Arylaniline and heteroarylaniline compounds for the treatment of bruises - Patent Application 20070233633

Abstract

Provided herein are compounds and pharmaceutical compositions thereof for treating a birthmark in a subject in need thereof, the compounds having formula (I), (II), (III), (IV), and (V): TIFF2022511127000456.tif94128, wherein X 1 , X 2 , X 3 , R 1 , R 2 , R 2a , R 13 , R 13a , R 23 , R 23a , R 23b , R 33 , R 33a , R 33b , R 43 , R 43a , R 51 , R 53 , R 53a , R 53b , the bond "a" and the subscript n are as described herein. TIFF2022511127000457.tif128128

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 769,844, filed November 20, 2018, the contents of which are incorporated herein in their entirety for all purposes. [Background technology]

[0002] Background of the Invention Benign skin tumors of the vascular, keratinocyte, and melanocytic compartments often occur at birth or during childhood. These lesions, referred to herein 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 occur as part of an underlying neurocutaneous syndrome.

[0003] Vascular birthmarks include, for example, port-wine stain / capillary malformation, hemangioma, lobular capillary hemangioma, arterial vascular malformation, lymphatic malformation, vascular malformation, hemangioma, and other angioma. Keratinocyte nevi include keratinocyte epidermal nevi and sebaceous nevi. Pigmented nevi (commonly known as moles) include, for example, congenital nevi, multiple lentigines (which can occur in syndromes such as LEOPARD), ephiledes (freckles), and nevus spilus.

[0004] Neurocutaneous syndromes, also known as birthmarks, such as port-wine stains, are associated with congenital low-flow vascular malformations (capillary malformations) in the skin, which, if left untreated, can enlarge and develop nodules (Minkis, K. et al., Lasers Surg Med. (2009) 41(6):pp. 423-426). Laser treatment is typically used to treat port-wine stains, but they often fail to completely resolve. Epidermal nevi are common cutaneous mosaic disorders subdivided into keratocytic nevi and organoid nevi. Organoid nevi include sebaceous nevi (NS). NS immunolabeling has been reported to be associated with increased phosphorylated ERK staining (Aslam, A. et al., Clinical and Experimental Dermatology (2014) 39:pp. 1-6). Non-organoid keratocytic epidermal nevi (KEN) are characterized by benign congenital hyperpigmented skin lesions. Epidermal nevi, which are localized thickenings of the epidermis, are present at birth or become visible during childhood. Other skin disorders that occur in childhood birthmarks include nevus cytoides, lobular capillary hemangiomas, congenital nevi, ephelides (freckles), multiple lentigines (which can occur in multiple syndromes, including LEOPARD syndrome), capillary hemangiomas, nevus spilus, arteriovenous malformations, lymphatic malformations, and congenital pigmented nevi. Lentigines can occur in childhood with mutations that activate the RAS / MAPK pathway (such as in LEOPARD syndrome), as well as in adults. In some cases, birthmarks are not amenable to surgical excision and / or laser treatment. In some cases, birthmarks, if left untreated, can progress to lesions and / or proliferative skin conditions.

[0005] Modulation of ERK / MEK pathway can have therapeutic effect on birthmark. RAS mutation has been reported in mosaic RAsopathies, namely non-organoid keloid nevus and sebaceous nevus (Farschtschi S et al., BMC Medical Genetics. (2015); 16: pp6 (Non-Patent Document 3); and Sun, BK et al., Journal of Investigative Dermatology, (2013); 3: pp824-827 (Non-Patent Document 4)). Therefore, inhibiting the Ras signaling pathway, including the Ras-MAPK cascade, can be useful in treating birthmark.

[0006] Four different MAPK cascades have been identified and named according to their MAPK modules. See Akinleye et al., Journal of Hematology & Oncology 6:27, 2013 (Non-Patent Document 5). MEK proteins belong to a family of enzymes located upstream of 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. MEK1 and MEK2 inhibitors have been shown to effectively inhibit MEK signaling downstream of Ras (Rice et al., Medicinal Chemistry Letters 3:416-421, 2012 (Non-Patent Document 6)), thus providing a rationale for targeting MEK in the treatment of bruises.

[0007] 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 reduced left ventricular ejection fraction, elevated creatine phosphokinase, interstitial pneumonitis, renal failure, diarrhea, infection, urticaria, and maculopapular rash, all of which limit doses or require permanent discontinuation. Furthermore, clinical trials have demonstrated one or more side effects associated with long-term, 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 demonstrated one or more neurological side effects related to ataxia, confusion, and syncope. Furthermore, numerous other side effects, including acneiform rash, elevated CPK, nausea, vomiting, diarrhea, abdominal pain, and fatigue, have been observed with systemic exposure to MEK inhibitors. Therefore, there is a need for a therapy that treats bruising and also limits one or more side effects associated with systemic exposure to MEK / ERK pathway inhibitors. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Minkis, K. et al., Lasers Surg Med. (2009)41(6):pp423-426 [Non-patent document 2] Aslam, A et al. Clinical and Experimental Dermatology (2014)39:pp1-6 [Non-patent document 3] Farschtschi S et al., BMC Medical Genetics.(2015);16:pp6 [Non-patent document 4] Sun, BK et al., Journal of Investigative Dermatology, (2013);3:pp824-827 [Non-Patent Document 5] Akinleye et al., Journal of Hematology&Oncology 6:27, 2013 [Non-patent document 6] Rice et al., Medicinal Chemistry Letters 3:416-421, 2012 [Non-Patent Document 7] Huang et al., J. Ocul. Pharmacol. Ther. 25:519-530, 2009 Summary of the Invention

