyethoxy)-5-methoxythieno[2,3- 6]pyridine-3-carboxamide

Step 1 : i2-Chloro-5-methoxypyridin-3-yl^')methanol

[0763] A solution of methyl 2-chloro-5-methoxynicotinate (0.5 g, 2.48 mmol) in anhydrous THF (5 mL) was cooled to 0 °C and treated with lithium aluminium hydride (0.19 g, 4.96 mmol) in a portion-wise manner. Upon completion of the addition, the mixture was heated to 50 °C for 1 h. The mixture was then cooled to 0 °C and treated with an aqueous solution of sodium sulphate, and the resulting mixture was stirred for 0.5 h at ambient temperature. The mixture was diluted with ethyl acetate (10 mL) and filtered through a pad of Celite. The pad was washed with ethyl acetate (2 ^c 20 mL) and the combined organic phases were dried over NaaSCL, filtered and concentrated under vacuum to give the crude product, which was purified by flash column chromatography eluting with a gradient of methanol (0-5%) in DICHLOROMETHANE to give the desired product as a brown oil (0.368 g, 86%). UPLC-MS (Acidic Method, 2 min): rt = 0.72 min, m/z 174.0/175.9 [M+H]⁺. Ή NMR (400 MHz, CDCb) d ppm 7.97 (d, 7=3.0 Hz, 1H), 7.47 (dt, 7=3.1, 0.8 Hz, 1H), 4.74 (s, 2H), 3.86 (s, 3H)

Step 2: (^'2-Chloro-5-methoxypyridin-3-vUmethyl methanesulfonate

[0764] A solution of (2-chloro-5-methoxypyridin-3-yl)methanol (2.74 g, 15.84 mmol) in anhydrous dichloromethane (60 mL) was cooled to 0 °C and treated sequentially with triethylamine (4.42 mL, 31.67 mmol) methanesulfonyl chloride (2.45 mL, 31.67 mmol), and the resulting mixture was slowly warmed up to ambient temperature with stirring over 1 h. The mixture was diluted with water (30 mL) and extracted with D1CHLOROMETHANE (2 ^c 30 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SC>4, filtered and concentrated under vacuum to afford the desired product as a brown oil (3.99 g,100%). UPLC-MS (Acidic Method, 2 min): rt = 0.87 min, m/z 252.0/254.0 [M+H]⁺ and 1.01 min, m/z 192.0/194.0 [M+H]⁺. Ή NMR (400 MHz, CDCb) d ppm 8.06-8.10 (m, 1H), 7.35-7.43 (m, 1H), 5.29 (s, 1H), 4.65 (s, 1H), 3.89 (s, 3H), 3.14 (s, 1H), 3.1 1 (s, 2H)

Step 3: 2-(2-Chloro-5-methoxypyridin-3-vDacetonitrile

[0765] A solution of (2-Chloro-5-methoxypyridin-3-yl)methyl methanesulfonate (200 mg, 0. 80 mmol) in anhydrous DMF (1 mL) was treated with sodium cyanide (1 17 mg, 2.39 mmol), and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 ^c 5 mL). The combined organic phases were washed sequentially with water (5 mL) and brine (5 mL), before being dried over Na2SC>4, filtered and concentrated under vacuum to give the crude product, which was purified by flash column chromatography eluting with a gradient of methanol (0-4%) in dichloromethane to give the desired product as a yellow solid (89 mg, 61%). UPLC-MS (Acidic Method, 2 min): rt =

0.86 min, m/z 183.0/185.0 [M+H]⁺. Ή NMR (400 MHz, CDCb) d ppm 8.07 (d, 7=2.9 Hz, 1H), 7.41-7.44 (m, 1H), 3.90 (s, 3H), 3.84 (s, 2H)

Step 4: 2-(2-Chloro-5-methoxypyridin-3-yl^')acetic acid

[0766] A suspension of 2-(2-chloro-5-methoxypyridin-3-yl)acetonitrile (1.19 g, 6.55 mmol) in a 15% (w/v) solution of aqueous sodium hydroxide (1 1.9 mL) was heated at 100 °C with stirring for 2 h, resulting in a clear solution. The reaction mixture was then cooled to 5 °C (ice bath) and cautiously treated with a 1 M solution of aqueous hydrogen chloride until the solution was acidic (pH = 1 ), leading to a formation of an off-white precipitate. The solid was collected by filtration and washed with water until the filtrate became pH neutral. The solid was then dried under vacuum to give the desired product as a beige solid (1.18 g, 89%). UPLC-MS (Acidic Method, 2 min): rt = 0.78 min, m/z 202.1/204.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-ufe) d ppm 8.03 (d, .7=3.0 Hz, 1H), 7.52 (d, .7=3.0 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 2H)

Step 5: /ert-Butyl 2-(^'2-chloro-5-methoxypyridin-3-vDacetate

[0767] A suspension of 2-(2-chloro-5-methoxypyridin-3-yl)acetic acid (980 mg, 4.80 mmol) in ier/-butanol (10.9 mL) was treated sequentially with di-tert-butyl dicarbonate (1.67 mL, 7.28 mmol) and 4-dimethylaminopyridine (59 mg, 0.48 mmol), and the resulting mixture was heated at 50 °C for 2 h. The mixture was cooled down to ambient temperature and concentrated under vacuum to give a residue, which was dissolved in ethyl acetate (20 mL). The solution was washed with water (20 mL) and the aqueous phase was extracted with ethyl acetate (120 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated under vacuum to give the crude product as an oil, which was purified by flash column chromatography eluting with a gradient of ethyl acetate (0-15%) in hexanes to afford the desired product as a yellow oil (990 mg, 79%). UPLC-MS (Acidic Method, 2 min): rt = 1.16 min, m/z 258.1/260.1 [M+H]⁺. 'H NMR (400 MHz, CDCb) d ppm 8.01 (d, .7=3.0 Hz, 1H), 7.21 (d, .7=3.0 Hz, 1H), 3.88 (s, 3H),

3.66 (s, 2H), 1.48 (s, 9H)

Step 6: tert- Butyl 2-((2-fluoro-4-iodophenv0amino^')-5-methoxythienor2.3-//lpyridine-3- carboxylate

[0768] A solution of ierf-butyl 2-(2-chloro-5-methoxypyridin-3-yl)acetate (50 mg, 0.194 mmol) in anhydrous THF (2 mL) was treated with sodium ieH-butoxide (20 mg, 0.213 mmol), and the resulting mixture was stirred at ambient temperature for 5 min. A solution of 2-fluoro-4- iodo-l-isothiocyanatobenzene (54 mg, 0.194 mmol) in anhydrous THF (0.5 mL) was then added to the reaction, and the resulting mixture was stirred at ambient temperature for 1.5 h, before being heated under microwave irradiation at 90 °C for 2 h. The mixture was cooled to ambient temperature and concentrated under vacuum to give the crude product as an oil, which and purified by flash column chromatography (Silica 12 g, 0-7% ethyl acetate in hexanes), followed by the trituration of the resulting solid with hexanes to afford the desired product as a pale yellow solid (33 mg, 34%). UPLC-MS (Acidic Method, 4 min): rt = 2.84 min, m/z 500.9

[M+H]⁺. Ή NMR (400 MHz, CDCb) d ppm 10.79 (br s, 1H), 8.08 (d, .7=2.9 Hz, 1H), 7.93 (d, .7=2.8 Hz, 1H), 7.45-7.56 (m, 3H), 3.90 (s, 3H), 1.71 (s, 9H)

Step 7: 2-((2-Fluoro-4-iodophenyl~)amino^')-5-methoxythienor2.3- flpyridine-3-carboxylic acid

[0769] A solution of tert-butyl 2-((2-fluoro-4-iodophenyl)amino)-5-methoxythieno[2,3- 6]pyridine-3-carboxylate (385 mg, 0.77 mmol) in dichloromethane (25 mL) was treated with trifluoroacetic acid (2.5 mL), and the resulting mixture was stirred at ambient temperature for 18 h. The mixture was then concentrated under vacuum to giver an oil, which was co-distilled from toluene (2 ^c 20 mL) to afford the desired product as yellow solid (342 mg, 100%). UPLC-MS (Acidic Method, 4 min): rt = 2.14 min, m/z 443.0 [M-H]\ Ή NMR (400 MHz, DMSO-7₆) d ppm 10.69 (s, 1H), 8.06 (d, 7=2.8 Hz, 1H), 7.88 (d, 7=2.8 Hz, 1H), 7.82 (dd, 7=10.2, 1.9 Hz, 1H), 7.65 (d, 7=8.7 Hz, 1H), 7.51 (t, 7=8.6 Hz, 1H), 3.85 (s, 3H).

Step 8: 2-r(^'2-Fluoro-4-iodophenyl)amino)-A/-(2-hvdroxyethoxy)-5-methoxythienor2.3- blpyridine-3-carboxamide

[0770] A suspension of 2-((2-fluoro-4-iodophenyl)amino)-5-methoxythieno[2,3-/>]pyridine-3- carboxylic acid (342 mg, 0.77 mmol) in THF (15 mL) was treated sequentially with PyBOP (546 mg, 1.05 mmol) and triethylamine (0.32 mL, 2.31 ), and the resulting mixture was stirred at ambient temperature for 0.5 h. (2-Aminooxy)ethanol (81 mg, 1.05 mmol) was added to the reaction, and the resulting mixture was stirred at ambient temperature for 18 h. The mixture was then diluted with ethyl acetate (10 mL), washed with water (2 ^c 10 mL), dried over Na2S04, filtered and concentrated to give the crude product, which was purified by preparatory HPLC to give the desired product as a yellow solid (131 mg, 34%). UPLC-MS (Acidic Method, 4 min): rt = 1.85 min, m/z 503.9 [M+H]⁺. Ή NMR (400 MHz, DMSO-r/e) d ppm 1 1 .29 (s, 1 H), 10.43 (br s, 1H), 8.09 (br s, 1H), 7.77 (br d, .7=10.3 Hz, 1H) 7.57-7.64 (m, 2H), 7.41 (t, 7=8.6 Hz, 1H),

4.78 (br s, 1H), 3.85-3.96 (m, 5H) 3.68-3.61 (m, 2H) Example 79: 2-((2-Fluoro-4-iodophenyl)amino)-/V-(2-hydroxyethoxy)-5-fluorothieno[2,3- b\ pyridine-3-carboxamide

Step 1 : f2-Chloro-5-fluoropyridin-3-yDmethanol

[0771] A solution of methyl 2-chloro-5-fluoronicotinate (100 mg, 0.53 mmol) in anhydrous THF (4 mL) was cooled to 0 °C and treated with sodium borohydride (120 mg, 3.17 mmol) in a portion-wise manner over a period of 5 min, and the resulting mixture was heated at 70 °C for 15 min. Methanol (0.8 mL) was then added in a dropwise manner over 15 min, resulting in considerable effervescence, and the resulting mixture was heated at 70 °C for 30 min. The mixture was cooled to ambient temperature and treated with a saturated solution of aqueous ammonium chloride (5 mL). Ethyl acetate (5 mL) was added, resulting in a biphasic mixture, which stirred for 30 min. The organic phase was collected and the aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic phases were then dried over Na2SC>4, filtered and concentrated under vacuum to give the desired product as an orange glass (84 mg, 99%). UPLC-MS (Acidic Method, 2 min): rt = 0.73 min, mlz 162.0/164.0 [M+H]⁺. 'H NMR (400 MHz, CDCI₃) d ppm 8.17 (d, .7=3.0 Hz, 1H), 7.71 (ddt, .7=8.3, 3.0, 0.9, 0.9 Hz, 1H), 4.78 (s, 2H).

Step 2: (2-Chloro-5-fluoropyridin-3-vnmethyl methanesulfonate

[0772] A solution of (2-chloro-5-fluoropyridin-3-yl)methanol (225 mg, 1.39 mmol) in anhydrous dichloromethane (5 mL) was cooled to 0 °C and treated with triethylamine (0.39 mL, 2.78 mmol) followed by methanesulfonyl chloride (0.22 mL, 2.78 mmol). The resulting mixture was then gradually warmed up to ambient temperature and stirred for 1 h. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2 ^c 5 mL). The combined organic phases were washed with brine (5 mL), dried over Na₂S0₄, filtered and concentrated under vacuum to afford the desired product as a brown oil (335 mg, 100%). UPLC-MS (Acidic Method, 2 min): rt = 0.88 min, m/z 240.1/242.0 [M+H]⁺ and 1.03 min, m/z 223.2 [M+H]⁺. ‘H NMR (400 MHz, CDCI3) d ppm 8.24-8.30 (m, 1H), 7.62-7.68 (m, 1H), 5.29 (s, 1H), 4.65 (s, 1H), 3.15 (s, 3H).

Step 3: 2-(^'2-Chloro-5-fluoropyridin-3-yl^')acetonitrile

[0773] A solution of (2-chloro-5-fluoropyridin-3-yl)methyl methanesulfonate (4.93 g, 20.6 mmol) in anhydrous DMF (20.6 mL) was treated with sodium cyanide (3.0 g, 61.7 mmol), and the resulting mixture was stirred at ambient temperature for 4 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 ^c 50 mL). The combined organic phases were washed sequentially with H2O (50 mL) and brine (50 mL), before being dried over Na2S04, filtered and concentrated under vacuum to give the crude product, which was purified by flash column chromatography eluting with a gradient of dichloromethane (0-80%) in hexanes to give the desired product as a light brown oil (1.38 g, 39%). UPLC-MS (Acidic Method, 2 min): rt = 0.84 min, m/z 171.1/173.1 [M+H]⁺. 'H NMR (400 MHz, CDCb) d ppm 8.30 (d, 7=2.9 Hz, 1H), 7.70 (ddt, 7=7.8, 2.9, 0.8, 0.8 Hz, 1H), 3.88 (t, 7=0.6 Hz, 2H).

Step 4: 2-(2-Chloro-5-fluoropyridin-3-vOacetic acid

[0774] A suspension of 2-(2-chloro-5-fluoropyridin-3-yl)acetonitrile (1.38 g, 8.09 mmol) in a 15% (w/v) aqueous solution of sodium hydroxide (13.8 mL) was heated at 100 °C with stirring for 0.5 h, resulting in a clear solution. The reaction mixture was then cooled to 5 °C (ice bath) and cautiously treated with a 1 M solution of aqueous hydrogen chloride until the solution was acidic (pH = 1), leading to a formation of an off- white precipitate. The solid was collected by filtration and washed with H2O until the filtrate became pH neutral. The solid was then dried under vacuum to give the desired product as an off-white solid (1.22 g, 80%). UPLC-MS (Acidic Method, 2 min): rt = 0.75 min, m/z 190.0/192.00 [M+H]⁺. Ή NMR (400 MHz, DMSO- de) d ppm 12.73 (br s, 1H), 8.38 (d, .7=3.0 Hz, 1H), 7.91 (dd, 7=8.8, 3.0 Hz, 1H), 3.76 (s, 2H).

Step 5 Butyl 2-(2-chloro-5-fluoropyridin-3-yl~)acetate

[0775] A suspension of 2-(2-chloro-5-fluoropyridin-3-yl)acetic acid (1.22 g, 6.43 mmol) in /erf-butanol (17 mL) was treated sequentially with di-tert-butyl dicarbonate (2.22 mL, 9.65 mmol) and 4-dimethylaminopyridine (82 mg, 0.643 mmol), and the resulting mixture was heated at 50 °C with stirring for 1.5 h. The mixture was then cooled down to ambient temperature and concentrated under vacuum to give a residue, which was dissolved in ethyl acetate (20 mL). The resulting solution was washed sequentially with water (20 mL) and brine (20 mL), before being dried over Na2SC>₄, filtered and concentrated under vacuum to give the crude product as an oil, which was purified by flash column chromatography eluting with a gradient of ethyl acetate (0- 10%) in hexanes to give the desired product as a pale yellow oil (1.25 g, 79%). UPLC-MS (Acidic Method, 2 min): rt = 1.16 min, m/z 246.1/248.1 [M+H]⁺. 'H NMR (400 MHz, CDCb) d ppm 8.20 (d, 7=3.0 Hz, 1H), 7.45 (dd, 7=8.0, 2.9 Hz, 1H), 3.69 (s, 2H), 1.47 (s, 9H).

Step 6: ferf-Butyl 2-(Y2-fluoro-4-iodophenyl~)amino)-5-fluorothienor2.3-/>1pyridine-3-carboxylate

|0776J A solution of /er/-butyl 2-(2-chloro-5-fluoropyridin-3-yl)acetate (1.15 g, 4.68 mmol) in anhydrous THF (34 mL) was treated with sodium /eri-butoxide (0.49 g, 5.148 mmol), and the resulting mixture was stirred at ambient temperature for 10 min. A solution of 2-fluoro-4-iodo- 1 -isothiocyanatobenzene (1.31 g, 4.68 mmol) in anhydrous THF (6 mL) was then added to the reaction, and the resulting mixture was stirred at ambient temperature for 1.5 h, before being heated under microwave irradiation at 90 °C for 2 h. The mixture was cooled to ambient temperature and concentrated under vacuum to give an oil, which was purified by flash column chromatography eluting with a gradient of ethyl acetate (0-5%) in hexanes to afford the desired product as a white solid (1.39 g, 56%). UPLC-MS (Acidic Method, 2 min): rt = 1.63 min, m/z 489.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-7₆) d ppm 10.44 (s, 1H), 8.34 (dd, 7=2.8, 0.8 Hz, 1H), 7.95 (dd, 7=10.6, 2.8 Hz, 1H), 7.85 (dd, 7=10.0, 1.9 Hz, 1H), 7.67 (d, 7=8.5 Hz, 1H), 7.50

(t, 7=8.5 Hz, 1H), 1.64 (s, 9H).