[0009] Brief Summary of the Invention In one aspect, provided herein is a method for treating birthmarks, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (II), (III), (IV) and (V): TIFF0007651101000001.tif94128, or an N-oxide, stereoisomer, mixture of stereoisomers and / or pharmaceutically acceptable salt thereof; During the ceremony, X 1 -CR 13b or N;X 2 is C1-C6 alkyl; X 3 is S or O; The subscript n is an integer from 0 to 2; The bond "a" is a single or double bond; R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 is an N-linked heterocycloalkyl substituted with; R 2 is halo, C1-C6 alkyl, -S-C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 2ais halo or C1-C6 alkyl; R 4 , R 5 and R 5b are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl, and each of the C3-C8 cycloalkyl group and heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is replaced by; R 5a is hydrogen or C1-C6 alkyl; Each R 6 are independently halo, hydroxy, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl or di-(C1-C6 alkyl)amino-C1-C6 alkyl; R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino; R 13 , R 13a and R 13b are each independently hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 23 , R 23a and R 23bare each independently hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C3-C8 cycloalkoxy; R 33 , 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; R 43 is cyano, -C(O)NR 48 R 48a or -C(O)R 46 and; R 43a is hydrogen, halo, C1-C6 alkyl; or R 43 and R 43a together form —CH2CH2C(O)— or —CH2CH2CH2C(O)—, each of which is unsubstituted or contains one or two R 49 is replaced by; R 46 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or heterocycloalkyl; R 48 and R 48a are independently hydrogen or C1-C6 alkyl; and Each R 49 are independently C1-C6 alkyl, C3-C8 cycloalkyl, or C3-C8 cycloalkyl-C1-C6 alkyl; R 51 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, R 7 -C(O)-C1-C6 alkyl or -OR 54wherein each of the C3-C8 cycloalkyl group and the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is replaced by; Each R 53 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 R 54 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl, and each of the C3-C8 cycloalkyl group and heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is replaced by . [The present invention 1001] A method for treating birthmarks, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formulas (I), (II), (III), (IV) and (V): TIFF0007651101000002.tif94128 or an N-oxide, stereoisomer, mixture of stereoisomers and / or pharmaceutically acceptable salt thereof, During the ceremony, X 1 -CR 13b or N;X 2 is C 1 ~C 6 is alkyl; X 3 is S or O; The subscript n is an integer from 0 to 2; The bond "a" is a single or double bond; R 1 -OR 4 , -NR 5 R5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 is an N-linked heterocycloalkyl substituted with; R 2 Ha, Halo, C 1 ~C 6 Alkyl, -SC 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 2 ~C 6 Alkenyl, or C 2 ~C 6 is alkynyl; R 2a is a halo or C 1 ~C 6 is alkyl; R 4 、R 5 and R 5b are each independently hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxy-C 1 ~C 6 Alkyl, Amino-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylamino-C 1 ~C 6 Alkyl, di-(C 1 ~C 6 Alkyl)amino-C 1 ~C 6 Alkyl, heterocycloalkyl, heterocycloalkyl-C 1 ~C 6 Alkyl, or R 7 -C(O)-C 1 ~C 6 alkyl, 3 ~C 8 Each of the cycloalkyl and heterocycloalkyl groups is unsubstituted or contains 1 to 6 R 6 is replaced by; R 5a is hydrogen or C1 ~C 6 is alkyl; Each R 6 are independently halo, hydroxy, oxo, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 -hydroxyalkyl, C 1 ~C 6 Haloalkyl, Amino, C 1 ~C 6 Alkylamino, di-(C 1 ~C 6 Alkyl)amino, amino-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylamino-C 1 ~C 6 Alkyl or di-(C 1 ~C 6 Alkyl)amino-C 1 ~C 6 is alkyl; R 7 is hydroxy, C 1 ~C 6 Alkoxy, Amino, C 1 ~C 6 Alkylamino, di-(C 1 ~C 6 alkyl)amino, hydroxyamino or NC 1 ~C 6 alkylhydroxyamino; R 13 、R 13a and R 13b are each independently hydrogen, halo, or C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 2 ~C 6 is alkynyl; R 23 、R 23a and R 23b are each independently hydrogen, halo, or C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Alkoxy, or C 3 ~C 8 is cycloalkoxy; R 33 、R 33a and R 33b are each independently hydrogen, halo, or C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Alkoxy, or C 3 ~C 8 is cycloalkoxy; R 43 is cyano, -C(O)NR 48 R 48a or -C(O)R 46 and; R 43a is hydrogen, halo, C 1 ~C 6 is alkyl; or R 43 and R 43a Together, -CH 2 CH 2 C(O)- or -CH 2 CH 2 CH 2 C(O)—, each of which is unsubstituted or has one or two R 49 is replaced by; R 46 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 8 is cycloalkyl or heterocycloalkyl; R 48 and R 48a are independently hydrogen or C 1 ~C 6 is alkyl; and Each R 49 independently, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, or C 3 ~C8 Cycloalkyl-C 1 ~C 6 is alkyl; R 51 is hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxy-C 1 ~C 6 Alkyl, Amino-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylamino-C 1 ~C 6 Alkyl, di-(C 1 ~C 6 Alkyl)amino-C 1 ~C 6 Alkyl, heterocycloalkyl, heterocycloalkyl-C 1 ~C 6 Alkyl, R 7 -C(O)-C 1 ~C 6 Alkyl or -OR 54 and C 3 ~C 8 Each of the cycloalkyl and heterocycloalkyl groups is unsubstituted or contains 1 to 6 R 6 is replaced by; Each R 53 are independently halo or C 1 ~C 6 is alkyl; R 53a and R 53b are each independently hydrogen, halo, or C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 2 ~C 6 alkynyl; and R 54 is hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxy-C 1 ~C 6 Alkyl, Amino-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylamino-C 1 ~C 6 Alkyl, di-(C 1 ~C 6 Alkyl)amino-C 1 ~C 6 Alkyl, heterocycloalkyl, heterocycloalkyl-C 1 ~C 6 Alkyl, or R 7 -C(O)-C 1 ~C 6 alkyl, 3 ~C 8 Each of the cycloalkyl and heterocycloalkyl groups is unsubstituted or contains 1 to 6 R 6 has been replaced by The method. [The present invention 1002] The compound has formula (Ia) or (Ib): TIFF0007651101000003.tif29128 The method of the present invention 1001, comprising: [The present invention 1003] R 13 、R 13a and R 13b are each independently hydrogen, halo, or C 1 ~C 6 The method of any one of claims 1001 to 1002, wherein the alkyl is alkyl. [The present invention 1004] R 13 The method according to any one of claims 1001 to 1003, wherein is hydrogen. [The present invention 1005] R 13a The method according to any one of claims 1001 to 1004, wherein is hydrogen. [The present invention 1006] R 13b The method according to any one of claims 1001 to 1005, wherein is hydrogen. [The present invention 1007] R 13b The method of any one of claims 1001 to 1005, wherein is halo. [The present invention 1008] R 13b The method of any one of claims 1001 to 1005 and 1007, wherein is fluoro. [The present invention 1009] X in formula (II) 2 C 1 ~C 3 The method of claim 1001, wherein the alkyl group is alkyl. [The present invention 1010] X 2 The method of any one of claims 1001 to 1009, wherein is methyl. [The present invention 1011] R 23 、R 23a and R 23b are independently hydrogen, halo, C 1 ~C 6 Alkyl, or C 1 ~C 6 The method according to any one of claims 1001 and 1009 to 1010, wherein the alkoxy is alkoxy. [The present invention 1012] R 23 and R 23b are hydrogen, and R 23a Halo, C 1 ~C 6 Alkyl, or C 1 ~C 6 The method of any one of claims 1001 and 1009 to 1011, wherein the alkoxy group is alkoxy. [The present invention 1013] R 23 and R 23b are hydrogen, and R 23a The method of any one of claims 1001, 1009 to 1011 and 1012, wherein is fluoro, methyl or methoxy. [The present invention 1014] R 23 、R 23a and R 23b and each of the formulas 1001 and 1009 to 1011 is hydrogen. [The present invention 1015] The compound has formula (IIIa) or (IIIb): TIFF0007651101000004.tif27128 The method of the present invention 1001, comprising: [The present invention 1016] R 33 、R 33a and R 33b are independently hydrogen, halo, C 1 ~C 6 Alkyl, or C 1 ~C 6 The method of any one of claims 1001 to 1015, wherein the alkoxy group is alkoxy. [The present invention 1017] R 33 、R 33a and R 33b The method of any one of claims 1001 and 1015 to 1016, wherein each is independently fluoro, methyl, or methoxy. [The present invention 1018] R 33a and R 33b are hydrogen, and R 33 The method of any of claims 1001 and 1015 to 1017, wherein is fluoro, methyl, or methoxy. [The present invention 1019] R 33 and R 33b are hydrogen, and R 33a The method of any of claims 1001 and 1015 to 1017, wherein is fluoro, methyl, or methoxy. [The present invention 1020] R 33 and R 33a are hydrogen, and R 33b The method of any of claims 1001 and 1015 to 1017, wherein is fluoro, methyl, or methoxy. [The present invention 1021] R 33 、R 33a and R 33b and each of the formulas 1001 and 1015 to 1016 is hydrogen. [The present invention 1022] The compound is TIFF0007651101000005.tif130128 1001. The method of claim 1001, having a formula selected from the group consisting of: [The present invention 1023] R 48 and R 48a The method of any one of claims 1001 to 1022, wherein is hydrogen. [The present invention 1024] R 46 But hydrogen, C 1 ~C 6 Alkyl, or C 1 ~C 6 The method of any one of claims 1001 to 1022, wherein the alkyl group is haloalkyl. [The present invention 1025] R 46 C 1 ~C 6 The method of any of claims 1001, 1022 and 1024, wherein the alkyl is alkyl. [The present invention 1026] R 46 The method of any one of claims 1001, 1022 and 1024 to 1025, wherein is methyl, ethyl, propyl or butyl. [The present invention 1027] R 43a The method according to any one of claims 1001 and 1022 to 1026, wherein is hydrogen. [The present invention 1028] R 43a The method of any one of claims 1001 and 1022 to 1026, wherein [The present invention 1029] R 43a C 1 ~C 6 The method of any one of claims 1001 and 1022 to 1026, wherein the alkyl is alkyl. [The present invention 1030] R 43a The method of any one of claims 1001, 1022 to 1026 and 1029, wherein is methyl. [The present invention 1031] Each R 9 independently C 1 ~C 6 The method of any one of claims 1001 to 1022, wherein the alkyl group is alkyl. [The present invention 1032] R 9 The method of the present invention 1001 or 1022, in which [The present invention 1033] R 1 But, -OR 4 , -NR 5 R 5a OR-N(OR 5b )R 5a The method of any one of claims 1001 to 1032 of the present invention. [The present invention 1034] R 1 -OR 4 and;R 4 But hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxy-C 1 ~C 6 Alkyl, Amino-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylamino-C 1 ~C 6 Alkyl, di-(C 1 ~C 6 Alkyl)amino-C 1 ~C 6 Alkyl, heterocycloalkyl, heterocycloalkyl-C 1 ~C 6 Alkyl, or R 7 -C(O)-C 1 ~C 6 alkyl; R 7 is hydroxy, C 1 ~C 6 alkoxy, amino or hydroxyamino; 3 ~C 8 Each of the cycloalkyl and heterocycloalkyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 are independently hydroxy or C 1 ~C 6 The method of any one of claims 1001 to 1033, wherein the alkyl is alkyl. [This invention 1035] R 1 But -OH, TIFF0007651101000006.tif51128 Any of the methods of claims 1001 to 1034, selected from the group consisting of: [The present invention 1036] R 1 Ga-NR 5R 5a and;R 5 But hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxy-C 1 ~C 6 Alkyl, Amino-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylamino-C 1 ~C 6 Alkyl, di-(C 1 ~C 6 Alkyl)amino-C 1 ~C 6 Alkyl, heterocycloalkyl, heterocycloalkyl-C 1 ~C 6 Alkyl, or R 7 -C(O)-C 1 ~C 6 alkyl; R 7 is hydroxy, C 1 ~C 6 alkoxy, amino or hydroxyamino; 3 ~C 8 Each of the cycloalkyl and heterocycloalkyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 are independently hydroxy or C 1 ~C 6 The method of any one of claims 1001 to 1033, wherein the alkyl is alkyl. [This invention 1037] R 5 But hydrogen, TIFF0007651101000007.tif40128 Any of the methods of 1001 to 1033 and 1036 of the present invention, selected from the group consisting of: [The present invention 1038] R 1 Ga-NR 5 R 5a and R 5 -OR 5b The method of any one of claims 1001 to 1033 of the present invention. [This invention 1039] R 1 -N(OR 5b )R 5a and;R 5b But hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxy-C 1 ~C 6 Alkyl, Amino-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylamino-C 1 ~C 6 Alkyl, di-(C 1 ~C 6 Alkyl)amino-C 1 ~C 6 Alkyl, heterocycloalkyl, heterocycloalkyl-C 1 ~C 6 Alkyl, or R 7 -C(O)-C 1 ~C 6 alkyl; R 7 is hydroxy, C 1 ~C 6 alkoxy, amino or hydroxyamino; 3 ~C 8 Each of the cycloalkyl and heterocycloalkyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 are independently hydroxy or C 1 ~C 6 The method of any one of claims 1001 to 1033 and 1038, wherein the alkyl is alkyl. [The present invention 1040] -OR 5b but, TIFF0007651101000008.tif77128 Any of the methods of inventions 1001 to 1033 and 1038 to 1039, selected from the group consisting of: [The present invention 1041] R 1 Ga-NR 5 R 5a OR-N(OR 5b )R 5a and R 5a The method according to any one of claims 1001 to 1033 and 1036 to 1040, wherein is hydrogen. [The present invention 1042] R 1 Ga-NR 5 R 5a OR-N(OR 5b )R 5a and R 5a C 1 ~C 6 The method of any one of claims 1001 to 1033 and 1036 to 1040, wherein the alkyl is alkyl. [This invention 1043] R 1 is unsubstituted or contains one or two R 6 The method of any one of claims 1001 to 1032, wherein the heterocycloalkyl is an N-linked heterocycloalkyl substituted with [This invention 1044] The method of any one of claims 1001 to 1032 and 1043, wherein said N-linked heterocycloalkyl is N-linked azetidinyl, N-linked pyrrolidinyl or N-linked isoxazolidinyl. [This invention 1045] Each R 7 is independently hydroxyl, oxo or amino. [The present invention 1046] The compound has formula (Va) or (Vb): TIFF0007651101000009.tif26128 The method of the present invention 1001, comprising: [This invention 1047] Each R 53 but independently, halo or C 1 ~C 3 The method of any one of claims 1001 to 1046, wherein the alkyl group is alkyl. [This invention 1048] The method of any one of claims 1001 to 1046, wherein the subscript n is 0. [This invention 1049] R 53a and R 53b are each independently hydrogen, halo, or C 1 ~C 6 The method of any one of claims 1001 to 1048, wherein the alkyl is alkyl. [The present invention 1050] R 53a The method of any one of claims 1001 and 1046 to 1049, wherein is hydrogen. [This invention 1051] R 53b The method according to any one of claims 1001 and 1046 to 1050, wherein is hydrogen. [This invention 1052] R 53b The method of any one of claims 1001 and 1046 to 1050, wherein is halo. [This invention 1053] R 53b The method of any one of claims 1001, 1046 to 1050, and 1052, wherein is fluoro. [This invention 1054] R 51 But hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxy-C 1 ~C 6 Alkyl, Amino-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylamino-C 1 ~C 6 Alkyl, di-(C 1 ~C 6 Alkyl)amino-C 1 ~C 6 Alkyl, heterocycloalkyl-C 1 ~C 6 Alkyl, or R 7 -C(O)-C 1 ~C 6 alkyl; R 7 is hydroxy, C 1 ~C 6 alkoxy, amino or hydroxyamino; 3 ~C 8 Each of the cycloalkyl and heterocycloalkyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 are independently hydroxy or C 1 ~C 6 The method of any one of claims 1001 and 1046 to 1053, wherein the alkyl is alkyl. [This invention 1055] R 51 -OR 54b and;R 54b But hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxy-C 1 ~C 6 Alkyl, Amino-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylamino-C 1 ~C 6 Alkyl, di-(C 1 ~C 6 Alkyl)amino-C 1 ~C 6 Alkyl, heterocycloalkyl-C 1 ~C 6 Alkyl, or R 7 -C(O)-C 1 ~C 6 alkyl; R 7 is hydroxy, C 1 ~C 6 alkoxy, amino or hydroxyamino; 3 ~C 8 Each of the cycloalkyl and heterocycloalkyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 are independently hydroxy or C 1 ~C 6 The method of any one of claims 1001 and 1046 to 1053, wherein the alkyl is alkyl. [This invention 1056] R 51 But hydrogen, -OH, TIFF0007651101000010.tif101128 Any of the methods of 1001 and 1046 to 1053 of the present invention, selected from the group consisting of: [This invention 1057] R 2 But, Haro C 1 ~C 6 Alkyl, -SC 1 ~C 6 Alkyl, or C 2 ~C 6 The method of any one of claims 1001 to 1056, wherein the compound is alkynyl. [This invention 1058] R 2 The method of any one of claims 1001 to 1057, wherein is halo. [This invention 1059] R 2 The method of any one of claims 1001 to 1058, wherein is iodine. [The present invention 1060] R 2 C 1 ~C 6 The method of any one of claims 1001 to 1057, wherein the alkyl is alkyl. [This invention 1061] R 2 is CH 3 The method of any one of claims 1001 to 1057 and 1060, [This invention 1062] R 2 Ga-SC 1 ~C 6 The method of any one of claims 1001 to 1057, wherein the alkyl is alkyl. [This invention 1063] R 2 Ga-SCH 3 The method of any one of claims 1001 to 1057 and 1060, [This invention 1064] R 2 C 2 ~C 6 The method of any one of claims 1001 to 1057, wherein the compound is alkynyl. [This invention 1065] R 2 The method of any one of claims 1001 to 1057 and 1060, wherein is acetylenyl. [The present invention 1066] R 2a The method of any one of claims 1001 to 1061, wherein [This invention 1067] R 2a The method of any one of claims 1001 to 1066, wherein is fluoro. [The present invention 1068] R 2a C 1 ~C 6 The method of any one of claims 1001 to 1061, wherein the alkyl is alkyl. [The present invention 1069] R 2a The method of any one of claims 1001 to 1061 and 1068, wherein is methyl. [The present invention 1070] The method of any one of claims 1001 to 1069, wherein said compound is selected from the group consisting of the compounds in Tables 1 to 5. [This invention 1071] The method of any of claims 1001 to 1070, wherein said compound is administered in a pharmaceutical composition together with a pharmaceutically acceptable carrier. [This invention 1072] Any of the methods of inventions 1001 to 1071, wherein the birthmark is selected from the group consisting of port wine stain / capillary malformation, pigmented nevus, dysplastic nevus, epidermal nevus, sebaceous nevus, nevus spilus, arteriovenous malformation, lymphatic malformation and congenital pigmented nevus. [This invention 1073] 1073. The method of any one of claims 1001 to 1072, wherein said birthmark is associated with activation of p-ERK. [This invention 1074] 1072. The method of claim 1072, wherein the birthmark associated with activation of p-ERK is selected from the group consisting of epidermal nevus, sebaceous nevus, nevus spilus, arteriovenous malformation, capillary malformation / port wine stain, congenital pigmented nevus, and lymphatic malformation. [This invention 1075] The method of any one of claims 1001 to 1074, wherein the compound having any one of formulas (I) to (V) or the pharmaceutical composition thereof is administered topically, subcutaneously, intradermally, or intralesionally. [This invention 1076] The method of any of claims 1001 to 1075, wherein the compound having any one of formulas (I) to (V) or the pharmaceutical composition thereof is administered as a lotion, spray, ointment, cream, gel, paste, and patch. [Brief explanation of the drawings]