Step 7: Fluoro-4-iodophenvf)aminoV5-fluorothienor2.3-blpyridine-3-carboxylic acid

[0777] A solution of tert- butyl 2-((2-fluoro-4-iodophenyl)amino)-5-fluoroythieno[2,3- 6]pyridine-3-carboxylate (1.39 g, 2.85 mmol) in dichloromethane (80 mL) was treated with trifluoroacetic acid (8 mL), and the resulting mixture was stirred at ambient temperature for 18 h. The mixture was then concentrated under vacuum to give an oil, which was co-distilled from toluene (2 x 20 mL) to afford the desired product as a pale yellow solid (1.22 g, 99%). UPLC- MS (Acidic Method, 2 min): rt = 1.30 min, m/z 431.0 [M-H]\ 'H NMR (400 MHz, DMSO-fife) d ppm 10.64 (s, 1H), 8.33 (dd, 7=2.7, 0.7 Hz, 1H), 8.07 (dd, 7=10.42, 2.76 Hz, 1H), 7.85 (dd, 7=10.1, 1.8 Hz, 5 H), 7.68 (dt, 7=8.5, 1.0 Hz, 1H), 7.51 (t, 7=8.5 Hz, 1H).

Ste^p 8: 2-⁽Y2-Fluoro-4-iodophenyl^')amino^')-A/-f2-hvdroxyethoxyV5-fluorothienor2.3-/>lpyridine- 3-carboxamide

[0778] A suspension of 2-((2-fluoro-4-iodophenyl)amino)-5-fluorothieno[2,3-b]pyridine-3- carboxylic acid (500 mg, 1.16 mmol) in THF (20 mL) was treated sequentially with PyBOP (822 mg, 1.58 mmol) and triethylamine (0.49 mL, 3.48 mmol), and the resulting mixture was stirred at ambient temperature for 0.5 h. (2-Aminooxy)ethanol (122 mg, 1.58 mmol) was then added to the reaction, and the resulting mixture was stirred at ambient temperature for 18 h. The mixture was diluted with ethyl acetate (10 mL), washed with water (2 x 10 mL), dried over Na SC> , filtered and concentrated under vacuum to give the crude product, which was purified by preparatory HPLC to give the desired product as a light yellow solid (1 15 mg, 20%). UPLC-MS (Acidic Method, 2 min): rt = 1.19 min, m/z 491.9 [M+H]⁺. 'H NMR (400 MHz, DMSO-7₆) d ppm 1 1.33 (s, 1H), 10.48 (s, 1H), 8.36 (s, 1H), 7.90 (d, =9.9 Hz, 1H), 7.81 (dd, 7=10.2, 1.8 Hz, 1H), 7.62 (d, 7=8.4 Hz, 1H), 7.43 (t, 7=8.5 Hz, 1H), 4.81 (br s, 1H), 3.95 (br t, 7=4.7 Hz, 2H), 3.64 (br d, 7=4.3Hz, 2H).

Example 80: Methyl 5-acetyl-4-ethyl-2-((2-fluoro-4-iodophenyl)amino)thiophene-3- carboxylate (General Procedure for Synthesis of Tetra-substituted Thiophene-3-esters)

[0779] A solution of 2-fluoro-4-iodo-l-isothiocyanatobenzene (2.0 g, 7.16 mmol), methyl-3- oxovalerate (0.9 mL, 7.16 mmol) in DMF (20 mL) was stirred at room temperature and K2CO3 (2.0 g, 14.33 mmol) was added. Stirring was maintained for 4.5 h prior to the addition of chloroacetone (10.6 mL, 7.16 mmol) and it was further continued for the next 18 h. The reaction was quenched with H2O (150 mL) and extracted with EtOAc (2 ^c 150 mL). The combined organic extracts were washed with brine (150 mL), dried over NaSCL, filtered and the solvent removed under vacuum. The crude was purified by flash column chromatography (Silica 40 g, 5-30% EtOAC in hexane) to give the product (2.2 g, 67.3%) as an off-white solid m/z 448.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-i/e): d ppm 7.82 - 7.87 (m, 1H), 7.67 - 7.70 (m, 1H), 7.45 (m, 1H), 3.86 (s, 3H), 3.15 - 3.23 (q, =7.3 Hz, 2H), 2.42 (s, 3H), 1.1 1 - 1.19 (t, J=7.3 Hz, 3H).

Example 81 : Ethyl 5-acetyl-2-((2-fluoro-4-iodophenyl)amino)-4-isopropylthiophene-3- carboxylate

[0780] The title material was synthesised according to the general procedure for tetra- substituted thiophenes as outlined in Example 1 , using 2-fluoro-4-iodo-l-isothiocyanatobenzene (2.0 g, 7.16 mmol), ethyl 4-methyl-3-oxopentanoate (1.2 mL, 7.16 mmol), DMF (20 mL), K2CO3 (2.0 g, 14.33 mmol), and chloroacetone (0.6 mL, 7.16 mmol). The product was isolated as a flocculant white solid (2.4 g, 69.3%) after purification by a flash column chromatography (Silica 40 g, 5-30% EtOAC in hexane) m/z 475.9 [M+H]⁺. Ή NMR (400 MHz, DMSO-cfe): d ppm 7.83 (dd, .7=10.2, 1.8 Hz, 1H), 7.67 (d, .7=8.5 Hz, 1H), 7.48 (t, .7=8.6 Hz, 1H), 4.33 (q, .7=7.0 Hz, 2H), 3.07 (sep, .7=6.6 Hz, 1H), 1.33 (t, .7=7.0 Hz, 3H), 1.08 (d, .7=6.7 Hz, 6H).

Example 82: Ethyl 5-acetyI-2-((2-fluoro-4-iodophenyl)amino)-4-methylthiophene-3- carboxylate

[0781] The title material was synthesized according to the general procedure for tetra- substituted thiophenes as outlined in Example 1, using 2-fluoro-4-iodo-l-isothiocyanatobenzene (1.0 g, 3.6 mmol), ethyl acetoacetate (0.5 mL, 3.6 mmol), DMF (10 mL), K2CO3 (1.0 g, 7.2 mmol), and chloroacetone (0.3 mL, 3.6 mmol). The product was isolated after work-up as an orange solid (1.6 g, 99%) and was used without further purification m/z 447.9 [M+H]⁺.

Ή NMR (400 MHz, CDCb): d ppm 7.50 - 7.58 (m, 2H), 7.44 - 7.50 (m, 1H), 4.43 (d, .7=7.1 Hz, 2H), 2.79 (s, 3H), 2.53 (s, 3H), 1.44 (t, .7=7.1 Hz, 3H).

Example 83 : 5-Acetyl-4-ethyl-2-((2-fluoro-4-iodophenyl)amino)thiophene-3-carboxylic acid (General Procedure for Ester Hydrolysis)

[0782] A solution of methyl 5-acetyl-4-ethyl-2-((2-fluoro-4-iodophenyl)amino)thiophene-3- carboxylate (1.8 g, 4.02 mmol), THF (72 mL), MeOH (24 mL), H2O (48 mL) was stirred at room temperature and treated with 1M LiOH (24.1 mL, 24.1 mmol). A reflux condenser was attached and the reaction mixture was stirred at 50°C for 18 h. The cooled reaction mixture was acidified with 1M HC1, extracted with EtOAc (2 ^c 100 mL), and the combined organic layers were washed with brine (150 mL), dried over NaSC>4, filtered and concentrated under vacuum to give a yellow solid. The crude solid was triturated with DCM to give the product (1.75 g, quantitative) and was used without further purification m/z 433.9 [M+H]⁺. 'H NMR (400 MHz, DMSO-cfe): d ppm 10.76 - 10.89 (br s, 1H), 7.79 - 7.81 (m, 1H), 7.65 - 7.70 (m, 1H), 7.46 - 7.52 (m, 1H), 3.20 - 3.27 (q, 7=7.2 Hz, 2H), 2.44 (s, 3H), 1.15 (t, 7=7.2 Hz, 3H).

Example 84: 5-Acetyl-2-((2-fluoro-4-iodophenyl)amino)-4-isopropylthiophene-3-carboxylic acid

[0783] The title material was synthesized according to the general procedure for ester hydrolysis as outlined in the synthesis of Example 4, using ethyl 5-acetyl-2-((2-fluoro-4- iodophenyl)amino)-4-isopropylthiophene-3-carboxylate (2.0 g, 4.2 mmol), THE (75.7 mL), EtOH (25.2 mL), H2O (50.5 mL) and 1M LiOH (25.2 mL, 25.2 mmol). The brown crude solid was purified by trituration with acetone to give the product as an off-white solid (1.0 g, 54.6%). m/z 447.9 [M+H]⁺. Ή NMR (400 MHz, DMSO-7₆): d ppm 10.82 (br s, 1H), 7.82 (dd, .7=10.4, 1.8 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.50 (t, 7=8.6 Hz, 1H), 3.10 (sep, 7=6.6 Hz, 1H), 2.67 - 2.74 (m, 3H), 1.09 (d, =6.6 Hz, 6H).

Example 85: 5-Acetyl-2-((2-fluoro-4-iodophenyl)amino)-4-methylthiophene-3-carboxylic acid

[0784] The title material was synthesized according to the general procedure for ester hydrolysis as outlined in Example 4, using ethyl 5-acetyl-2-((2-fluoro-4-iodophenyl)amino)-4- methylthiophene-3-carboxylate (1.6 g, 3.6 mmol), THF (64 mL), EtOH (21.3 mL), H2O (42.8 mL) and 1M LiOH (21.3 mL, 21.3 mmol). The brown crude solid was purified by trituration with acetone to give the product as a brown solid (0.8 g, 68.7%). m/z 419.9 [M+H]⁺. 'H NMR (400 MHz, DMSO-rfe): d ppm 13.43 (br s, 1H), 10.82 (br s, 1H), 7.81 (dd, 7=10.4, 1.8 Hz, 1H), 7.68 (m, 1H), 7.48 (t, 7=8.6 Hz, 1H), 2.70 (s, 3H), 2.45 (s, 3H).

[0785] The following compounds were prepared according to the general procedure given above using the appropriate starting intermediates and reagents:

Example 88: 5-Acetyl-4-ethyl-2-((2-fluoro-4-iodophenyl)amino)-./V-(2-hydroxyethoxy) thiophene-3-carboxamide (General Procedure for Amide Coupling)

[0786] A solution of 5-acetyl-4-ethyl-2-((2-fluoro-4-iodophenyl)amino)thiophene-3-carboxylic acid (200 mg, 0.46 mmol), HATU (340 mg, 0.92 mmol), DMF (4.45 mL) in a Reacti-Vial™ was treated with DIPEA (0.15 mL, 0.92 mmol). The Reacti-Vial™ was sealed and the reaction mixture was heated to 50°C for 1 h, then cooled down to room temperature and 2- (aminooxy)ethanol (48 mΐ, 0.69 mmol) was added. The Reacti-Vial™ was re-sealed and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was purified by preparatory HPLC to give the product (28 mg, 12.3%) as an off-white/yellow solid.

m/z 493.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-7₆): d ppm 1 1.40 - 1 1.49 (br s, 1H), 8.98 - 9.10 (br s, 1H), 7.70 (br d, 7=10.2 Hz, 1H), 7.53 (br d, 7=8.1 Hz, 1H), 7.17 (br t, 7=8.2 Hz, 1H),

4.78 - 4.85 (br s, 1H), 3.81 (t, 7=4.0 Hz, 2H), 3.53 - 3.59 (t, 7=4.0 Hz, 2H), 2.93 (m, 2H), 2.38 (s, 3H), 1.10 (t, 7=7.4 Hz, 3H).

Example 89: 5-Acetyl-2-((2-fluoro-4-iodophenyl)amino)-/V-(2-hydroxyethoxy)-4- isopropylthiophene-3-carboxamide

[0787] The title material was synthesized according to the general procedure for amide coupling as outlined in Example 9, using 5-acetyl-2-((2-fluoro-4-iodophenyl)amino)-4- isopropylthiophene-3 -carboxylic acid (100 mg, 0.22 mmol), HATU (170 mg, 0.44 mmol), DMF (2.2 mL), DIPEA (70 mΐ, 0.44 mL), and 2-(aminooxy)ethanol (23 mΐ, 0.33 mL). The reaction mixture was purified by preparatory HPLC to give the product (9.0 mg, 7.9%) as a pale yellow/off-white solid m/z 506.9 [M+H]⁺. 'H NMR (400 MHz, DMSO-7₆): d ppm 1 1.35 (br s, 1H), 9.45 (br s, 1H), 7.73 (br d, 7=9.4 Hz, 1H), 7.56 (br d, 7=8.5 Hz, 1H), 7.26 (br t, 7=8.5 Hz, 1H), 4.81 (br s, 1H), 3.80 - 3.91 (m, 2H), 3.40 - 3.64 (m, 2H), 3.04 (sep, 7= 6.6 Hz, 1H), 1.07 (d, 7=6.6 Hz, 6H). Example 90: 5-Acetyl-7V-(cyclopropylmethoxy)-2-((2-fluoro-4-iodophenyl)amino)-4- isopropylthiophene-3-carboxamide

(0788] The title material was synthesized according to the general procedure for amide synthesis as outlined in the synthesis of Example 9, using 5-acetyl-2-((2-fluoro-4- iodophenyl)amino)-4-isopropylthiophene-3-carboxylic acid (100 mg, 0.22 mmol), HATU (170 mg, 0.44 mmol), DMF (2.2 mL), DIPEA (70 mΐ, 0.44 mL), and a solution of O- cyclopropylmethyl-hydroxylamine hydrochloride (41 mg, 0.33 mL) in pyridine (0.25 mL). The reaction mixture was purified by preparatory HPLC to give the product (7.2 mg, 7.8%) as a pale yellow/off-white solid m/z 516.9 [M+H]⁺. 'H NMR (400 MHz, CD CN) d ppm 7.58 - 7.65 (m, 2H), 7.47 (t, 7=8.6 Hz, 1H), 3.77 - 3.79 (d, 7=7.2, 2H), 3.09 - 3.20 (m, 1H), 2.66 (s, 3H), 1.78 - 1.81 (m, 1H), 1.15 - 1.18 (d, 7=6.6 Hz, 6H), 0.57 - 0.62 (m, 2H), 0.29 - 0.34 (m, 2H).

Example 91 : 5-Acetyl-2-((2-fluoro-4-iodophenyl)amino)-4-isopropylthiophene-3- carboxamide

[0789] The title material was synthesized according to the general procedure for amide synthesis as outlined in the synthesis of Example 9, using 5-acetyl-2-((2-fluoro-4- iodophenyl)amino)-4-isopropylthiophene-3 -carboxylic acid (100 mg, 0.22 mmol), HATU (170 mg, 0.44 mmol), DMF (2.2 mL), DIPEA (70 mΐ, 0.44 mL), and 0.5M NH₃ in 1 ,4-dioxane (0.67 mL, 0.33 mmol). The reaction mixture was purified by preparatory HPLC to give the product (13.4 mg, 13.4%) as an off-white solid m/z 446.9 [M+H]⁺. 'H NMR (400 MHz, CD₃CN): d ppm 1 1.05 - 1 1.14 (br s, 1H), 7.55 - 7.62 (m, 2H), 7.43 - 7.50 (m, 1H), 6.19 - 6.30 (br s, 2H), 3.06 - 3.18 (m, 1H), 2.71 (s, 3H), 1.13 (d, J=6.7 Hz, 6H).

Example 92: 5-Acetyl-2-((2-fluoro-4-iodophenyl)amino)-/V-(2-hydroxyethoxy)-4- methylthiophene-3-carboxamide

[0790] A solution of 5-acetyl-2-((2-fluoro-4-iodophenyl)amino)-4-methylthiophene-3- carboxylic acid (400 mg, 0.95 mmol), PyBOP (631 mg, 1.21 mmol), THF (4.8 mL) in a Reacti- Vial™ was treated with triethylamine (0.16 mL, 1.12 mmol), sealed and stirred for 30 min at room temperature. Then 2-(aminooxy)ethanol (106 mg, 1.38 mmol) was added, the Reacti- Vial™ was re-sealed and stirring continued for 18 h. The reaction mixture was diluted with EtOAc (150 mL), washed sequentially with H₂O (100 mL) and brine (100 mL), dried over Na₂SC>₄, filtered and concentrated under vacuum. The crude product was purified by preparatory HPLC to give the product (103 mg, 22.6%) as a yellow solid m/z 479.28 [M+H]⁺. 'H NMR (400 MHz, CD₃CN): d ppm 7.59 - 7.66 (m, 2H), 7.45 (t, =8.8 Hz, 1H), 3.99 - 4.05 (m, 2H), 3.70 - 3.73 (m, 2H), 2.64 (s, 3H), 2.46 (s, 3H).

Example 93 : (S)-5-acetyl-N-(2,4-dihydroxybutyl)-2-((2-fIuoro-4-iodophenyl)amino)-4- methylthiophcne-3-carboxamide

Step 1 : (5)-5-acetyl-N-((2.2-dimethyl-L3-dioxolan-4-yl)methyl)-2-((2-fluoro-4- iodophenyl)amino)-4-methylthiophene-3-carboxamide

[0791] A solution of 5-acetyl-4-ethyl-2-((2-fluoro-4-iodophenyl)amino)thiophene-3-carboxylic acid (1.00 g, 2.39 mmol), PyBOP (1.61 g, 3.10 mmol) and Et3N (0.4 mL, 2.87 mmol) in THF (12.5 mL) was stirred for 30 min at room temperature, then it was treated with (S)-(+)-(2,2- dimethyl-l ,3-dioxolan-4-yl)methanamine (0.47 g, 3.59 mmol) and stirred for 2 h. The reaction mixture was concentrated in vacuo , the residue was dissolved in EtOAc (30 mL) and washed with water (30 mL), then brine (30 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated in vacuo. The crude solid was purified by flash column chromatography (Silica 40 g, 0-35% EtOAc in hexane) to afford the desired product as an off-white solid (0.87 g, 69%). m/z 533.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-<¾): d ppm 9.67 (s, 1H), 8.16 (t, J= 5.9 Hz, 1H), 7.74 (dd, .7=10.5, 1.8 Hz, 1H), 7.58 (d, .7=8.4 Hz, 1H), 7.29 (t, y=8.7 Hz, 1H), 4.13 (quin, .7=5.9 Hz, 1H), 3.94 (dd, .7=8.3, 6.3 Hz, 1H), 3.67 (dd, .7=8.3, 5.6 Hz, 1H), 3.36 - 3.44 (m, 1H), 3.24 - 3.33 (m, 1H), 2.54 (s, 3 H), 2.43 (s, 3H), 1.34 (s, 3H) 1.26 (s, 3H).

Step 2: (5^-5-acetyl-N-(2.4-dihvdroxybutyl)-2-((2-fluoro-4-iodophenyl)amino)-4- methylthiophene-3-carboxamide

[0792] A solution of (S)-5-acetyl-N-((2,2-dimethyl-l ,3-dioxolan-4-yl)methyl)-2-((2-fluoro-4- iodophenyl)amino)-4-methylthiophene-3-carboxamide (0.64 g, 1.20 mmol) in 1,4-dioxane (5 mL) was treated with 4M HC1 in 1 ,4-dioxane (0.75 mmol) and stirred at room temperature for 4 h. The formed precipitate was filtered off, washed with 1,4-dioxane, Et₂0 and EtOH to give the product (0.351 g, 59%) as an off-white solid m/z 492.9 [M+H]⁺. 'H NMR (400 MHz, DMSO- d₆): 5 ppm 9.87 (s, 1H), 7.91 (t, .7=5.8 Hz, 1H), 7.73 (dd, .7=10.5, 1.9 Hz, 1H), 7.59 (d, =8.4 Hz, 1H), 7.34 (t, 7=8.7 Hz, 1H), 4.83 (d, 7=5.0 Hz, 1H), 4.61 (t, 7=5.7 Hz, 1H), 3.58 - 3.65 (m, 1H),

3.33 - 3.41 (m, 3H), 3.10 - 3.25 (m, 1H), 2.55 (s, 3H), 2.43 (s, 3H).

Example 94: (7?)-5-acetyl-N-(2,4-dihydroxybutyl)-2-((2-fluoro-4-iodophenyI)amino)-4- methylthiophene-3-carboxamide

Step 1 : (7?)-5-acetyl-N-((2.2-dimethyl- 1.3-dioxolan-4-yl)methyl)-2-((2-fluoro-4- iodophenyl)amino)-4-methylthiophene-3-carboxamide

[0793] To a solution of 5-acetyl-2-((2-fluoro-4-iodophenyl)amino)-4-methylthiophene-3- carboxylic acid (1.00 g, 2.39 mmol) in THF (12.5 mL) was added Et3N (0.4 mL, 2.87 mmol) and PyBOP (1.62 g, 3.1 1 mmol). The resultant mixture was stirred for 30 min, before the addition of (7?)-(-)-(2,2-dimethyl-[l,3]dioxolan-4-yl) methylamine (471 mg, 3.59 mmol) as a solution in THF (0.5 mL). The reaction mixture was stirred for 4 h, before the solvent was removed in vacuo and the crude residue was partitioned between EtOAc and H2O. The organic layer was separated, washed with brine, dried over Na2SC>4, and the solvent removed in vacuo. The crude material was purified by flash column chromatography (Silica 40 g, 20-30% EtOAc in hexane) to give the product (969 mg, 76%) as a light purple solid m/z 533.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-i/e): d ppm 9.66 (s, 1 H), 8.14 (t, .7=5.9 Hz, 1H), 7.73 (dd, .7=10.5, 1.9 Hz, 1H), 7.57 (d, .7=8.4 Hz, 1H), 7.28 (t, .7=8.7 Hz, 1H), 4.13 (quin, .7=5.9 Hz, 1H), 3.94 (dd, .7=8.3, 6.3 Hz, 1H), 3.67 (dd, .7=8.4, 5.6 Hz, 1H), 3.35 - 3.46 (m, 1H), 3.23 - 3.31 (m, 1H), 2.54 (s, 3H), 2.42 (s, 3H), 1.33 (s, 3H), 1.25 (s, 3H).

Step 2: (7?V5-acetyl-N-(2.4-dihvdroxybutyl)-2-((2-fluoro-4-iodoDhenyl)amino)-4- methylthiophene-3 -carboxamide

[0794] To a solution of (7?)-5-acetyl-7V-((2, 2-dimethyl- 1,3 -dioxolan-4-yl)methyl)-2-((2-fluoro- 4-iodophenyl)amino)-4-methylthiophene-3-carboxamide (417 mg, 0.783 mmol) in dioxane (5 mL) was added 4 N HC1 in dioxane (0.49 mL, 1.96 mmol). The reaction mixture was stirred at room temperature for 18 h, resulting in the formation of a precipitate. The solid material was filtered and washed with Et20 to give the product (331 mg, 86%) as a light purple solid m/z 492.9 [M+H]⁺. Ή NMR (400 MHz, DMSO-*): d ppm 9.88 (s, 1H), 7.93 (br t, .7=5.6 Hz, 1H), 7.74 (dd, .7=10.4, 1.8 Hz, 1H), 7.59 (d, .7=8.4 Hz, 1H), 7.34 (t, .7=8.7 Hz, 1H), 4.86 (d, .7=5.0 Hz,

1H), 4.64 (t, J= 5.7 Hz, 1H), 3.61 (br d, .7=6.7 Hz, 1H), 3.29 - 3.43 (m, 3H), 3.13 - 3.22 (m, 1H), 2.56 (s, 3H), 2.42 (s, 3H).

Example 95: (/?)-5-acetyl-2-((2-fluoro-4-iodophenyl)amino)-4-methyl-N-(piperidin-3- yl)thiophene-3-carboxamide

Step 1 : (RVtert-butyl 3-(5-acetyl-2-((2-fluoro-4-iodophenyl)amino)-4-methylthiophene-3- carboxamidolpiperidine- 1 -carboxyl ate

[0795] Following the general synthetic examples given above, the title compound was prepared using the appropriate starting intermediates and reagents. m/z\ 600.2 [M-l]⁺.

Step 2: (^'R^')-5-acetyl-2-(^'(2-fluoro-4-iodophenvDaminoV4-methyl-N-fpiperidin-3-yl~)thiophene-3- carboxamide

[0796] A round bottom flask was charged with (R)-tert-butyl 3-(5-acetyl-2-((2-fluoro-4- iodophenyl)amino)-4-methylthiophene-3-carboxamido)piperidine-l -carboxylate (0.062 g, 0.1 mmol) in dichloromethane (8 mL) and 4M hydrogen chloride in dioxan (0.26 mL, 1.0 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction was only 50% complete even after addition of more acid (0.13 mL). The solid formed was isolated by centrifuge, washed with dichloromethane 3 times, and dried by the lyophillizer to give the title compound as a light salmon colored solid (19 mg, 37%). m/z 502.2 [M+l]⁺. 'H NMR (300 MHz, DMSO[-d6): d 9.51 (s, 1 H), 8.93-8.80 (m, 2H), 8.23 (d, J=7.8 Hz, 1 H), 7.70 (d, J=9.9 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.24 (t, J=8.9 Hz, 1H), 4.08-4.05 (m, 1H), 3.24-3.12

(m, 2H), 2.73-2.70 (m, 2H), 2.49 (s, 3H), 2.39 (s,3H), 1.84-1.80 (m, 2H), 1.67-163 (m, 1H), 1.48-1.45 (m, 1H).

Example 96: (R)-5-acetyl-2-((2-fluoro-4-iodophenyl)amino)-4-methyl-N-(pyrrolidin-3- yl)thiophene-3-carboxamide

[0797] The title compound was prepared by the two step procedure according to Example 14. m/z 488.1 [M+l]⁺. Ή NMR (300 MHz, DMSO-d6): d 9.54 (s, 1H), 9.02-8.92 (m,2H), 8.36 (d, J=6.0 Hz, 1H), 7.73 (dd, J=1.8 and 1.8 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.25 (t, J=8.4 Hz, 1H), 4.45-4.38 (m, 1H), 3.24-3.08 (m, 4H), 2.51 (s, 3H), 2.40 (s, 3H), 2.15-2.07 (m, 1H), 1.91-1.85 (m, 1 H).

Example 97: (R)-l-(4-(3-aminopyrrolidine-l-carbonyl)-5-((2-fluoro-4-iodophenyl)amino)- 3-methylthiophen-2-yl)ethanone

[0798] The title compound was prepared by the two step procedure according to Example 14. m/z 488.1 [M+l]⁺.

[0799] The following compounds were prepared according to the general procedure given above using the appropriate starting intermediates and reagents:

Example 106: Ethyl 2-((2-fluoro-4-iodophenyl)amino)-7-oxo-4,5,6,7-tetrahydrobenzo

[6]thiophene-3-carboxylate

Step 1 : 2-Fluoro-4-(trimethylsilyl)aniline

[0800] To a solution of 4-bromo-2-fluoroaniline (5.00 g, 26.31 mmol) in anhydrous THF (33 mL) under N2 cooled down to -78 °C, n-BuLi (1.6M in hexanes, 65.75 mL, 105.25 mmol) was added dropwise over 20 min with internal temperature kept below -60 °C. Then the cooling bath was removed and when internal temperature reached 0 °C an ice-cold 2M HC1 (150 mL) was added to the mixture and stirred vigorously for 10 min. Organic phase was separated, washed with water (100 mL) and saturated NaHC0₃ solution (100 mL). Aqueous phase was additionally extracted with DCM (4 ^c 100 mL) and the organic phase was washed with saturated NaHC0₃ solution (2 ^c 200 mL). Combine organic phases were dried over Na₂S0₄ and concentrated in vacuo. The crude was purified by flash column chromatography (Silica 80 g, 0-10% EtOAC in hexane) to give the product (2.71 g, 56%) as a red-brown oil. m/z 184.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-r/i): d ppm 7.02 (dd, 7=1.2, 1 1.8 Hz, 1H), 6.97 (dd, 7=1.2, 7.6 Hz, 1H), 6.76 (dd, 7=7.8, 8.9 Hz, 1H), 5.21 (br s, 2H), 0.17 (s, 9H).

Step 2: Ethyl 2-bromo-7-oxo-4.5.6.7-tetrahydrobenzor/?lthiophene-3-carboxylate

[0801] To a solution of copper(II) bromide (6.53 g, 29.25 mmol) in acetonitrile (77 mL) in a 3- neck flask under N₂ cooled to 0 °C, ierf-butyl nitrite (90%, 3.2 mL, 24.03 mmol) was added dropwise. The mixture was stirred for 20 min at 0°C followed by a portionwise addition of solid ethyl 2-amino-7-oxo-4,5,6,7-tetrahydrobenzo[6]thiophene-3-carboxylate (5.00 g, 20.89 mmol) using a funnel under N₂ flow. The mixture was stirred under N₂ at 0°C for further 30 min and then partitioned between 2M HC1 aqueous solution (250 mL) and EtOAc (200 mL). Aqueous phase was additionally extracted with EtOAc (4 x 100 mL). Combined organic phases were washed with brine (100 mL), dried over Na₂S0₄ and concentrated in vacuo. The crude was purified by flash column chromatography (Silica 120 g, 0-100% DCM in hexane) to give the product (3.85 g, 61%) as a light brown solid m/z 304.9 [M+H]⁺. Ή NMR (400 MHz, CDCI₃): d ppm 4.40 (q, 7=7.1 Hz, 2H), 3.08 (t, 7=6.1 Hz, 2H), 2.61 (dd, 7=7.2, 6.0 Hz, 2H), 2.01 - 2.35 (m, 2H), 1.42 (t, 7=7.2 Hz, 3H). Step 3: Ethyl 2-(Y2-fluoro-4-(trimethylsilvOphenyOaminoT7-oxo-4,5,6.7- tetrahvdrobenzorfelthiophene-3-carboxylate

[0802] A solution of Pch(dba)3 (91 mg, 0.098 mmol) and BINAP (124 mg, 0.199 mmol) in dry toluene (24 mL) in a Reacti-Vial™ was bubbled through with N2 for 1 min followed by an addition of ethyl 2-bromo-7-oxo-4,5,6,7-tetrahydrobenzo[Z?]thiophene-3-carboxylate (600 mg, 1.979 mmol), CS2CO3 (904 mg, 2.774 mmol), and 2-fluoro-4-(trimethylsilyl)aniline (436 mg, 2.379 mmol) diluted with dry toluene (2 mL). The mixture was further bubbled through with N2 for 1 min, sealed and stirred at 120 °C for 48 h. The reaction was quenched with saturated NH4CI aqueous solution (120 mL) and extracted with EtOAc (4 ^c 50 mL). Combined organic phases were washed with brine (200 mL), dried over Na2SC>4, and concentrated in vacuo. The crude was purified by flash column chromatography (Silica 80 g + 12 g dry-load, 0-15% EtOAc in hexane) to give the product (716 mg, 89%) as a light yellow solid m/z 406.1 [M+H]⁺.

Ή NMR (400 MHz, CDCI3): d ppm 10.93 (br s, 1 H), 7.68 (t, .7=8.0 Hz, 1H), 7.28 - 7.35 (m, 2H), 4.41 (q, .7=7.2 Hz, 2H), 3.11 (t, .7=6.1 Hz, 2H), 2.51 - 2.66 (m, 2H), 2.18 (quin, 7=6.3 Hz, 2H),

1.43 (t, .7=7.2 Hz, 3H), 0.29 (s, 9H).

Step 4: Ethyl 2- fluoro-4-iodophenyOaminoV7-oxo-4,5.6.7-tetrahvdrobenzoi/ 1thiophene-3-

carboxylate

[0803] A solution of AgBF4 (3.72 g, 19.13 mmol) in dry DCM (22 mL) under N2 cooled to -

50 °C and protected from light was stirred for 15 min. A solution of ethyl 2-((2-fluoro-4- (trimethylsilyl)phenyl)amino)-7-oxo-4,5,6,7-tetrahydrobenzo[7]thiophene-3-carboxylate (2.59 g, 6.38 mmol) in dry DCM (50 mL) was added dropwise over 8 min and the mixture was further stirred at -50 °C for 30 min. Iodine monochloride (0.35 mL, 7.01 mmol) in dry DCM (10 mL) was added dropwise over 10 min and the reaction was stirred for 30 min. Reaction was quenched with saturated Na₂S₂C>₃ aqueous solution (200 mL) and it was extracted with EtOAc (4 x 100 mL). Combined organic phases were washed with brine, dried over Na2SC>4, and concentrated in vacuo. The crude was purified by recrystallisation from EtOH (160 mL) to give the product (2.37 g, 81%) as a creamy solid m/z 459.9 [M+Hf. Ή NMR (400 MHz, CDCb): d ppm 10.92 (br s, 1H), 7.47 - 7.57 (m, 2H), 7.35 - 7.47 (m, 1H), 4.40 (q, .7=7.2 Hz, 2H), 3.09 (t, .7=6.1 Hz, 2H), 2.57 (dd, .7=5.9, 7.3 Hz, 2H), 2.17 (quin, .7=6.3 Hz, 2H), 1.42 (t, 7=7.2 Hz, 3H).