[0010] [Figure 1-1] Figure 1 shows the suppression of p-ERK in human epidermal nevus explants after application of topical formulations containing vehicle only, compound 2.003, or compound 4.013 using the protocol described in Example 1. Figure 1A: No treatment; Figure 1B: Vehicle only; Figure 1C: Compound 2.003; and Figure 1D: Compound 4.013. [Figure 1-2] See the description of Figure 1-1. [Figure 2] FIG. 2 shows hyperproliferative lesions overlapping with p-ERK expression by Ki-67 staining of epidermal nevus using the protocol described in Example 1. [Figure 3] Figure 3 shows the suppression of p-ERK in human sebaceous nevus explants after application of topical gel formulations containing vehicle alone, trametinib, compound 2.003, and compound 4.029 using the protocol described in Example 1. [Figure 4] Figure 4 shows the suppression of p-ERK in human sebaceous nevus explants after application of topical gel formulations containing vehicle alone, trametinib, compound 2.003, and compound 4.029 using the protocol described in Example 1. [Figure 5]FIG. 5 shows the suppression of p-ERK in human sebaceous nevus explants after application of vehicle alone and a gel topical formulation containing compound 2.003 using the protocol described in Example 1. [Figure 6] FIG. 6 shows the dose response of compound 2.003 in suppressing p-ERK in human sebaceous nevus explants after application of vehicle alone and a topical gel formulation containing compound 2.003 using the protocol described in Example 1. [Figure 7] FIG. 7 shows a synthetic scheme I-1 for preparing compounds of formula (Ia). [Figure 8] FIG. 8 shows synthetic scheme I-2 for preparing compounds of formula (Ia). [Figure 9] FIG. 9 shows synthetic scheme I-3 for preparing compounds of formula (Ib). [Figure 10] FIG. 10 shows a synthetic scheme II-1 for preparing compounds of formula (II). [Figure 11] FIG. 11 shows synthetic scheme II-2 for preparing compounds of formula (II). [Figure 12] FIG. 12 shows synthetic scheme II-3 for preparing compounds of formula (II). [Figure 13] FIG. 13 shows synthetic scheme II-4 for preparing compounds of formula (II). [Figure 14] FIG. 14 shows synthetic scheme II-5 for preparing compounds of formula (II). [Figure 15] FIG. 15 shows a synthetic scheme III-1 for preparing compounds of formula (IIIa). [Figure 16] FIG. 16 shows synthetic scheme III-2 for preparing compounds of formula (IIIa). [Figure 17] FIG. 17 shows a synthetic scheme IV-1 for preparing a compound of any one of formulas (IVa), (IVb), and (IVc). [Figure 18]FIG. 18 shows synthetic scheme IV-2 for preparing compounds of any one of formulae (IVd-1), (IVd-2), (IVe-1) and (IVe-2). [Figure 19] FIG. 19 shows synthetic scheme IV-3 for preparing compounds of formula (IVa). [Figure 20] FIG. 20 shows synthetic scheme V-1 for the preparation of compounds of formula (Va). [Figure 21] FIG. 21 shows synthetic scheme V-2 for the preparation of compounds of formula (Va). [Figure 22] FIG. 22 shows synthetic scheme V-3 for preparing compounds of formula (Vb). DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description of the Invention I. Overview Provided herein are methods of using compounds and pharmaceutical compositions comprising the compounds to treat bruises.