Example 107: 2-((2-Fluoro-4-iodophenyl)amino)-7-oxo-4, 5,6,7- tetrahydrobenzo[Z»]thiophene-3-carboxylic acid

[0804] To a solution of ethyl 2-((2-fluoro-4-iodophenyl)amino)-7-oxo-4, 5,6,7- tetrahydrobenzo[6]thiophene-3-carboxylate (2.37 g, 5.16 mmol) in THF (93 mL), EtOH (31 mL) and H2O (62 mL), 1M LiOH aqueous solution (31 mL) was added. The mixture was stirred at 60 °C for 48 h. The solvents were removed in vacuo and the residue was sonicated with 1M HC1 aqueous solution (200 mL) for 2.5h. The resulting precipitate was filtered and triturated with acetone (25 mL) to give the product (1.89 g, 85%) as a pale beige solid m/z 431.9 [M+H]⁺.

Ή NMR (400 MHz, DMSO-cfc): d ppm 13.37 (br s, 1 H), 10.92 (br s, 1 H), 7.81 (dd, 7=1.9, 10.3 Hz, 1H), 7.58-7.72 (m, 1H), 7.47 (t, 7=8.6 Hz, 1H), 3.04 (t, 7=6.0 Hz, 2H), 2.46 (br t, 7=6.5 Hz, 2H), 2.06 (quin, 7=6.0 Hz, 2H).

Example 108: 2-((2-Fluoro-4-iodophenyl)amino)-./V-(2-hydroxyethoxy)-7-oxo-4, 5,6,7- tetrahydrobenzo[6]thiophene-3-carboxamide

[0805] A solution of 2-((2-fluoro-4-iodophenyl)amino)-7-oxo-4,5,6,7- tetrahydrobenzo[6]thiophene-3-carboxylic acid (509 mg, 1.180 mmol), HATU (897 mg, 2.360 mmol), and pyridine (191 pL, 2.360 mmol) in DMF (24 mL) was stirred at 45 °C and monitored towards completion of HATU-activation of the acid. After 3 h the reaction was cooled down to room temperature, 2-aminooxyethanol (182 mg, 2.360 mmol) was added and it was stirred at room temperature for 26 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (4 ^c 50 mL). Combined organic phases were washed with ice-cold brine (2 ^c 200 mL), dried over NaaSCL, and concentrated in vacuo. The crude was purified by preparative HPLC to give the product (238 mg, 41%) as a white solid m/z 490.9 [M+H]⁺. 'H NMR (400 MHz, DMSO-r/i): d ppm 1 1.07 (br s, 1 H), 10.25 (br s, 1 H), 7.77 (d, =9.8 Hz, 1H), 7.61 (d, 7=7.9 Hz, 1H), 7.36 (t, 7=8.6 Hz, 1H), 4.76 (br t, 7=4.0 Hz, 1H), 3.90 (br t, 7=4.6 Hz, 2H), 3.55 - 3.74 (m, 2H), 2.92 (br t, 7=4.0 Hz, 2H), 2.45 (br t, 7=6.1 Hz, 2H), 2.04 (br quin, 7=6.0 Hz,

2H).

Example 109: (if)-7V-(2,3-Dihydroxypropoxy)-2-((2-fluoro-4-iodophenyl)amino)-7-oxo- 4,5,6,7-tetrahydrobenzo[Z>]thiophene-3-carboxamide

[0806] A solution of 2-((2-fluoro-4-iodophenyl)amino)-7-oxo-4, 5,6,7- tetrahydrobenzo[£]thiophene-3-carboxylic acid (330 mg, 0.765 mmol), HATU (582 mg, 1.530 mmol), and pyridine (124 pL, 1 .530 mmol) in DMF (16 mL) was stirred at 45 °C and monitored towards completion of HATU-activation of the acid. After 18 h the reaction was cooled down to room temperature, (/?)-C>-((2,2-dimethyl-l ,3-dioxolan-4-yl)methyl)hydroxylamine (168 mg,

1.148 mmol) was added and it was stirred at room temperature for 1 h. The reaction mixture was diluted with ¾0 (80 mL) and extracted with EtOAc (4 ^c 50 mL). Combined organic phases were washed with ice-cold brine (2 x 200 mL), dried over Na₂S0₄, and concentrated in vacuo. The crude residue was dissolved in MeOH (5.3 mL) followed by an addition of p-toluene sulfonic acid monohydrate (56 mg, 0.294 mmol) and ethylene glycol (210 pL, 3.722 mmol). The resultant mixture was stirred at room temperature 5 h, followed by an addition of Et3N (105 pL, 0.767 mmol) to the reaction mixture and the solvent was removed in vacuo. The crude product was purified by preparatory HPLC to give the product (174 mg, 43%) as a light- yellow solid. m/z 520.9 [M+H]+. Ή NMR (400 MHz, DMSO-i/<s): d ppm 1 1.09 (br s, 1H), 10.25 (br s, 1H), 7.77 (br d, 7=10.5 Hz, 1 H), 7.62 (d, .7=8.4 Hz, 1H), 7.37 (t, .7=8.6 Hz, 1H), 4.89 (br d, .7=3.9 Hz, 1H), 4.62 (t, .7=5.7 Hz, 1H), 3.94 (br dd, .7=2.4, 9.1 Hz, 1H), 3.63 - 3.84 (m, 2H), 3.34 - 3.49 (m, 2H), 3.01 - 2.84 (m, 2H), 2.39 - 2.48 (m, 2H), 1.91 - 2.12 (m, 2H).

Example 110: 2-((2-FIuoro-4-iodophenyl)amino)-./V-hydroxy-7-oxo-4, 5,6,7- tetrahydrobenzo[6]thiophene-3-carboxamide

[0807] A solution of 2-((2-fluoro-4-iodophenyl)amino)-7-oxo-4, 5,6,7- tetrahydrobenzo[6]thiophene-3-carboxylic acid (300 mg, 0.696 mmol), HATU (529 mg, 1.391 mmol), and pyridine (112 pL, 1.391 mmol) in DMF (12 mL) was stirred at 40 °C and monitored towards completion of HATU-activation of the acid. After 18 h the reaction was cooled down to room temperature, hydroxylamine hydrochloride (725 mg, 1 .044 mmol) and pyridine (1 12 pL, 1.391 mmol) were added and it was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (4 x 50 mL). Combined organic phases were washed with ice-cold brine (2 x 150 mL), dried over Na2SC> , and concentrated in vacuo. The crude was purified by preparative HPLC (Reach Separations, UK) to give the product (137 mg, 44%) as a light-yellow solid m/z 447.0 [M+H]⁺. 'H NMR (400 MHz, DMSO- d₍,) d ppm 10.58 (br s, 1H), 10.48 (br s, 1H), 9.16 (br s, 1H), 7.75 (br d, .7=9.5 Hz, 1H), 7.61 (br d, .7=8.8 Hz, 1H), 7.38 (br t, 7=8.7 Hz, 1H), 2.92 (br t, 7=5.0 Hz, 2H), 2.43 (br t, 7=5.0 Hz, 2H), 1.98 - 2.06 (br m, 2H).

Example 111: yV-(Cyclopropylmethoxy)-2-((2-fluoro-4-iodophenyl)amino)-7-oxo- 4,5,6,7-tetrahydrobenzo [ b ] thiophene-3-carboxamide

[0808] A solution of 2-((2-fluoro-4-iodophenyl)amino)-7-oxo-4, 5,6,7- tetrahydrobenzo[6]thiophene-3-carboxylic acid (44 mg, 0.102 mmol), HATU (2 ^c 78 mg, 0.408 mmol), and pyridine (2 x 16 pL, 0.408 mmol) in DMF (2 mL) was stirred initially at room temperature for 18 h, and then at 40 °C for 1.5 h being monitored towards completion of HATU- activation of the acid. The reaction was cooled down to room temperature,

0-(cyclopropylmethyl)-hydroxylamine hydrochloride (15+7+7 mg, 0.245 mmol) was added and it was stirred at room temperature for 48 h. The reaction mixture was directly purified by preparative HPLC to give the product (9 mg, 17%) as an off-white solid m/z 500.9 [M+H]⁺.

Ή NMR (400 MHz, DMSO-7₆): d ppm 1 1.00 (br s, 1 H), 10.25 (br s, I H), 7.69 - 7.83 (m, 1 H), 7.52 - 7.66 (m, 1H), 7.21 - 7.45 (m, 1H), 3.66 (d, 7=7.5 Hz, 2H), 2.88 - 2.96 (m, 2H), 2.38 - 2.48

(m, 2H), 1.99 - 2.12 (m, 2H), 1.02 - 1.17 (m, 1H), 0.44 - 0.60 (m, 2H), 0.21 - 0.31 (m, 2H). Example 112: 7V-(2-Aminoethoxy)-2-(2-fluoro-4-iodophenylamino)-7-oxo-4, 5,6,7- tetrahydrobenzo[6]thiophene-3-carboxamidc hydrochloride

Step 1 : fe/7-Butyl 2-(2-(2-fluoro-4-iodophenylamino)-7-oxo-4.5.6.7-tetrahvdrobenzo lAlthiophene-B-carboxamidooxytethylcarbamate

[0809] To a solution of 2-((2-fluoro-4-iodophenyl)amino)-7-oxo-4, 5,6,7- tetrahydrobenzo[6]thiophene-3-carboxylic acid (600 mg, 1.391 mmol) and HATU (1.06 g, 2.783 mmol) in DMF (18 mL) stirred at room temperature DIPEA (0.486 ml, 2.783 mmol) was added dropwise and the reaction was monitored towards completion of HATU-activation of the acid. After 40 min tert- butyl 2-(aminooxy)-ethylcarbamate (368 mg, 2.086 mmol) was added to the reaction mixture and it was stirred at room temperature for 1 h. The reaction mixture was quenched with H2O (30 mL) and a precipitate formed which was filtered and washed with H2O. The crude was purified by flash column chromatography (Silica 40 g, 0-60% EtOAc in hexanes) to give the product (473 mg, 58%) as a creamy solid m/z 590.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-cfc): d ppm 10.95 (br s, 1 H), 10.31 (br s, 1 H), 7.77 (d, J=10.3 Hz, 1H), 7.62 (d, 7=8.5 Hz, 1H), 7.37 (t, 7=8.8 Hz, 1H), 6.84 (br s, 1H), 3.93 - 3.78 (m, 2H), 3.26 - 3.14 (m, 2H), 3.00 - 2.85 (m, 2H), 2.46 - 2.37 (m, 2H), 2.13 - 1.99 (m, 2H), 1.39 (d, 7=2.5 Hz, 9H). Step 2: 7V-(2-Aminoethoxy)-2-(2-fluoro-4-iodophenylamino)-7-oxo-4.5.6.7- tetrahvdrobenzor61thiophene-3-carboxamide hydrochloride

[0810] A suspension of tert- butyl 2-(2-(2-fluoro-4-iodophenylamino)-7-oxo-4, 5,6,7- tetrahydrobenzo-[6]thiophene-3-carboxamidooxy)ethylcarbamate (50 mg, 84.8 pmol) in dioxane (0.5 ml) was stirred at room temperature and 4N HC1 in dioxane (36 mΐ, 144.2 mhioΐ) was added. After 30 min a further portion of 4N HC1 in dioxane (0.5 ml, 2.0 mmol) was added to the reaction mixture. After 18 h the suspension was filtered and the collected crude material was washed sequentially with dioxane and Et₂0 to give the product (40.5 mg, 98%) as a yellow solid. m/z 490.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-cfe): d ppm 1 1.35 (br s, 1H), 10.22 (br s, 1H), 8.00 (br s, 3H), 7.79 (dd, .7=10.4, 1.9 Hz, 1H), 7.70 - 7.59 (m, 1H), 7.38 (t, .7=8.6 Hz, 1H), 4.08 (t, .7=5.2 Hz, 2H), 3.09 (q, .7=5.5 Hz, 2H), 2.95 (t, .7=5.9 Hz, 2H), 2.50 - 2.42 (m, 2H), 2.12 - 1.96 (m, 2H).

Example 113: (5)-7V-(2,3-dihydroxypropyl)-2-((2-fluoro-4-iodophenyl)amino)-7-oxo- 4,5,6,7-tetrahydrobenzo[A]thiophene-3-carboxamide

Step 1 : ((2.2-dimethyl-1.3-dioxolan-4-yl)methyl)-2-((2-fluoro-4-iodophenyl)amino)-7- oxo-4.5.6.7-tetrahydrobenzo G &1thiophene-3 -carboxamide

[0811] A solution of 2-((2-fluoro-4-iodophenyl)amino)-7-oxo-4,5,6,7- tetrahydrobenzo[6]thiophene-3-carboxylic acid (500 mg, 1.159 mmol), HATU (882 mg, 2.319 mmol), and Et N (320 pL, 2.319 mmol) in DMF (15 mL) was stirred at room temperature and monitored towards completion of HATU -activation of the acid (5 min). (5 -(+)-(2,2-Dimethyl- [l ,3]-dioxolan-4-yl)-methylamine (229 mg, 1.738 mmol) was added and it was stirred at room temperature for 1 h. The reaction mixture was diluted with H O (50 mL) and a precipitation occurred. Solids were collected by filtration and washed with water. Aqueous filtrate was extracted with EtOAc (3 x 25 mL). Combined organic phases were washed with ice-cold brine (2 x 100 mL), dried over Na₂S0₄, and concentrated in vacuo. The combined crude was purified by flash column chromatography (Silica 40 g, 0-50% EtOAc in hexane) to give the product (314 mg, 50%) as a light purple solid m/z 545.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-rfe): d ppm 10.64 (d, 7=1.1 Hz, 1H), 7.71-7.82 (m, 2H), 7.62 (d, .7=8.4 Hz, 1H), 7.38 (t, .7=8.7 Hz,

1H), 4.20 (quin, .7=5.6 Hz, 1H), 3.98 (dd, 7=6.3, 8.3 Hz, 1H), 3.69 (dd, 7=5.6, 8.4 Hz, 1H), 3.40- 3.49 (m, 1H), 3.32-3.48 (m, 1H), 2.97 (q, 7=5.5 Hz, 2H), 2.36-2.47 (m, 2H), 2.00-2.07 (m, 2H), 1.35 (s, 3H), 1.26 (s, 3H).

Step 2: (53-7V-12.3-dihvdroxypropyn-2-(Y2-fluoro-4-iodophenvI~)amino -7-oxo-4.5.6.7- tetrahydrobenzoi d thiophene-3 -carboxamide

[0812] A solution of (S)-N-((2, 2-dimethyl- l ,3-dioxolan-4-yl)methyl)-2-((2-fluoro-4- iodophenyl)amino)-7-oxo-4,5,6,7-tetrahydrobenzo[Z>]thiophene-3-carboxamide (314 mg, 0.577 mmol) in dioxane (15 ml) was treated with 4N HC1 solution in dioxane (0.36 ml, 1.442 mmol) and stirred at room temperature. After 24h additional portion of 4N HC1 in dioxane (0.36 ml,

1.442 mmol) was added and reaction was transferred to a rotary evaporator for 2 h to remove forming acetone at 40 °C at 500 mbar. A precipitate formed with concentration thus additional dioxane (5 ml) and 4N HC1 in dioxane (0.36 ml, 1.442 mmol) were added to the reaction stirred at room temperature for further 18h until completion. Formed precipitate was filtered and washed with dioxane and Et₂0 to give the product (186 mg, 64%) as a light yellow solid. m/z 505.0 [M+H]⁺. ^]H NMR (400 MHz, DMSO-4«): d ppm 1 0.92 (d, =1.1 Hz, 1H), 7.77 (dd, 7=1.9, 10.5 Hz, 1H), 7.63 (d, 7=8.4 Hz, 1H), 7.52 (t, 7=5.7 Hz, 1H), 7.42 (t, 7=8.7 Hz, 1H), 4.88 (d, 7=5.1 Hz, 1 H), 4.66 (t, 7=5.7 Hz, 1H), 3.60-3.72 (m, 1H), 3.33-3.50 (m, 3H), 3.14-3.26 (m,

1 H), 2.93-3.07 (m, 2H), 2.44-2.47 (m, 2H), 2.02-2.16 (m, 2H).

Example 114: (K)-7V-(2,3-dihydroxypropyl)-2-((2-fluoro-4-iodophenyl)amino)-7-oxo- 4,5,6,7-tetrahydrobenzo[6]thiophene-3-carboxamide

Step 1 : (7?)-A-((2.2-dimethyl-1.3-dioxolan-4-yl)methyl)-2-((2-fluoro-4-iodophenyl >aminoV7- oxo-4.5,6.7-tetrahydrobenzor61thiophene-3-carboxamide

[0813] A solution of 2-((2-fluoro-4-iodophenyl)amino)-7-oxo-4,5,6,7- tetrahydrobenzo[6]thiophene-3-carboxylic acid (500 mg, 1.159 mmol), HATU (882 mg, 2.319 mmol), and Et3N (320 pL, 2.319 mmol) in DMF (10 mL) was stirred at room temperature and monitored towards completion of HATU-activation of the acid (5 min). (7?)-(-)-(2,2-Dimethyl- [l ,3]-dioxolan-4-yl)-methylamine (229 mg, 1.738 mmol) was added and it was stirred at room temperature for 1 h. The reaction mixture was diluted with ¾0 (40 mL) and a precipitation occurred. Solids were collected by filtration and washed with water. Aqueous filtrate was extracted with EtOAc (3 * 25 mL). Combined organic phases were washed with ice-cold brine (2 x 100 mL), dried over Na₂SC>₄, and concentrated in vacuo. The combined crude was purified by flash column chromatography (Silica 40 g, 0-80% EtOAc in hexane) to give the product (340 mg, 54%) as a light purple solid m/z 545.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-*): d ppm 10.64 (s, 1 H), 7.77 (dd, J=\ .9, 10.3 Hz, 2H), 7.62 (d, .7=8.3 Hz, 1H), 7.38 (t, y=8.7 Hz, 1H), 4.14-4.25 (m, 1H), 3.98 (dd, J=6.3, 8.3 Hz, 1H), 3.70 (dd, =5.6, 8.3 Hz, 1H), 3.40-3.51 (m, 1H), 3.27-3.38 (m, 1H), 2.97 (q, J=5.7 Hz, 2H), 2.44-2.47 (m, 2H), 2.01 -2.1 1 (m, 2H), 1.36 (s, 3H), 1.26 (s, 3H).

Step 2: (R)-N-(2.3-dihydroxypropyl)-2-((2-fluoro-4-iodophenyl)amino)-7-oxo-4.5.6.7- tetrahydrobenzorblthiophene-3-carboxamide

[0814] To a solution of (/?)-N-((2,2-dimethyl-l ,3-dioxolan-4-yl)methyl)-2-((2-fluoro-4- iodophenyl)amino)-7-oxo-4,5,6,7-tetrahydrobenzo[Z?]thiophene-3-carboxamide (330 mg, 0.606 mmol) in dioxane (10 mL) was added 4 N HC1 in dioxane (0.38 mL, 1.52 mmol). The reaction mixture was stirred at room temperature for 18 h, resulting in the formation of a precipitate. The solid material was filtered and washed with Et₂0 to give the product (214 mg, 70%) as a light yellow solid m/z 505.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-*): d ppm 10.92 (s, 1 H), 7.77 (dd, .7=10.5, 1.8 Hz, 1H), 7.62 (s, 1 H), 7.52 (br t, .7=5.5 Hz, 1 H), 7.41 (t, .7=8.7 Hz, 1H), 4.89 (d, .7=5.0 Hz, 1 H), 4.66 (t, .7=5.7 Hz, 1H), 3.60 - 3.71 (m, 1H), 3.33 - 3.49 (m, 3H), 3.16 - 3.26 (m, 1H), 2.96 - 3.05 (m, 2H), 2.47 (br d, .7=6.8 Hz, 2H), 2.07 (br t, .7=5.9 Hz, 2H).

Example 115: (7?)-2-(2,3-Dihydroxypropyl)-8-(2-fluoro-4-iodophenylamino)-2,6- naphthyridin-l(2//)-one

Step 1 : Methyl 3-bromo-5-fluoroisonicotinate

[0815] To a solution of dry diisopropylamine (8.8 mL, 62.5 mmol) in dry THF (300 mL) stirred at 0°C n-BuLi (2.5M in hexanes, 25 mL, 62.5 mmol) was added. The reaction mixture was stirred for 30 min at room temperature, then cooled down to -78°C and a solution of 3- bromo-5-fluoropyridine (10 g, 56.8 mmol) in dry THF (300 mL) was added. The reaction mixture was stirred for 1 h and treated with methyl chloroformate (5.3 mmol, 68.2 mmol). The reaction mixture was stirred for 1.5 h and then was quenched with a saturated NH4CI aqueous solution at 0°C, extracted with EtOAc (3 x 100 mL), washed with H2O (100 mL) and brine (100 mL), dried over Na₂S0₄ and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-7% EtOAc in hexanes) to give the product (10.43 g, 78%) as a yellowish liquid. UPLC-MS (Acidic Method, 2 min): rt 0.86 min, m/z 234.0/236.0 [M+H]⁺.

Ή NMR (400 MHz, CDCh): d ppm 8.69 (t, 7=0.5 Hz, 1H), 8.57 (d, 7=8.4 Hz, 1H), 4.08 (s, 3H).

Step 2: 2-f2-Ethoxyvinyl)-4.4.5.5-tetramethyl-1.3.2-dioxaborolane (the compound of formula

[0816] To a mixture of pinacolborane (20 g, 156 mmol) and ethyl vinyl ether (61.4 mL, 640 mmol) was added palladium(ll) acetate (0.176 g, 0.781 mmol) carefully due to an exothermic process. The reaction mixture was stirred at room temperature for 18 h. Then the reaction mixture was concentrated in vacuo and the residue was passed through a silica plug (0-10% EtOAc in hexanes) to give the product (24.6 g, 85%) as a yellow liquid. UPLC-MS (Acidic Method, 2 min): rt 0.92 and 1.03 min, m/z 199.2 [M+H]⁺. Ή NMR (400 MHz, CDCh): d ppm {Note: a mixture of E:Z isomers 1.25: 1) 7.03 (d, 7=14.4 Hz, 1.25H), 6.64 (d, 7=0.4 Hz, 1H), 4.43 (d, 7=14.4 Hz, 1.25H), 4.11 (dd, 7=7.8, 4.4 Hz, 1H), 3.94 (q, 7=7.1 Hz, 2H), 3.84 (q, 7=7.1 Hz, 2.5H), 1.28 - 1.24 (m, 31H), 0.95 - 0.84 (m, 3H).

Step 3: Methyl 3-(2-ethoxwinyl)-5-fluoroisonicotinate (a compound of formula (104))

[0817] A degassed solution of methyl 3-bromo-5-fluoroisonicotinate (10 g, 42.70 mmol), 2-(2- ethoxyvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (12.7 g, 64.05 mmol), CS2CO3 (48.7 g, 49.45 mmol) and PdXPhos G2 catalyst (3.4 g, 4.27 mmol) in THF/H2O (9: 1 v/v, 90: 10 mL) was stirred at 85°C for 18 h. The reaction mixture was diluted with EtOAc (100 mL) and filtered through a Celite pad. The organic filtrate was washed with H2O (100 mL), brine (100 mL), dried over Na2S0₄, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-25% EtOAc in hexanes) to give the product (7.07 g, 74%) as a brown oil. UPLC-MS (Acidic Method, 2 min): rt 1.01 and 1.10 min, m/z 226.1 [M+H]⁺. 'H NMR (400 MHz, CDCI3): d ppm (Note: a mixture of E:Z isomers 1.15 : 1) 9.18 - 9.13 (m, 1H), 8.48 (s, 1.15H), 8.30 (dd, 7=5.2, 0.8 Hz, 2.15H), 7.03 (d, 7=12.9 Hz, 1.15H), 6.41 (dd, .7=7.1 , 0.7 Hz,

1H), 5.91 (d, .7=12.9 Hz, 1.15H), 5.27 (d, 7=7.1 Hz, 1H), 4.05 (q, 7=7.1 Hz, 2H), 4.01 - 3.90 (m, 8.75H), 1.37 (td, 7=7.1, 2.8 Hz, 6.5H).

Step 4: 8-Fluoro- ranor4.3-clpyridin-l-one hydrochloride (a compound of formula P05Ϊ)

[0818] To methyl 3-(2-ethoxyvinyl)-5-fluoroisonicotinate (2.07 g, 9.2 mmol) was added 4M

HC1 (26 mL, 104 mmol) and the reaction mixture was stirred at 100°C for 18 h. The reaction mixture was cooled down and the formed precipitate was isolated by filtration, washed with dioxane (3 ^c 5 mL) and dried in vacuo to give the product (0.93 g, 50%) as a pale-brown solid. UPLC-MS (Acidic Method, 2 min): rt 0.60, m/z 166.0 [M+H]⁺. Ή NMR (400 MHz, CDCb): d ppm 8.69 (s, 1H), 8.63 (d, 7=2.2 Hz, 1H), 7.41 (d, 7=5.6 Hz, 1H), 6.60 (dd, 7=5.6, 2.5 Hz, 1H). Step 5: (7?)-2-((2.2-Dimethyl-1.3-dioxolan-4-yl)methyl)-8-fluoro-2.6-naphthyridin-l - one

[0819] To a solution of 8-fluoro-17/-pyrano[4,3-c]pyridin-l-one hydrochloride (300 mg, 1.82 mmol) in MeOH (13 mL) was added

2-dimethyl- 1, 3 -dioxolan-4-yl)methanamine (334 mg,

2.55 mmol) and the reaction mixture was heated at 80 °C for 72 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc, washed with H2O (30 mL), brine (30 mL), dried over NaaSCL, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-80% EtOAc in hexanes) to give the product (94 mg, 19%) as an off-white solid. UPLC-MS (Acidic Method, 2 min): rt 0.84 min, m/z 279.2 [M+H]⁺. 'H NMR (400 MHz, CDCb): d 8.74 (s, 1H), 8.46 (d, 7= 3.1 Hz, 1H), 7.37 (d, 7=7.4 Hz, 1H), 6.55 (dd, .7=7.4, 2.3 Hz, 1H), 4.52 (qd, .7=6.6, 3.0 Hz, 1H), 4.39 (dd, .7=13.8, 3.0 Hz, 1H), 4.16 (dd, .7=8.8, 6.5 Hz, 1H), 3.91 (dd, .7=13.8, 7.0 Hz, 1H), 3.74 (dd, 7=8.8, 6.3 Hz, 1H), 1 ,43 (s, 3H),

1.34 (s, 3H).

Step 6: (7?)-2-((2,2-Dimethyl-L3-dioxolan-4-yl)methyl)-8-(2-fluoro-4-iodophenylamino)-2,6- naphthyridin- 1 -one

[0820] A solution of 2-fluoro-4-iodoaniline (49 mg, 0.21 mmol) in dry THF (1 mL) stirred at -78°C was treated with LiHMDS (1M in THF, 0.3 mL, 0.3 mmol) and the reaction mixture was stirred for 10 min. Then a solution of (7?)-2-((2,2-dimethyl-l ,3-dioxolan-4-yl)methyl)-8-fluoro- 2,6-naphthyridin-l (2 )-one (60 mg, 0.216 mmol) in dry THF (1 mL) was added and the reaction mixture was stirred at -78°C for 15 min, and then let to warm up to room temperature. The reaction mixture was quenched with a saturated NH4CI aqueous solution (1 mL) at 0°C and extracted with EtOAc (3 * 7 mL). The combined organic phase was washed with H2O (7 mL), brine (7 mL), dried over Na₂S0₄, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-50% EtOAc in hexanes) to give the product (68 mg, 64%) as a yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.17 min, m/z 496.1 [M+H]⁺.

'H NMR (400 MHz, CDCI3): d 10.56 (s, 1 H), 8.41 (s, 1 H), 8.28 (s, 1 H), 7.56 - 7.43 (m, 2H),

7.33 (t, 7=8.4 Hz, 1H), 7.25 (d, 1H), 6.50 (d, 7=7.4 Hz, 1H), 4.51 (qd, 7=6.5, 3.1 Hz, 1H), 4.36 (dd, 7=13.8, 3.1 Hz, 1H), 4.16 (dd, 7=8.7, 6.5 Hz, 1H), 3.88 (dd, 7=13.8, 7.0 Hz, 1H), 3.75 (dd, 7=8.7, 6.2 Hz, 1H), 1.44 (s, 3H), 1.35 (s, 3H).

Step 7: (7?)-2-(2.3-Dihvdroxypropyn-8-(2-fluoro-4-iodophenylamino)-2.6-naDhthyridin-l (27n- one

[0821] A solution of (R)-2-((2, 2-dimethyl- 1 , 3-dioxolan-4-yl)methyl)-8-(2-fluoro-4- iodophenylamino)-2,6-naphthyridin-l (2//)-one (68 mg, 0.137 mmol) in dioxane (3.5 mL) was treated with 4M HC1 in dioxane (0.086 mL) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give the product (62 mg, 100%) as an orange solid. UPLC-MS (Acidic Method, 2 min): rt 0.87 min, m/z 456.0 [M+H]⁺. Ή NMR (400 MHz, CD₃CN): d 1 1.13 (s, 1 H), 8.30 (s, 1 H), 7.94 (s, 1 H), 7.69 (dd, .7=10.1, 1.9 Hz, 1H), 7.61 (dd, 7=16.5, 7.9 Hz, 2H), 7.36 (t, 7=8.4 Hz, 1H), 6.75 (d, 7=7.3 Hz, 1H), 4.31 (dd, 7=13.5, 3.2 Hz, 1H), 4.03 - 3.91 (m, 1H), 3.87 (dd, 7=13.4, 8.2 Hz, 1H), 3.58 - 3.44 (m, 2H).

Example 116: (5}-2-(2,3-Dihydroxypropyl)-8-(2-fluoro-4-iodophenylamino)-2,6- naphthyridin-l(2//)-one

Step 1 2-r(2.2-Dimethyl-1.3-dioxolan-4-yl~)methvn-8-fluoro-2.6-naphthyridin-l (2//)-one

[0822] To a solution of 8-fluoro-l//-pyrano[4,3-c]pyridin-l -one hydrochloride (500 mg, 3.03 mmol) in MeOH (22 mL) was added (S)-(2, 2-dimethyl- l ,3-dioxolan-4-yl)methanamine (556 mg, 4.24 mmol) and the reaction mixture was stirred at 80°C for 72 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc, washed with ¾0 (50 mL), brine (50 mL), dried over Na2S04, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-100% EtOAc in hexanes) to give the product (165 mg, 20%) as a yellow solid. UPLC-MS (Acidic Method, 2 min): rt 0.76 min, m/z 279.1 [M+H]⁺. Ή NMR (400 MHz, CDCb): d 8.74 (s, 1 H), 8.46 (d, .7=3.1 Hz, 1H), 7.37 (d, 7=7.4 Hz, 1H), 6.55 (dd, 7=7.4, 2.3 Hz, 1H), 4.52 (qd, 7=6.5, 3.0 Hz, 1H), 4.39 (dd, 7=13.8, 3.0 Hz, 1H), 4.16 (dd, 7=8.8, 6.5 Hz, 1H), 3.90 (dd, 7=13.8, 7.0 Hz, 1H), 3.74 (dd, 7=8.8, 6.3 Hz, 1H), 1.43 (s, 3H),

1.34 (s, 3H).

Step-2: ( )-2-((2.2-Dimethyl-1.3-dioxolan-4-vnmethyl~)-8-(2-fluoro-4-iodophenylaminoV 2.6-naphthyridin- 1 (2/f)-one

[0823] A solution of 2-fluoro-4-iodoaniline (53 mg, 0.222 mmol) in dry THF (1 mL) stirred at -78°C was treated with LiHMDS (1M in THF, 0.33 mL, 0.33 mmol) and the reaction mixture was stirred for 10 minutes. Then, a solution of (S)-2-((2,2-dimethyl-l ,3-dioxolan-4-yl)methyl)- 8-fluoro-2,6-naphthyridin-l(2//)-one (65 mg, 0.234 mmol) in dry THF (1 mL) was added and the reaction mixture was stirred at -78°C for 15 minutes, then let to warm up to room temperature. The reaction mixture was quenched with a saturated NH4CI aqueous solution (1 mL) at 0°C and extracted with EtOAc (3 * 7 mL). The combined organic phase was washed with H2O (7 mL), brine (7 mL), dried over Na2S04, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-50% EtOAc in hexanes) to give the product (77 mg, 66%) as a yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.14 min, m/z 496.0 [M+H]⁺. 'H NMR (400 MHz, CDCI3): d 10.55 (s, 1H), 8.40 (s, 1H), 8.27 (s, 1H), 7.55 - 7.42 (m, 2H),

7.32 (t, 7=8.4 Hz, 1H), 7.24 (d, 1H), 6.49 (d, 7=7.3 Hz, 1H), 4.50 (qd, 7=6.6, 3.2 Hz, 1H), 4.35 (dd, 7=13.8, 3.1 Hz, 1H), 4.15 (dd, 7=8.8, 6.5 Hz, 1H), 3.87 (dd, 7=13.8, 7.0 Hz, 1H), 3.74 (dd, 7=8.7, 6.2 Hz, 1H), 1.43 (s, 3H), 1.34 (s, 3H).

Step 3 -(2,3-Dihvdroxypropyl)-8-(2-fluoro-4-iodophenylamino)-2.6-naphthyridin-l(^,2//V one

[0824J A solution of (5)-2-((2,2-dimethyl-l ,3-dioxolan-4-yl)methyl)-8-(2-fluoro-4- (trimethylsilyl)phenyl-amino)-2,6-naphthyridin-l(2/ )-one (67 mg, 0.136 mmol) in dioxane (3.5 mL) was treated with 4M HC1 in 1 ,4-dioxane (85 pL) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was concentrated in vacuo and the crude material was purified by preparatory HPLC to give the product (16 mg, 26%) as a yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.02 min, m/z 456.1 [M+H]⁺. 'H NMR (400 MHz, CD₃CN): d 10.73 (s, IH), 8.35 (d, .7=1.3 Hz, 1H), 8.32 (s, 1H), 7.62 (dd, J=10.4, 2.0 Hz, 1H), 7.55 (ddd, 7=8.5, 2.1 , 1.0 Hz, 1H), 7.44 (t, 7=8.5 Hz, 1H), 7.37 (d, 7=7.4 Hz, 1H), 6.60 (d, 7=7.4 Hz, 1H), 4.23 (dd, 7=13.4, 3.6 Hz, 1H), 3.95 (m, 1H), 3.85 (dd, 7=13.4, 7.8 Hz, 1H), 3.54 - 3.46 (m, 2H). Example 117: 2-(3-Aminopropyl)-8-(2-fluoro-4-iodophenylamino)-2,6-naphthyridin-l(2//)- one hydrochloride

Step 1 : tert- Butyl 3-(8-f1uoro-l-oxo-2.6-naphthyridin-2n//)-yl)propylcarbamate

[0825] A solution of 8-fluoro-l//-pyrano[4,3-c]pyridin-l -one hydrochloride (0.50 g, 2.48 mmol) and te/7-butyl 3-aminopropylcarbamate (0.74 g, 4.24 mmol) in MeOH (22 mL) was heated at 80°C for 18 h and then concentrated in vacuo. The crude residue was treated with EtOAc and the collected organic phases were washed with brine, dried over Na₂SC>₄, filtered and concentrated in vacuo to give the crude product (1.02 g, 35% pure) that was taken to the next step without further purification. UPLC-MS (Acidic Method, 2 min): rt 0.97 min, m/z 322.1 [M+H]⁺.