[0012] Birthmarks of the present invention are defined and described as follows.

[0013] In some embodiments, the birthmark is a port-wine stain (capillary malformation). Port-wine stains can be present at birth. Port-wine stains can occur anywhere on the body, and the affected area of ​​skin grows proportionally with overall growth. Thickening of the lesion or the development of small lumps can occur in adulthood and can interfere with normal function (e.g., if the port-wine stain is near the eye or mouth). Port-wine stains can, in some cases, be part of a syndrome such as Sturge-Weber syndrome or Klippel-Trenaunay-Weber syndrome.

[0014] In some embodiments, the birthmark is an epidermal nevus. Epidermal nevus is a benign skin growth with localized thickening of the epidermis that is often present at birth or within the first year of life. Epidermal nevus typically appear as one or more oval or linear growths with brown or gray-colored skin. The surface may be warty or smooth and have a well-defined border. Malignant transformation may occur in some cases in middle-aged or elderly subjects. Epidermal nevus is subdivided into keratocytic nevus and organoid nevus. Organoid nevus includes sebaceous nevus (NS). In some embodiments, the birthmark is a sebaceous nevus. Non-organoid keratocytic nevus (KEN) is characterized by a benign congenital hyperpigmented skin lesion. Other types of epidermal nevus, including comedonal nevus, are contemplated within the scope of the embodiments presented herein. Nevus comedonale (NC), like other epidermal nevi, is a hamartoma of the pilosebaceous unit that typically appears at birth or during childhood. Clinically, NC lesions consist of linear arrays or clusters of dilated follicular openings plugged with keratin plugs, resembling comedones.

[0015] In some embodiments, the birthmark is a pigmented nevus, including congenital nevus, blue nevus and acquired pigmented nevus.Malignant melanoma sometimes develops from pigmented nevus (also known as nevus cytoplasmic nevus, nevus cell nevus, commonly known as mole).The reasons for treating pigmented nevus (i.e., nevus cytoplasmic nevus) include preventing malignant changes, limiting malignant progression, cosmetic improvement, or preventing other functional or anatomical changes.

[0016] In some embodiments, the birthmark is a dysplastic nevus.Dysplastic nevus (or atypical mole) is a benign mole that has an unusual appearance and may resemble melanoma.People with atypical moles are at increased risk of developing melanoma in the mole or elsewhere on the body.

[0017] In some embodiments, the birthmark is a nevus spilus. A nevus spilus (also known as nevus punctatus and nevus zosteriformis) is a skin lesion that appears as a light brown patch of pigmentation with multiple smaller dark brown spots within the patch.

[0018] In some embodiments, the birthmark is an intracutaneous arteriovenous malformation that can present as a skin lesion composed of a compressible blue subcutaneous nodule (eg, blue rubber nipple nevus syndrome).

[0019] In some embodiments, the birthmark is a lymphatic malformation. Lymphatic malformations are a type of vascular nevi or birthmark caused by malformed and dilated lymphatic vessels. Cysts (also called "cystic lymphangioma" and "lymphangioma cysticum") are "macrocystic" lymphatic malformations, consisting of large fluid-filled spaces. Cysts appear as swellings under the skin, slightly transparent, reddish or bluish in color. Cavernous lymphangiomas can occur anywhere on the body, including the tongue. Localized lymphangiomas are "microcystic" lymphatic malformations. Localized lymphangiomas appear as a collection of small, firm blisters filled with lymph, resembling frog eggs.

[0020] In some embodiments, the birthmark is a congenital pigmented nevus.Congenital pigmented nevus appears as a localized, light brown to black spot or plaque, with a heterogeneous consistency, covering any surface area of ​​any size and any part of the body.Congenital pigmented nevus carries the risk of malignant degeneration.

[0021] As used herein, the term "bruise" does not include cafe au lait spots.

[0022] II. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0023] When substituents are specified by their conventional chemical formula written from left to right, they equivalently include the substituents obtained by writing the structure from right to left, e.g., -CH2O- includes -OCH2-.

[0024] "Alkyl" refers to a straight or branched, saturated, aliphatic group having the specified number of carbon atoms (i.e., C1-C6 means 1 to 6 carbons). Alkyl can be any number of carbons, e.g., C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C1-C7, C1-C8, C1-C9, C1-C 10 , 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, and the like. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, including, but not limited to, heptyl, octyl, nonyl, decyl, and the like.

[0025] "Alkylene" refers to a straight-chain or branched, saturated, aliphatic, i.e., divalent hydrocarbon group having the specified number of carbon atoms (i.e., C1-C6 means 1 to 6 carbons) and linking at least two other groups. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) n - divalent group, 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.

[0026] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least two carbon atoms and at least one double bond, and having the specified number of carbon atoms (i.e., C2-C6 means 2-6 carbons). Alkenyl can be any number of carbons, e.g., C2, C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C 10, C3, C3-C4, C3-C5, C3-C6, C4, C4-C5, C4-C5, C5, C5-C6, and C6. The alkenyl group can include 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.

[0027] "Alkynyl" refers to either a straight or branched chain hydrocarbon having at least two carbon atoms and at least one triple bond, and having the number of carbon atoms specified (i.e., C2-C6 means 2-6 carbons). Alkynyl can be any number of carbons, e.g., C2, C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C 10 , 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.

[0028] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms specified. Cycloalkyl includes rings of any number of carbons, e.g., C3-C6, C4-C6, C5-C6, C3-C8, C4-C8, C5-C8, C6-C8, C3-C9, C3-C10 , C3~C 11 , and C3 to C 12

[0033] Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds within the ring. Representative partially unsaturated cycloalkyl groups 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), norbornene, and norbornadiene. When cycloalkyl is a saturated monocyclic C3-C8 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0029] "Cycloalkylalkyl" refers to a group having an alkyl component and a cycloalkyl component, where the alkyl component connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent alkylene to connect the cycloalkyl component and the point of attachment. The alkyl component can contain any number of carbons, e.g., 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 C5-C6. The cycloalkyl component is as defined above. Exemplary cycloalkyl-alkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0030] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to its point of attachment: alkyl-O-. The alkoxy group can have any suitable number of carbon atoms, e.g., C1-C6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0031] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which at least one of the hydrogen atoms has been replaced with a hydroxy group. With respect to the alkyl group, the hydroxyalkyl group can have any suitable number of carbon atoms, e.g., C1-C6. Exemplary hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (hydroxy in the 1- or 2-position), hydroxypropyl (hydroxy in the 1-, 2-, or 3-position), hydroxybutyl (hydroxy in the 1-, 2-, 3-, or 4-position), hydroxypentyl (hydroxy in the 1-, 2-, 3-, 4-, or 5-position), hydroxyhexyl (hydroxy in the 1-, 2-, 3-, 4-, 5-, or 6-position), 1,2-dihydroxyethyl, and the like.

[0032] "Alkoxyalkyl" refers to a group having an alkyl and an alkoxy component, where the alkyl component connects the alkoxy component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent alkylene to connect the alkoxy component and the point of attachment. The alkyl component can contain any number of carbons, e.g., 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 alkoxy-alkyl groups include, but are not limited to, 2-ethoxy-ethyl and methoxymethyl.

[0033] "Halogen" or "halo" refers to fluoro, chloro, bromo, or iodo.

[0034] "Haloalkyl" refers to an alkyl, as defined above, in which some or all of the hydrogen atoms have been replaced with halogen atoms. With respect to the alkyl group, the haloalkyl group can have any suitable number of carbon atoms, for example, C1 to C6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, and the like. In some cases, the term "perfluoro" can be used to define a compound or group in which all hydrogen atoms have been replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0035] As used herein, unless otherwise specified, "amino" refers to --NH.sub.2.

[0036] As used herein, unless otherwise specified, "alkylamino" refers to -NHR, where R is alkyl, as defined herein, or its N-oxide derivative. In some embodiments, alkylamino is C1-C6-alkyl-amino. In some embodiments, C1-C6-alkyl-amino is methylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert-butylamino, or methylamino-N-oxide, etc.

[0037] As used herein, unless otherwise stated, "dialkylamino" refers to -NR'R, where R and R' are independently alkyl as defined herein, or its N-oxide derivative. In some embodiments, dialkylamino is di-C1-C6-alkyl-amino. In some embodiments, di-C1-C6-alkyl-amino is dimethylamino, methyl-ethylamino, diethylamino, or dimethylamino-N-oxide, etc.