Step 2: ferf-Butyl 3-(8-(2-fluoro-4-iodophenylamino)-l-oxo-2,6-naphthyridin-2

vDpropylcarbamate

[0826] A solution of 2-fluoro-4-iodoaniline (680 mg, 2.87 mmol) in dry THF (15 mL) stirred at -78°C under N2 was treated with LiHMDS (1M in THF, 4.23 mL, 4.23 mmol) added dropwise. The reaction mixture was stirred for 15 min at -78°C and then a suspension of tert- butyl 3-(8-fluoro-l-oxo-2,6-naphthyridin-2(177)-yl)propylcarbamate (970 mg, 35% pure, 1.06 mmol) in dry THF (15 mL) was added. The reaction mixture was further stirred at -7 °C and then let to warm up to room temperature. After 1 h the reaction mixture was re-cooled down to -78°C and treated with additional portions of LiHMDS (1M in THF, 4.23 mL, 4.23 mmol) added dropwise; this addition was repeated once more. The reaction mixture was further stirred for 1 h and let to warm up to room temperature. Then the reaction mixture was quenched with a saturated NH4CI aqueous solution at 0°C and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na₂SC>₄, filtered and concentrated in vacuo to give the crude material which was purified by flash column chromatography (Silica, 0-90% EtOAc in hexane) to give the product (73 mg, 13%). UPLC-MS (Acidic Method, 2 min): rt 1.28 min, m/z 539.0 [M+H]⁺. ‘H NMR (400 MHz, CDCI3): d ppm 10.57 (s, 1H), 8.38 (d, =1.3 Hz, 1H), 8.26 (s, 1H), 7.52 (dd, .7=9.8, 2.0 Hz, 1H), 7.46 (dt, >8.5, 1.5 Hz, 1H), 7.31 (t, >8.3 Hz, 1H), 7.16 (d, > 7.3 Hz, 1H), 6.52 (d, >7.3 Hz, 1H), 5.01 (br s, 1H), 4.03 (t, > 6.7 Hz, 2H), 3.18 (q, >6.3 Hz, 2H), 1.96 (p, >6.6 Hz, 2H), 1.44 (s, 9H).

Step 3: 2-(3-AminopropyD-8-f2-fluoro-4-iodophenylamino)-2.6-naphthyridin-l(^'2//)-one hydrochloride

[0827] A solution of tert- butyl 3-(8-(2-fluoro-4-iodophenylamino)-l-oxo-2,6-naphthyridin- 2(177)-yl)propylcarbamate (73 mg, 0.136 mmol) in dry dioxane (1 mL) stirred at room temperature was treated with HC1 solution (4 N in dioxane, 50 pi, 0.195 mmol). After 1.5 h an additional portion of HC1 solution (4 N in dioxane, 2 x 50 mΐ, 0.390 mmol) was added and the reaction mixture was further stirred for 18 h. The reaction mixture was then concentrated in vacuo to give the product (62 mg, 97%) as a yellow solid. UPLC-MS (Acidic Method, 2 min): rt 0.85 min, m/z 439.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-rfe): d ppm 10.83 (s, 1 H), 8.45 (d, >1.6 Hz, 1H), 8.31 (s, 1H), 7.89 (br s, 3H), 7.77 (dd, >10.4, 1.9 Hz, 1H), 7.72 (d, >7.7 Hz, 1H), 7.58 (dd, .7=8.3, 2.0 Hz, 1H), 7.50 (t, 7=8.5 Hz, 1H), 6.81 (dd, 7=7.2, 1.3 Hz, 1H), 4.07 (t, 7=6.9 Hz, 2H), 2.84 (q, 7=7.2, 6.8 Hz, 2H), 2.01 (p, 7=7.0 Hz, 2H).

Example 118: 2-(8-(2-Fluoro-4-iodophenylamino)-l-oxo-2,6-naphthyridin-2(l//)-yl)acetic acid

Step 1 : Methyl 2-(8-fluoro-l-oxo-2.6-naphthyridin-2(17/)-yl)acetate

[0828] A suspension of glycine methyl ester hydrochloride (0.53 g, 4.24 mmol) in MeOH (5 mL) was treated with Et₃N (0.59 mL, 4.24 mmol) and the resultant solution was added to a solution of 8-fluoro-177-pyrano[4,3-c]pyridin-l -one hydrochloride (0.50 g, 2.48 mmol) in MeOH (17 mL). The reaction mixture was heated at 80°C for 72 h and then concentrated in vacuo. The crude residue was treated with EtOAc multiple times and the collected organic phases were washed with water, brine, dried over Na₂S0₄, filtered and concentrated in vacuo to give the product (465 mg, 80%) that was taken to the next step without further purification. UPLC-MS (Acidic Method, 2 min): rt 0.71 min, m/z 237.1 [M+H]⁺. 'H NMR (400 MHz, CDCI₃): d ppm 8.75 (s, 1H), 8.48 (d, 7=3.0 Hz, 1H), 7.16 (d, 7=7.4 Hz, 1H), 6.59 (dd, .7=7.3, 2.3 Hz, 1H), 4.69 (s, 2H), 3.80 (s, 3H). Step 2: 2-f8-Fluoro-l-oxo-2.6-naphthyri acid

[0829] A solution of methyl 2-(8-fluoro-l-oxo-2,6-naphthyridin-2(177)-yl)acetate (465 mg,

1.97 mmol) in MeOH (12 mL) and H2O (12 mL) stirred at 0°C was treated with 1M LiOH aqueous solution (3.9 mL, 3.94 mmol). The reaction mixture was stirred for 30 min and let to warm up to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was extracted with EtOAc. The aqueous phase was acidified with citric acid aqueous solution (pH 2) to reach pH 3 and then was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04, filtered and concentrated in vacuo to give the product (153 mg, 50%) as an off-white solid. UPLC-MS (Acidic Method, 2 min): rt 0.17 min, m/z 223.0

[M+H]⁺. Ή NMR (400 MHz, DMSO-i/₆): d ppm 13.09 (s, 1 H), 8.91 (s, 1 H), 8.55 (d, =3.3 Hz, 1H), 7.67 (d, .7=7.3 Hz, 1H), 6.80 (dd, .7=7.4, 2.4 Hz, 1H), 4.69 (s, 2H).

Step 3: 2-(^'8-f^'2-Fluoro-4-iodophenylamino')-l-oxo-2.6-naphthyridin-2 acetic acid

[0830] A solution of 2-fluoro-4-iodoaniline (155 mg, 0.655 mmol) in dry THF (2 mL) stirred at -78°C under N2 was treated with LiHMDS (1M in THF, 1.65 mL, 1.65 mmol) added dropwise. The reaction mixture was stirred for 10 min at -78°C and then a suspension of 2-(8- fluoro-l-oxo-2,6-naphthyridin-2(17/)-yl)acetic acid (153 mg, 0.689 mmol) in dry THF (3 mL) was added. The reaction mixture was further stirred and let to warm up to room temperature. After 2.5 h the reaction mixture was re-cooled down to -78°C and treated with additional portions of LiHMDS (1M in THF, 2 x 0.8 mL, 1.60 mmol) added dropwise. The reaction mixture was further stirred for 18 h and let to warm up to room temperature. Then the reaction mixture was quenched with a saturated NH4CI aqueous solution at 0°C and extracted with EtOAc. The aqueous phase was acidified with citric acid aqueous solution (pH 2) to reach pH 3 and then was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04, filtered and concentrated in vacuo to give the crude material which was purified by preparative HPLC purification to give the product (32 mg, 1 1%) as a yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.01 min, m/z 440.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-i¾): d ppm 13.16 (s, 1H), 10.56 (s, 1H), 8.39 (s, 1H), 8.30 (d, .7=1.2 Hz, 1H), 7.75 (dd, =10.4, 1.9 Hz, 1H), 7.60 (d, 7=7.3 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.49 (t, 7=8.5 Hz, 1H), 6.73 (d, 7=7.3 Hz, 1H), 4.70 (s, 2H).

Example 119: Methyl 2-(8-(2-fluoro-4-iodophenylamino)-l-oxo-2,6-naphthyridin-2(l//)- yl)acetate

[0831] A solution of 2-(8-(2-fluoro-4-iodophenylamino)-l-oxo-2,6-naphthyridin-2(l//)- yl)acetic acid (200 mg, 0.46 mmol) in MeOH (1 mL) stirred at 0°C was treated with SOCb (0.12 mL, 1.61 mmol) added dropwise. The reaction mixture was stirred for 18 h and let to warm up to room temperature. The reaction mixture was concentrated in vacuo to give the crude material which was purified by preparative HPLC purification to give the product (1 1 mg, 8%). UPLC- MS (Acidic Method, 2 min): rt 1.14 min, m/z 454.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-cfe): d ppm 10.46 (s, l H), 8.39 (s, 1 H), 8.30 (d, 7=1.3 Hz, 1H), 7.75 (dd, 7=10.4, 1.9 Hz, 1H), 7.61 (d, 7=7.3 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.48 (t, 7=8.5 Hz, 1H), 6.76 (d, 7=7.3 Hz, 1H), 4.82 (s, 2H),

3.71 (s, 3H).

Example 120: 8-(2-Fluoro-4-iodophenylamino)-2-hydroxy-2,6-naphthyridin-l(2//)-one

Step 1 : 8-Fluoro-2-hvdroxy-2.6-naphthyridin-l (2/7)-one

[0832] A suspension of hydroxyamine hydrochloride (0.29 g, 4.24 mmol) in MeOH (5 mL) was treated with Et3N (0.59 mL, 4.24 mmol) and the resultant solution was added to a solution of 8-fluoro-l/ -pyrano[4,3-c]pyridin-l-one hydrochloride (0.50 g, 2.48 mmol) in MeOH (17 mL) with added 4 A molecular sieves. The reaction mixture was heated at 80°C for 18 h and then at room temperature for 72 h. The reaction mixture was concentrated in vacuo , the crude residue was treated with EtOAc and the collected organic phases were concentrated in vacuo to give the product (0.26 g, 58%) that was taken to the next step without further purification. UPLC-MS (Acidic Method, 2 min): rt 0.17 min, m/z 181.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-7₆): d ppm 10.75 (s, 1H), 8.52 (d, =0.9 Hz, 1 H), 8.49 (s, 1H), 7.42 (t, 7=5.3 Hz, 1H), 6.76 (t, 7=5.2 Hz,

1H).

Step 2: 8-(2-Fluoro-4-iodophenylamino)-2-hvdroxy-2.6-naphthyridin- l -one

[0833] A solution of 2-fluoro-4-iodoaniline (95 mg, 0.40 mmol) in dry THF (2 mL) stirred at

-78°C under N2 was treated with LiHMDS (1M in THF, 1.00 mL, 1.00 mmol) added dropwise. The reaction mixture was stirred for 10 min at -78°C and then a suspension of 8-fluoro-2- hydroxy-2,6-naphthyridin-l(27/)-one (76 mg, 0.42 mmol) in dry THF (1 mL) was added. The reaction mixture was further stirred at -78°C for 15 min and then let to warm up to room temperature. After 30 min the reaction mixture was re-cooled down to -78°C and treated with additional portions of LiHMDS (1M in THF, 1.00 mL, 1.00 mmol) added dropwise. The reaction mixture was further stirred and let to warm up to room temperature then it was quenched with a saturated NH4CI aqueous solution at 0°C. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na₂S0₄, filtered and concentrated in vacuo at room temperature to give the crude material which was purified by preparative HPLC purification to give the product (9.5 mg, 6%) as a yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.00 min, m/z 398.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-^): d ppm 11.98 (br s, 1H), 10.70 (br s, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.75 (dd, =10.4, 1.9 Hz, 1H), 7.59 - 7.46 (m, 2H), 6.72 (d, .7=7.5 Hz, 1H).

Example 121 : 8-(2-Fluoro-4-iodophenylamino)-2-(2-hydroxyethoxy)-2,6-naphthyridin- l(2/ )-one

Step 1 : 2-(2- Butyldiphenylsilyloxy)ethoxy)-8-(2-fluoro-4-iodophenylamino)-2.6-

naphthyridin- 1 (2H)-one

[0834] To a solution of 0-(2-(½/'i-butyl-diphenylsilyloxy)ethyl)hydroxylamine (0.70 g, 2.22 mmol), Et3N (0.31 mL, 2.22 mmol) and HC1 (4N in dioxane, 1.1 mL, 4.44 mmol) in dioxane (5 mL) stirred at room temperature for 15 min was added methyl 3-(2-ethoxyvinyl)-5- fluoroisonicotinate (0.50 g, 2.22 mmol). The reaction mixture was stirred at 50°C for 18 h. The reaction mixture was cooled down to room temperature, was treated with LiHMDS (1M in THF, 7.1 mL, 7.10 mmol) added dropwise and stirred for 30 min. Then 2-fluoro-4-iodoaniline (0.53 g, 2.22 mmol) was added to the reaction mixture followed by LiHMDS (1M in THF, 2.7 mL, 2.66 mmol) added dropwise and it was further stirred at room temperature. After 45 min an additional portion of LiHMDS (1M in THF, 1.3 mL, 1.33 mmol) was added and the reaction mixture was stirred for 30 min. Then the reaction mixture was quenched with a saturated NH4CI aqueous solution and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04, filtered and concentrated in vacuo to give the crude material which was purified by flash column chromatography (Silica, 0-30% EtOAc in hexane + 1% Et3N) to give the product (250 mg, 16%) as a yellow glass. UPLC-MS (Acidic Method, 2 min): rt 1.61 min, /z 680.2 [M+H]⁺. Ή NMR (400 MHz, DMSO-7₆): d ppm 10.45 (s, 1 H), 8.42 (s, 1 H), 8.30 (d, .7=1.3 Hz, 1H), 7.82 (d, 7=7.6 Hz, 1H), 7.77 (dd, 7=10.4, 1.9 Hz, 1H), 7.65 - 7.50 (m, 5H), 7.50 - 7.33 (m, 7H), 6.74 (d, 7=7.7 Hz, 1H), 4.49 - 4.34 (m, 2H), 3.97 (t, 7=4.3 Hz, 2H),

0.93 (s, 9H).

Step 2: 8-(2-Fluoro-4-iodophenylamino)-2-(2-hvdroxyethoxy)-2.6-naphthyridin- l -one

[0835] To a solution of 2-(2-(/eH-butyldiphenylsilyloxy)ethoxy)-8-(2-fluoro-4- iodophenylamino)-2,6-naphthyridin-l(2T0-one (250 mg, 0.368 mmol) in THE (5 mL) stirred at room temperature TBAF (1M in THF, 0.37 mL, 0.368 mmol) was added. After 30 min reaction was complete and a saturated NaHCCb aqueous solution was added. The mixture was extracted twice with EtOAc, the organic phase was washed with ¾0 and brine, dried over Na2S04, filtered and concentrated in vacuo. A half of the crude material was purified by preparative HPLC purification followed by SFC purification to give the product (30 mg, 64%). UPLC-MS (Acidic Method, 2 min): rt 1.03 min, m/z 442.0 [M+H]⁺. 'H NMR (400 MHz, DMSO-i e): d ppm 10.42 (s, 1H), 8.42 (s, 1H), 8.29 (d, 7=1.3 Hz, 1H), 7.86 (d, 7=7.6 Hz, 1H), 7.76 (dd, 7=10.4, 1.9 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.49 (t, 7=8.5 Hz, 1H), 6.74 (d, 7=7.7 Hz, 1H), 4.97 (t, 7=5.5 Hz, 1H), 4.28 (dd, 7=5.2, 4.1 Hz, 2H), 3.68 (q, 7=5.1 Hz, 2H).

Example 122: 8-(2-Fluoro-4-iodophenylamino)-2-isopropoxy-3,4-dihydro-2,6- naphthyridin-l(2//)-onc

Step 1 : Methyl S-fluoro-S-^-nsopropoxyiminolethvDisonicotinate

[0836] To a solution of (9-isopropylhydroxylamine hydrochloride (495 mg, 4.44 mmol), Et3N (0.62 mL, 4.44 mmol) and HC1 (4N in dioxane, 1.1 mL, 4.44 mmol) in dioxane (8 mL) placed in a pressure tube was added a solution of methyl 3-(2-ethoxyvinyl)-5-fluoroisonicotinate (1.0 g, 4.44 mmol) in dioxane (2 mL). The reaction mixture was sealed and stirred at 50°C for 18 h. Note: the reaction mixture is in a form of a dense suspension of formed NH4CI salt during the process and should be efficiently stirred for best results. Then the reaction mixture was concentrated in vacuo. The crude material was dry loaded on Celite and was purified by flash column chromatography (40 g silica, 0-15% EtOAc in hexanes modified with 1% Et3N) to give the product (795 mg, 70%, mixture of two isomers) as a pale oil. UPLC-MS (Acidic Method, 2 min): rt 1.07 min, m/z 255.1 [M+H]⁺ . Ή NMR (400 MHz, DMSO-7₆): d ppm 8.66 (dd, 7=4.0,

1.1 Hz, 2H), 8.53 (s, 1H), 8.49 (s, 1H), 7.47 (t, 7=5.4 Hz, 1H), 6.84 (t, 7=5.1 Hz, 1H), 4.27 (p, 7=6.2 Hz, 1H), 4.15 (p, 7=6.2 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.72 (d, 7=5.1 Hz, 2H), 3.68 (d, 7=5.4 Hz, 2H), 1.17 (d, 7=6.2 Hz, 6H), 1.1 1 (d, 7=6.2 Hz, 6H).

Step 2: 8-Fluoro-2-isopropoxy-3.4-dihydro-2.6-naphthyridin-l -one

[0837] To a solution of methyl 3-fluoro-5-(2-(isopropoxyimino)ethyl)isonicotinate (400 mg, 1.575 mmol) in MeOH (4 mL) stirred at room temperature under N2 flow, with an output to a Drechsel bottle with a solution of bleach and 1M NaOH, NaCNBH3 (297 mg, 4.724 mmol) was added at once followed by 1M HC1 aqueous solution (1.57 mL, 1.575 mmol) added dropwise. The reaction mixture was stirred for 5 days at room temperature. Reaction was quenched with H2O (50 mL) and extracted with EtOAc (6 ^c 25 mL). The organic phase was washed with brine, dried over Na₂S0₄, filtered and concentrated in vacuo to give the product (275 mg, 78%) as a white soft solid used in the next step without further purification. UPLC-MS (Acidic Method, 2 min): rt 0.78 min, m/z 225.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-_<7₆): d ppm 8.56 (d, .7=3.0 Hz, 1H), 8.48 (s, 1H), 4.33 (p, .7=6.2 Hz, 1H), 3.82 (t, .7=6.6 Hz, 2H), 3.19 (t, .7=6.6 Hz, 2H), 1.22 (d, .7=6.2 Hz, 6H).

Step 3: 8-f2-Fluoro-4-iodophenylamino)-2-isopropoxy-3.4-dihvdro-2.6-naphthyridin-l -one

[0838] A solution of 2-fluoro-4-iodoaniline (106 mg, 0.45 mmol) in dry THF (1 mL) stirred at -78°C under N2 was treated with LiHMDS (1M in THF, 0.45 mL, 0.45 mmol) added dropwise and the reaction mixture was stirred for 15 min. Then a solution of 2-(cyclopropylmethoxy)-8- fluoro-3,4-dihydro-2,6-naphthyridin-l (2//)-one (100 mg, 0.45 mmol) in dry THF (1 mL) was added and the reaction mixture was further stirred at and let to warm up to room temperature. After 18 h the reaction mixture was re-cooled to -78°C and LiHMDS (1M in THF, 0.45 mL, 0.45 mmol) was added dropwise and the reaction mixture was further stirred at and let to warm up to room temperature. After 18 h the reaction mixture was quenched with a saturated NH4CI aqueous solution (15 mL) and extracted with EtOAc (3 >< 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SC>4, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-60% EtOAc in hexanes) to give the product (61 mg, 31%) as an orange gum. UPLC-MS (Acidic Method, 4 min): rt 1.21 min, m/z 442.1 [M+H]⁺. Ή NMR (400 MHz, DMSO-rfe): d ppm 10.13 (s, 1H), 8.34 (d, .7=1.4 Hz, 1H), 7.98 (s, 1H), 7.73 (dd, .7=10.4, 1.9 Hz, 1H), 7.53 (dt, .7=8.5, 1.4 Hz, 1H), 7.36 (t, .7=8.6 Hz,

1H), 4.36 (p, J= 6.2 Hz, 1H), 3.82 (t, .7=6.7 Hz, 2H), 3.12 (t, .7=6.6 Hz, 2H), 1.24 (d, .7=6.2 Hz, 6H). Example 123: 2-(Cyclopropylmethoxy)-8-(2-fluoro-4-iodophenylamino)-3,4-dihydro-2,6- naphthyridin-l(2//)-one

Step 1 : Methyl 3-(2-(cvclopropylmethoxyimino)ethyl)-5-fluoroisonicotinate

[0839] To a solution of 0-(cyclopropylmethyl)hydroxylamine hydrochloride (546 mg, 4.44 mmol), Et3N (0.62 mL, 4.44 mmol) and HC1 (4N in dioxane, 1.1 mL, 4.44 mmol) in dioxane (8 mL) placed in a pressure tube was added a solution of methyl 3-(2-ethoxyvinyl)-5- fluoroisonicotinate (1.0 g, 4.44 mmol) in dioxane (2 mL). The reaction mixture was sealed and stirred at 50 °C for 18 h. Note : the reaction mixture is in a form of a dense suspension of formed NH4CI salt during the process and should be efficiently stirred for best results. An additional portion of Et3N (0.62 mL, 4.44 mmol), HC1 (4N in dioxane, 1.1 mL, 4.44 mmol) and O- (cyclopropylmethyl)hydroxylamine hydrochloride (273 mg, 2.22 mmol) were added to the reaction mixture stirred at 50°C in further 30 h. Then the reaction mixture was concentrated in vacuo. The crude material was dry loaded on Celite and was purified by flash column chromatography (45 g silica, 0-10% EtOAc in hexanes modified with 1% Et3N) to give the product (791 mg, 67%, mixture of two isomers) as a pale oil. UPLC-MS (Acidic Method, 2 min): rt 1.07 min, m/z 267.1 [M+H]⁺. 'H NMR (400 MHz, DMSO-<7e): d ppm 8.66 (dd, .7=2.4, 1.0 Hz, 2H), 8.54 (s, 1H), 8.50 (s, 1H), 7.52 (t, .7=5.4 Hz, 1H), 6.85 (t, .7=5.2 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.86 (d, .7=7.1 Hz, 2H), 3.76 (d, .7=5.2 Hz, 2H), 3.72 (d, .7=7.1 Hz, 2H), 3.68

(d, .7=5.4 Hz, 2H), 1.14 - 0.91 (m, 2H), 0.57 - 0.38 (m, 4H), 0.23 (dt, .7=6.1 , 4.3 Hz, 2H), 0.18 (dt, .7=6.1, 4.3 Hz, 2H). Step 2: 2-fCvclopropylmethoxy)-8-fluoro-3.4-dihvdro-2.6-naphthyridin- l -one

[0840] To a solution of methyl 3-(2-(cyclopropylmethoxyimino)ethyl)-5-fluoroisonicotinate (600 mg, 2.253 mmol) in MeOH (6 mL) stirred at room temperature under N2 flow, with an output to a Drechsel bottle with a solution of bleach and 1M NaOH, NaCNB¾ (425 mg, 6.760 mmol) was added at once followed by 1M HC1 aqueous solution (2.25 mL, 2.253 mmol) added dropwise. The reaction mixture was stirred for 5 days at room temperature. Reaction was quenched with ¾0 (50 mL) and extracted with EtOAc (6 ^c 25 mL). The organic phase was washed with brine, dried over Na2S04, filtered and concentrated in vacuo to give the product (582 mg, 96%) as a light-yellow oil used in the next step without further purification. UPLC-MS

(Acidic Method, 2 min): rt 0.81 min, m/z 237.1 [M+H]⁺. Ή NMR (400 MHz, DMSO-7₆): d ppm 8.56 (d, 7= 2.9 Hz, 1H), 8.47 (s, 1H), 3.90 (t, =6.6 Hz, 2H), 3.82 (d, 7=7.3 Hz, 2H), 3.19 (t,

7=6.6 Hz, 2H), 1.19 - 1.03 (m, 1H), 0.55 (dd, 7=8.1 , 1.9 Hz, 2H), 0.30 (dd, 7=4.7, 1.7 Hz, 2H).

Step 3: 2-(^'Cvclooropylmethoxy^')-8-(^'2-fluoro-4-iodophenylaminoV3.4-dihvdro-2.6-naDhthyridin- l(2H)-one

[0841] A solution of 2-fluoro-4-iodoaniline (201 mg, 0.85 mmol) in dry THF (2 mL) stirred at -78°C under N2 was treated with LiHMDS (1M in THF, 0.85 mL, 0.85 mmol) added dropwise and the reaction mixture was stirred for 15 min. Then a solution of 2-(cyclopropylmethoxy)-8- fluoro-3,4-dihydro-2,6-naphthyridin-l (2//)-one (200 mg, 0.85 mmol) in dry THF (2 mL) was added and the reaction mixture was further stirred at and let to warm up to room temperature. After 18 h the reaction mixture was re-cooled to -78°C and LiHMDS (1M in THF, 0.21 mL, 0.21 mmol) was added dropwise and the reaction mixture was further stirred at and let to warm up to room temperature. After 18 h the reaction mixture was quenched with a saturated NH4CI aqueous solution (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phase was washed with brine (20 mL), dried over Na₂SC>₄, and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 0-60% EtOAc in hexanes) to give the product (132 mg, 34%) as an orange gum. UPLC-MS (Acidic Method, 4 min): rt 1.22 min, m/z 454.1 [M+H]⁺. Ή NMR (400 MHz, DMSO-7₆): d ppm 10.1 1 (s, 1H), 8.34 (s, 1H), 7.98 (s, 1H), 7.73 (dd, .7=10.5, 1.9 Hz, 1H), 7.53 (dt, =8.3, 1.3 Hz, 1H), 7.36 (t, 7=8.6 Hz, 1H), 3.90 (t, 7=6.8 Hz, 2H), 3.84 (d, 7=7.3 Hz, 2H), 3.1 1 (t, 7=6.7 Hz, 2H), 1.20 - 1.09 (m, 1H), 0.64 - 0.50 (m, 2H), 0.41 - 0.23 (m, 2H).

Example 124: 8-(2-Fluoro-4-iodophenylamino)-2-(2-hydroxyethoxy)-3,4-dihydro-2,6- naphthyridin-l(2//)-one

Step 1 : Methyl 3-(9.9-dimethyl-8.8-diphenyl-4.7-dioxa-3-aza-8-siladec-2-enyl)-5- fluoroisonicotinate

[0842] A solution of methyl 3-(2-ethoxyvinyl)-5-fluoroisonicotinate (1.0 g, 4.44 mmol) in dioxane (10 mL) was treated with HC1 (4 N in dioxane, 2.2 mL, 8.88 mmol) and stirred at 45°C for 18 h. Then the reaction mixture was cooled down to room temperature and a solution of O- (2-(/er/-butyl-diphenylsilyloxy)ethyl)hydroxylamine (1.75 g, 5.55 mmol) and Et3N (0.62 mL, 4.44 mmol) in dioxane (2 mL) was added. The reaction mixture was stirred for 3 days at room temperature and then concentrated in vacuo. The crude material was dry loaded on Celite and was purified by flash column chromatography (80 g silica, 0-10% MeOH in DCM) to give the product (760 mg, 35%, mixture of two isomers) as a light-yellow oil. UPLC-MS (Acidic

Method, 4 min): rt 2.65, 2.67 min (two isomers 1 : 1), m/z 495.2 [M+H]⁺. 'H NMR (400 MHz, DMSO-rfe): d ppm 8.66 (dd, 7=2.4, 1.0 Hz, 2H), 8.50 (d, 7=0.9 Hz, 1H), 8.46 (d, 7=0.8 Hz, 1H), 7.68 - 7.57 (m, 8H), 7.54 (t, .7=5.5 Hz, 1H), 7.49 - 7.33 (m, 12H), 6.90 (t, 7= 5.2 Hz, 1H), 4.21 - 4.14 (m, 2H), 4.06 - 4.00 (m, 2H), 3.85 (s, 3H), 3.88 - 3.84 (m, 2H), 3.83 (s, 3H), 3.81 - 3.77 (m, 2H), 3.76 (d, .7=5.1 Hz, 2H), 3.66 (d, .7=5.5 Hz, 2H), 0.99 (s, 9H), 0.96 (s, 9H).

Step 2: 2-f2-ffe;7-Bufyldiphenylsilyloxy)ethoxy)-8-fluoro-3.4-dihvdro-2.6-naphthyridin- l

[0843] To a solution of methyl 3-(9,9-dimethyl-8,8-diphenyl-4,7-dioxa-3-aza-8-siladec-2- enyl)-5-fluoroisonicotinate (2.82 g, 5.71 mmol) in MeOH (28 mL) stirred at room temperature under N2 flow, with an output to a Drechsel bottle with a solution of bleach and 1M NaOH, NaCNBH3 (1.07 g, 17.1 mmol) was added at once followed by 1M HC1 aqueous solution (2.86 mL, 2.86 mmol) added dropwise. After 7 h additional portion of 1M HC1 aqueous solution (1.43 mL, 1.43 mmol) was added and the reaction mixture was stirred further for 3 days. Reaction was quenched with 1M NaOH aqueous solution and extracted twice with EtOAc. The organic phase was washed with H2O and brine, dried over Na2S04, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 20-50% EtOAc in heptane) to give the product (1.90 g, 72%) as a light-yellow solid. UPLC-MS (Acidic Method, 2 min): rt 1.37 min, m/z 465.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-7₆): d ppm 8.56 (d, .7=2.9 Hz, 1H), 8.46 (s, 1H), 7.71 - 7.60 (m, 4H), 7.51 - 7.33 (m, 6H), 4.15 (dd, 7=5.5, 4.0 Hz, 2H), 3.93 - 3.83 (m, 4H), 3.16 (t, 7=6.6 Hz, 2H), 1.00 (s, 9H).

Step 3: 2-(2-(/er/-Butyldiphenylsilyloxy)ethoxy)-8-(2-fluoro-4-iodophenylamino)-3.4- dihvdro-2.6-naphthyridin- 1 ( 2771-one

[0844] To a solution of 2-fluoro-4-iodoaniline (512 mg, 2.16 mmol) in THF (2.5 mL) stirred at room temperature LiHMDS (1M in THF, 2.6 mL, 2.59 mmol) was added. The mixture was stirred for 15 min and then added dropwise to a solution of 2-(2-(/er/-butyldiphenylsilyloxy) ethoxy)-8-fluoro-3,4-dihydro-2,6-naphthyridin-l (2//)-one (536 mg, 1.08 mmol) in THF (2.5 mL) stirred at room temperature. The reaction mixture was stirred for 18 h at room temperature. The reaction was then quenched with a saturated NH4CI aqueous solution and extracted twice with EtOAc. The organic phase was washed with brine, dried over Na₂SC>₄, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (Silica, 10-40% EtOAc in heptane) to give the product (316 mg, 43%). UPLC-MS (Acidic Method, 2 min): rt 1.58 min, m/z 682.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-7₆): d ppm 10.10 (s, 1 H), 8.35 (d, 7=1.4 Hz, 1H), 7.97 (s, 1H), 7.73 (dd, J=10.4, 2.0 Hz, 1H), 7.68 - 7.62 (m, 4H), 7.53 (ddd,

7=8.4, 2.0, 0.9 Hz, 1H), 7.49 - 7.39 (m, 6H), 7.35 (t, 7=8.6 Hz, 1H), 4.21 - 4.13 (m, 2H), 3.95 - 3.85 (m, 4H), 3.09 (t, 7=6.7 Hz, 2H), 1.00 (s, 9H).

Step 4: 8-(2-Fluoro-4-iodophenylamino)-2-(2-hvdroxyethoxy)-3.4-dihvdro-2.6-naphthyridin- l

[0845] To a solution of 2-(2-(/eri-butyldiphenylsilyloxy)ethoxy)-8-(2-fluoro-4- iodophenylamino)-3,4-dihydro-2,6-naphthyridin-l (27/)-one (360 mg, 0.530 mmol) in THF (4 mL) stirred at room temperature TBAF (1M in THF, 0.53 mL, 0.530 mmol) was added. After 10 min reaction was complete and a saturated NaHCC>3 aqueous solution was added. The mixture was extracted twice with EtOAc, the organic phase was washed with H2O and brine, dried over Na₂S0₄, filtered and concentrated in vacuo. A half of the crude material (200 mg) was purified by preparative HPLC purification to give the product (75.8 mg, 64%) as a yellow solid. UPLC- MS (Acidic Method, 2 min): rt 0.99 min, m/z 444.0 [M+H]⁺. Ή NMR (400 MHz, DMSO-cfe): d ppm 10.07 (s, 1H), 8.34 (d, 7=1.4 Hz, 1H), 7.98 (s, 1H), 7.73 (dd, 7=10.5, 2.0 Hz, 1H), 7.54 (dt, .7=8.4, 1.4 Hz, 1H), 7.36 (t, =8.6 Hz, 1H), 4.80 (t, 7=5.5 Hz, 1H), 4.05 (dd, 7=5.8, 3.9 Hz, 2H), 3.90 (t, 7=6.7 Hz, 2H), 3.63 (q, 7=5.1 Hz, 2H), 3.12 (t, 7=6.7 Hz, 2H).