[0038] As used herein, unless otherwise specified, "aminoalkyl" refers to an alkyl group substituted with one or two NH2. In some embodiments, the aminoalkyl is amino-C1-C6-alkyl.

[0039] As used herein, unless otherwise specified, "alkylaminoalkyl" refers to an alkyl group substituted with one or two -NH(alkyl) groups. In some embodiments, the alkylaminoalkyl is C1-C6-alkyl-amino-C1-C6-alkyl.

[0040] As used herein, unless otherwise specified, "dialkylaminoalkyl" refers to an alkyl group substituted with one or two -N(alkyl) groups. In some embodiments, the dialkylaminoalkyl is di-C1-C6-alkyl-amino-C1-C6-alkyl.

[0041] As used herein, unless otherwise specified, "hydroxyamino" refers to --NHOH.

[0042] As used herein, unless otherwise specified, "N-alkylhydroxyamino" refers to an -NHOH group in which the amine hydrogen is replaced with alkyl, as defined herein. In some embodiments, the N-alkylhydroxyamino group is N-C1-C6 alkyl-hydroxyamino. In some embodiments, the N-C1-C6 alkyl-hydroxyamino group is N-methylhydroxyamino, N-ethylhydroxyamino, N-(n-, iso-propyl)-hydroxyamino, or N-(n-, iso-, tert-butyl)hydroxyamino, etc.

[0043] "Heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. The heteroatoms can be optionally oxidized, including, but not limited to, -S(O)- and -S(O)-. A heterocycloalkyl group can contain any number of ring atoms, for example, 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 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in a heterocycloalkyl group, for example, 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. Heterocycloalkyl groups 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. Heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form elements such as, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted, for example, with C1-C6 alkyl or oxo (=O), among many others.

[0044] The heterocycloalkyl group can be attached at 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, and 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.

[0045] "N-linked heterocycloalkyl" or "nitrogen-linked heterocycloalkyl" refers to a heterocycloalkyl group attached at the N position on the ring. For example, N-linked aziridinyl is aziridin-1-yl, N-linked azetidinyl is azetidin-1-yl, N-linked pyrrolidinyl is pyrrolidin-1-yl, N-linked piperidinyl is piperidin-1-yl, N-linked pyrazolidinyl can be pyrazolidin-1-yl or pyrazolidin-2-yl, N-linked imidazolidinyl can be imidazolidin-1-yl or imidazolidin-3-yl, N-linked piperazinyl can be piperazin-1-yl or piperazin-4-yl, N-linked oxazolidinyl can be oxazolidin-3-yl, N-linked isoxazolidinyl can be isoxazolidin-2-yl, N-linked thiazolidinyl can be thiazolidin-3-yl, N-linked isothiazolidinyl can be isothiazolidin-2-yl, and N-linked morpholinyl can be 4-morpholinyl.

[0046] When a heterocycloalkyl contains 3 to 8 ring elements and 1 to 3 heteroatoms, representative elements include, but are not limited to, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, oxanyl, tetrahydrothiophenyl, thianyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl. Heterocycloalkyls can also form rings containing 5 to 6 ring elements and 1 to 2 heteroatoms, representative elements include, but are not limited to, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and morpholinyl.

[0047] A "protecting group" refers to a compound that renders a functional group unreactive under a particular set of reaction conditions, but which can then be removed in a subsequent synthetic step to restore the functional group to its original state. Such protecting groups are well known to those skilled in the art and include those disclosed in "Protective Groups in Organic Synthesis," 4th edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons, New York, 2006, the disclosure of which is incorporated herein by reference in its entirety.

[0048] "Salt" refers to an acid or base salt of the compound of the present invention. Examples of pharmaceutically acceptable salts include mineral acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Additional information about 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.

[0049] Pharmaceutically acceptable salts of acidic compounds of the invention are salts formed with bases, i.e., alkali and alkaline earth metal salts such as sodium, lithium, potassium, calcium, magnesium, and the like, and cationic salts such as ammonium salts, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts.

[0050] Likewise, acid addition salts with mineral acids, organic carboxylic acids and organic sulfonic acids, such as hydrochloric acid, methanesulfonic acid, maleic acid, etc., are also possible, provided that a basic group such as pyridyl forms part of the structure.

[0051] 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 the salts are otherwise equivalent to the parent form of the compound for purposes of this invention.

[0052] "Isomers" refer to compounds that have the same chemical formula but are structurally distinguishable. Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.

[0053] "Tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one form to another.

[0054] "Solvate" refers to a compound provided herein or a salt thereof that further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0055] "Hydrate" refers to a compound complexed with at least one water molecule. The compounds of the present invention can be complexed with 1 to 10 water molecules.

[0056] "Substantially free of stereoisomers" or "substantially in the absence of stereoisomers" with respect to a composition refers to a composition that comprises at least 85 or 90% by weight, and in some embodiments, 95%, 98%, 99%, or 100% by weight of the specified stereoisomer of the compound in the composition. In some embodiments, in the methods and compounds provided herein, the compound is substantially free of stereoisomers.

[0057] "Isolated" with respect to a composition refers to a composition that contains at least 85%, 90%, 95%, 98%, 99% to 100% by weight of a particular compound, with the remainder containing other chemical species or stereoisomers.

[0058] As used herein, "composition" is intended to include a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0059] A "pharmaceutically acceptable excipient" refers to a substance that aids in the administration and absorption of an active substance by a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and coloring agents. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0060] "I C 50 " refers to the amount, concentration, or dose of a particular test compound that achieves 50% inhibition of a maximal response in an assay that measures that response.

[0061] "Inhibition," "inhibit," and "inhibitor" refer to a compound or method that prevents a specific action or function.

[0062] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, to a subject.