Example 125: 2-ethoxy-8-((2-fluoro-4-iodophenyl)amino)-3,4-dihydro-2,6-naphthyridin- l(2H)-one

[0846] Compound 5.01 1 can be prepared as described in Example 108, replacing the O- isopropylhydroxylamine hydrochloride in Step 1 with an appropriate 0-ethylhydroxylamine which is commercially available or prepared using conditions known to one of ordinary skill in the art.

Example 126: 8-((2-Fluoro-4-iodophenyl)amino)-3,4-dihydro-2,6-naphthyridin-l(2//)-one

[0847] A solution of 2-ethoxy-8-(2-fluoro-4-iodophenylamino)-3,4-dihydro-2,6-naphthyridin- l(2//)-one (40 mg, 93.6 pmol) in dry THF (1.1 mL) stirred at room temperature under N2 was treated with SmL (0.1M in THF, 3.74 mL, 0.374 mmol) added dropwise and the reaction mixture was stirred for 5 min. Then the reaction mixture was quenched with a saturated Na2S2C>4 aqueous solution (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine, dried over Na2SC>₄, and concentrated in vacuo. The crude material (31.4 mg) was purified by preparative HPLC purification to give the product (8.1 mg, 23%) as a yellow solid. [0848] Alternatively, a solution of 2-(cyclopropylmethoxy)-8-(2-fluoro-4-iodophenylamino)- 3,4-dihydro-2,6-naphthyridin-l (2/7)-one (40 mg, 88.2 pmol) in dry THF (1.1 mL) stirred at room temperature under 2 was treated with Sml2 (0.1M in THF, 3.74 mL, 0.374 mmol) added dropwise and the reaction mixture was stirred for 5 min. Then the reaction mixture was quenched with a saturated Na₂S₂C>₄ aqueous solution (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine, dried over Na₂S0₄, and concentrated in vacuo. The crude material (31.6 mg) was purified by preparative HPLC purification to give the product (14.6 mg, 43%) as a yellow solid.

[0849] UPLC-MS (Acidic Method, 2 min): rt 1.00 min, m/z 383.9 [M+H]⁺. Ή NMR (400 MHz, DMSO-G?₆) d ppm 10.30 (s, 1 H), 8.50 (br s, 1 H), 8.40 (s, 1 H), 8.00 (s, 1 H), 7.71 (dd,

.7=10.5, 2.0 Hz, 1H), 7.51 (dd, 7=8.4, 1.7 Hz, 1H), 7.37 (t, 7=8.6 Hz, 1H), 3.41 (td, 7=6.6, 2.8 Hz, 2H), 2.87 (t, 7=6.6 Hz, 2H).

[0850] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

WHAT IS CLAIMED IS:

1. A gelled topical formulation for the treatment of skin disorders comprising:

a) a MEK inhibitor;

b) one or more organic solvents in an amount of about 70% to about 99% by weight; and c) a gelling agent;

wherein the one or more organic solvents are selected from the group consisting of C2-6 alcohol, a C2-6 alkylene glycol, a di-(C2-6 alkylene) glycol, a polyethylene glycol, C1 -3 alkyl-(OCH2CH2)i-5- OH, DMSO, ethyl acetate, acetone, N-methyl pyrrolidone, benzyl alcohol, glycerin, and an oil; the gelling agent is hydroxypropyl cellulose having a molecular weight ranging from about 40,000 Da to about 2,500,000 Da; and wherein the gelled topical formulation has a viscosity of from 1 to 25,000 cps; and DMSO, when present, is combined with at least one other of said organic solvents such that DMSO is present in an amount of less than 50% by weight.

2. The gelled topical formulation of claim 1, wherein the MEK inhibitor is an aniline-based MEK inhibitor comprising a moiety of formula:

wherein

R² is halo, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl;

R^2a is halo or Ci -C₆ alkyl; and

the wavy line indicates the point of attachment to the remainder of the MEK inhibitor.

3. The gelled topical formulation of claim 1, wherein the MEK inhibitor is selected from the group consisting of WX-554, CH5126766 (R05126766), G-573, Arry 300, SHR 7390, MSC2015103B (AS-703988), LY 2228820 (Ralimetinib), and CS 3006.

4. The gelled topical formulation of claim 1 or 2, wherein the MEK inhibitor is selected from the group consisting of Binimetinib, Cobimetinib, Pimasertib, Refametinib, Selumetinib, Trametinib, PD0325901, PD184352 (CI-1040), RO-4987655, GDC-0623, TAK- 733, and AZD-8330.

5. The gelled topical formulation of claim 1 or 2, wherein the MEK inhibitor has a formula selected from the group consisting of formula (I), (11), (111), (IV), and (V):

or a N-oxide, stereoisomer, mixture of stereoisomers, and/or a pharmaceutically acceptable salt thereof,

wherein:

X¹ is -CR^nb or N; X² is C1-C6 alkyl; X³ is S or O;

subscript n is an integer from 0 to 2;

bond“a” is a single or double bond;

R¹ is -OR⁴, -NR⁵R^5a, -N(OR^5b)R^5a, or a N-linked heterocycloalkyl which is unsubstituted or substituted with one or two R⁶;

R² is halo, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R^2a is halo or C1-C6 alkyl; R⁴, R⁵, and R^5b are each independently hydrogen, Ci-Ce alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl-Ci-C6 alkyl, C1-C6 hydroxyalkyl, C₁-C6 alkoxy-Ci-Ce alkyl, amino-Ci-C₆ alkyl, C1-C6 alkylamino-Ci-C6 alkyl, di-(Ci-C6 alkyl)amino-Ci-C6 alkyl, heterocycloalkyl, heterocycloalkyl-Ci-C₆ alkyl, or R⁷-C(0)-C_I-C₆ alkyl, wherein each of the C₃-C₈ cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R⁶;

R^5a is hydrogen or C₁-C₆ alkyl;

each R⁶ is independently halo, hydroxy, oxo, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₁-C₆

alkoxy, Ci-C6-hydroxyalkyl, C₁-C₆ haloalkyl, amino, C₁-C₆ alkylamino, di-(Ci-C₆ alkyl)amino, amino-Ci-C6 alkyl, C1-C6 alkylamino-Ci-C6 alkyl, or di-(Ci-C₆ alkyl)amino-Ci-C6 alkyl;

R⁷ is hydroxy, C1-C6 alkoxy, amino, C₁-C₆ alkylamino, di-(Ci-C₆ alkyl)amino,

hydroxyamino, or N-Ci-Ce alkyl hydroxyamino;

R¹³, R^{l 3a}, and R^{l 3b} are each independently hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl;

R²³, R^23a, and R^23b are each independently hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, or C₃-C₈ cycloalkoxy;

R³³, R^33a, and R^33b are each independently hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C2-C6 alkynyl, C₁-C₆ alkoxy, or C₃-C₈ cycloalkoxy;

R⁴³ is cyano, -C(0)NR⁴⁸R^48a, or -C(0)R⁴⁶;

R^43a is hydrogen, halo, C₁-C₆ alkyl; or

R⁴³ and R^43a together form -CH₂CH₂C(0)- or -CH₂CH₂CH₂C(0)-, each of which is

unsubstituted or substituted with one or two R⁴⁹;

R⁴⁶ is hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₈ cycloalkyl or heterocycloalkyl;

R⁴⁸ and R^48a are independently hydrogen or C₁-C₆ alkyl; and

each R⁴⁹ is independently C1-C6 alkyl, C3-C8 cycloalkyl, or C₃-C₈ cycloalkyl-Ci-C₆ alkyl;

R⁵¹ is hydrogen, C1-C6 alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl-Ci-C₆ alkyl, C₁-C₆ hydroxyalkyl, C1-C6 alkoxy-Ci-C6 alkyl, amino-Ci-C₆ alkyl, C₁-C₆ alkyl ami no -Ci-Ce alkyl, di-(Ci-C₆ alkyl)amino-Ci-C₆ alkyl, heterocycloalkyl, heterocycloalkyl-C ₁ -Ce alkyl, R⁷-C(0)-C_I -C₆ alkyl, or -OR⁵⁴, wherein each of the C3-C8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R⁶; each R⁵³ is independently halo or C1-C6 alkyl;

R^53a and R^53b are each independently hydrogen, halo, Ci-Ce alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and

R⁵⁴ is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-Ci-C₆ alkyl, C1-C6 hydroxyalkyl, C\-Ce alkoxy-Ci-Ce alkyl, amino-Ci-C6 alkyl, C1-C6 alkylamino-C]-C₆ alkyl, di-(Ci-C6 alkyl)amino-Ci-C6 alkyl, heterocycloalkyl, heterocycloalkyl-Ci-Ce alkyl, or R⁷-C(0)-C _I-C₆ alkyl, wherein each of the C3-C8 cycloalkyl and heterocycloalkyl groups is unsubstituted or substituted with one to six R⁶.

6. The gelled topical formulation of any one of claim 1-5, wherein the MEK inhibitor is an allosteric MEK inhibitor.

7. The gelled topical formulation of claim 1, wherein the hydroxypropyl cellulose has the molecular weight selected from the group consisting of 40,000 Da, 80,000 Da, 95,000 Da, 100,000 Da, 140,000 Da, 180,000 Da, 280,000 Da, 370,000 Da, 700,000 Da, 850,000 Da, 1,000,000 Da, 1 ,150,000 Da, and 2,500,000 Da.

8. The gelled topical formulation of claim 1 or 7, wherein the hydroxypropyl cellulose has the molecular weight selected from the group consisting of 95,000 Da, 100,000 Da, 370,000 Da, 850,000 Da, and 1 ,150,000 Da.

9. The gelled topical formulation of claim 1 or 7, wherein the hydroxypropyl cellulose is selected from the group consisting ofHY117, HY1 19, HY121 , Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, Nisso VH, Klucel ELF, Klucel EF, Klucel LF, Klucel JF, Klucel GF, Klucel MF, and Klucel HF.

10. The gelled topical formulation of claim 1, wherein the C2-6 alcohol is selected from the group consisting of ethanol, propanol, isopropanol, n-butanol, isobutanol,

2 -butanol, tert-butanol, and combinations thereof.

11. The gelled topical formulation of claim 1 or 10, wherein the C2-6 alcohol is ethanol or isopropanol.

12. The gelled topical formulation of claim 1, wherein the C2-6 alkylene glycol is propylene glycol.

13. The gelled topical formulation of claim 1, wherein the polyethylene glycol is PEG400.

14. The gelled topical formulation of claim 1, wherein the C1 -3 alkyl- (OCH₂CH )_I-5-OH is 2-(2-ethoxyethoxy)ethanol.

15. The gelled topical formulation of claim 1, wherein the oil is selected from the group consisting of almond oil, apricot kernel oil PEG-6 esters, castor oil, cedar leaf oil, coconut oil, hydrogenated castor oil, hydrogenated palm/palm kernel oil, lemon oil, mineral oil, olive oil, peanut oil PEG-54 hydrogenated castor oil, peppermint oil, safflower oil, soybean oil, spearmint oil, spermaceti, tall oil, and vegetable oil.

16. The gelled topical formulation of claim 1, wherein DMSO, when present, is combined with at least one other of said organic solvents such that DMSO is present in an amount of less than 40%, less than 30%, or less than 20% by weight of the base formulation.

17. The gelled topical formulation of claim 1, wherein DMSO, when present, is combined with at least one other of said organic solvents such that DMSO is present in an amount of from 40% to 30%, from 40% to 20%, from 40% to 10%, from 30% to 20%, from 30% to 10%, or from 20% to 10% by weight of the base formulation.

18. The gelled topical formulation of claim 1, wherein the oil, when present, is combined with at least one other of said organic solvents such that the oil is present in an amount of less than 90% or less than 80% by weight of the base formulation.

19. The gelled topical formulation of claim 1, wherein the oil, when present, is combined with at least one other of said organic solvents such that the oil is present in an amount of from 85% to 40%, from 85% to 50%, from 85% to 60%, from 75% to 40%, from 75% to 50%, from 75% to 60%, 70% to 60%, or 70% to 65% by weight of the base formulation.

20. The gelled topical formulation of any one of claims 1-5, wherein water, when present, is present in an amount of less than 15%, less than 10%, or less than 5% by weight of the base formulation.

21. The gelled topical formulation of any one of claims 1-5, wherein water is absent.

22. The gelled topical formulation of any one of claims 1-21, further comprising one or more additives.

23. The gelled topical formulation of claim 22, wherein the one or more additives are an enhancer, a thickening agent, or combinations thereof.

24. The gelled topical formulation of claim 22 or 23, wherein the one or more additives are selected from the group consisting of dimethyl isosorbide, a fatty alcohol, a fatty acid, a fatty ester, a fatty acid amide, and combinations thereof.

25. The gelled topical formulation of claim 24, wherein the fatty alcohol is selected from the group consisting of capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, and combinations thereof.

26. The gelled topical formulation of claim 24, wherein the fatty acid is selected from the group consisting of lauric acid, myristic acid, palmitic acid, stearic acid, lauroleic acid, myristoleic acid, palmitoleic acid, oleic acid, and combinations thereof.

27. The gelled topical formulation of claim 24, wherein the fatty ester is selected from the group consisting of a glyceride, ethylene glycol monoester and diester of a fatty acid, propylene glycol monoester and diester of a fatty acid, a Ci-₆ alkyl ester of a fatty acid, and a di-(Ci-₆ alkyl) ester of adipic acid and sebacic acid.

28. The gelled topical formulation of claim 24, wherein the fatty acid amide is a N-acylethanolamine.

29. The gelled topical formulation of any one claims 1-28, further comprising a stabilizer.

30. The gelled topical formulation of claim 29, wherein the stabilizer is Polysorbate 20.

31. The gelled topical formulation of any one of claims 1-30, wherein the MEK inhibitor is present in an amount of from 0.005% to 10%, from 0.1% to 5%, or from 0.1% to 1% by weight of the base formulation.

32. The gelled topical formulation of any one of claims 1-31, having a visual appearance as clear, transparent, or monophasic.

33. The gelled topical formulation of claim 32, wherein the visual appearance is maintained over a period of 4 weeks at a temperature of 40°C.

34. The gelled topical formulation of any one of claims 1-31, wherein a viscosity of from 500 to 5000 cps is maintained over a period of 4 weeks at a temperature of 40°C.

35. A method of treating a skin disorder comprising administering the gelled topical formulation of any one of claims 1-31.

36. The method of claim 35, wherein the skin disorder is a MEK-inhibitor responsive dermal disorder or a MEK-mediated dermal disorder.

37. The method of claim 36, wherein the MEK-inhibitor responsive dermal disorder or MEK-mediated dermal disorder is neurofibromatosis type 1.

38. The method of claim 36, wherein the MEK-inhibitor responsive dermal disorder or MEK-mediated dermal disorder is dermal neurofibroma.

39. The method of claim 36, wherein the MEK-inhibitor responsive dermal disorder or MEK-mediated dermal disorder is subdermal neurofibroma.

40. The method of claim 36, wherein the MEK-inhibitor responsive dermal disorder or MEK-mediated dermal disorder is superficial plexiform neurofibroma.

41. The method of claim 36, wherein the MEK-inhibitor responsive dermal disorder or MEK-mediated dermal disorder is dermal rasopathy.

42. The method of claim 41, wherein the dermal rasopathy is selected from the group consisting of psoriasis, keratocanthoma (KA), hyperkeratosis, papilloma, Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), Costello syndrome (faciocutaneoskeletal syndrome or FCS syndrome), oculoectodermal syndrome, cafe au lait spots, and Multiple lentigines syndrome (formerly called Leopard syndrome).

43. The method of claim 35, wherein the skin disorder is a birthmark.

44. The method of claim 43, wherein the birthmark is selected from the group consisting of port-wine stains/capillary malformations, nevus cellular nevus, displastic nevi, capillary angioma, epidermal nevi, nevus sebaceous, nevus spilus, arterio-venous malformations, lymphatic malformations, and congenital melanocytic nevus.

45. The method of claim 43 or 44, wherein the birthmark is associated with activation of p-ERK.

46. The method of claim 44 or 45, wherein the birthmark associated with activation of p-ERK is selected from the group consisting of epidermal nevi, nevus sebaceous, nevus spilus, arterio-venous malformations, capillary malformations/port-wine stain, congenital melanocytic nevus, and lymphatic malformations.

47. The method of any one of claims 35-46, wherein the gelled topical formulation is administered topically.

1 48. The method of any one of claims 35-47, wherein the gelled topical

2 formulation is administered as a paint, a lotion, a spray, an ointment, a cream, a gel, or a patch.