[0063] "Treat," "treating," and "treatment" refer to any indicator of success in treating or ameliorating an injury, condition, or state, including any objective or subjective parameter, such as reduction; remission; a decrease in symptoms or making the injury, condition, or state more tolerable to the patient; a slowing of the rate of degeneration or decline; a less debilitating end point of degeneration; or an improvement in the patient's physical or mental well-being. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0064] In some embodiments, "treating" or "treatment" a birthmark refers to improving the appearance or severity of a birthmark present in a subject. In some embodiments, "treating" or "treatment" includes improving at least one physical parameter. In some embodiments, "treating" or "treatment" includes physically modulating the appearance of the birthmark (e.g., stabilizing or reducing a discernible symptom or characteristic of the birthmark, such as the size, volume, color, thickness, and / or texture of the birthmark). In some embodiments, "treating" or "treatment" includes reducing or eliminating one or more of the size, color, thickness, and / or texture of the birthmark.

[0065] In some embodiments, "prophylactically treating" and "preventing" the malignant progression of a birthmark refer to reducing a subject's risk of malignant progression of a birthmark. In some embodiments, "prophylactically treating" or "preventing" includes delaying the onset of a malignant tumor resulting from a birthmark. In some embodiments, "prophylactically treating" or "preventing" includes delaying the progression of a birthmark to a malignant tumor or ameliorating one or more symptoms associated with the progression of a birthmark to a malignant tumor.

[0066] "Patient" or "subject" refers to an organism suffering from or prone to a disease or condition that can be treated by administering a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer and other non-mammals. In some embodiments, the patient is a human.

[0067] "Therapeutically effective amount" or "effective amount" refers to the amount of a compound or pharmaceutical composition that is useful for treating or ameliorating a identified disease or symptom (e.g., birthmark as described herein) or for exhibiting a detectable therapeutic or inhibitory effect. The exact amount depends on the purpose of treatment and can be determined by those skilled in the art using known techniques (see, for example, 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).

[0068] A "therapeutically effective amount" or "effective amount," in some embodiments, refers to the amount of a compound or composition that, when administered to a subject for treating the appearance of a birthmark, is sufficient to alter the appearance of the birthmark. An "effective amount" can vary depending, among other things, on the compound, the birthmark and its severity, the size of the birthmark to be treated, and the age, weight, etc. of the subject to be treated.

[0069] "Topical" refers to the application to the skin of a suitable compound (e.g., an active agent) or a composition containing a compound (e.g., an active agent) for treating a birthmark. "Subcutaneous" refers to the application of a suitable compound (e.g., an active agent) or a composition containing a compound (e.g., an active agent) to the epidermis and layers below the dermis. "Intradermal" refers to the application of a suitable compound (e.g., an active agent) or a composition containing a compound (e.g., an active agent) in the dermis or subcutaneous layer. "Intralesional" refers to the injection of a suitable compound (e.g., an active agent) or a composition containing a compound (e.g., an active agent) at the site of a lesion (e.g., a birthmark).

[0070] In some embodiments, "topical" refers to the application of a suitable compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) to the skin with sufficient penetration of the epidermis or dermis to treat a birthmark in the epidermis and / or dermis. In some embodiments of topical application, the compound or composition penetrates the epidermis or dermis without significant systemic exposure or with the intent to treat or prevent disease in another organ system. In some embodiments, "subcutaneous" refers to the injection of a suitable compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) into the layers below the epidermis and dermis. In some embodiments, "intradermal" refers to the injection of a compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) into the dermal layer. In some embodiments, "intralesional" refers to the injection of a compound (e.g., an active agent) or a composition comprising a compound (e.g., an active agent) directly into a lesion, such as a birthmark, for the purpose of treating the birthmark or lesion.

[0071] The present disclosure provides "soft" MEK inhibitors, compositions comprising the "soft" MEK inhibitors, and methods for treating and / or ameliorating bruising (e.g., MEK inhibitor-responsive or MEK-mediated bruising). For example, the methods described herein provide for administration, e.g., local or non-systemic administration, e.g., topical, subcutaneous, transdermal, intradermal, or intralesional administration, of a MEK inhibitor, e.g., a "soft" MEK inhibitor, e.g., a "soft" MEK inhibitor described herein, thereby significantly reducing one or more side effects exhibited with systemic exposure, e.g., one or more known side effects exhibited with MEK inhibitors designed for systemic delivery.

[0072] In some embodiments, "soft MEK inhibitors" are compounds that inhibit MEK1 and / or 2 and are characterized by predictable and controllable metabolism / degradation into non-toxic, biologically less active or inactive (i.e., do not inhibit or inhibit MEK1 and / or 2 to a lesser extent) products after achieving their therapeutic role in the skin.

[0073] "Hard MEK inhibitor" refers to MEK inhibitors known in the art. In some embodiments, hard MEK inhibitors are designed for oral bioavailability. This is necessary for systemic delivery to deliver therapeutically effective levels of MEK inhibitors to peripheral lesions. Hard MEK inhibitors include, for example, PD0325901; PD184161; SMK-17; AS703026 (pimasertib, MSC1936369); RO-4987655; selumetinib (AZD6244, ARRY142886); binimetinib (MEK162, ARRY-162, ARRY-438162); refametinib; These include cobimetinib (GDC-0973, XL518); GDC-0623; AZD8330 (ARRY-424704); CI-1040 (PD184352); PD198306; trametinib; RO-4987655; GDC-0623; TAK-733; WX-554; CH5126766 (also known as RO5126766); G-573; Arry 300; SHR 7390; MSC2015103B (also known as AS-703988); CS 3006; and LY 2228820 (also known as ralimetinib).

[0074] Without wishing to be bound by theory, soft MEK inhibitors, such as the "soft" MEK inhibitors described herein, are believed to be more metabolically unstable than known "hard" MEK inhibitors. Due to their inherent metabolic instability, e.g., due to degradation upon reaching the systemic circulation, "soft" MEK inhibitors, such as those described herein, are transdermally active but have low systemic exposure when administered locally or non-systemically, e.g., topically, subcutaneously, intradermally, or intralesionally (because they are rapidly degraded upon exposure to metabolic enzymes in plasma, blood, or the liver). Unlike "soft" MEK inhibitors, known MEK inhibitors have historically been designed for oral bioavailability, which requires good stability in plasma or blood and good stability against hepatic metabolism to enable systemic delivery at therapeutically effective or efficacious levels, making them more susceptible to one or more undesirable side effects and increased toxicity. As a result, "soft" MEK inhibitors, such as those described herein, have lower systemic toxicity.

[0075] "a," ​​"an," or "a(n)," when used herein with respect to a group of substituents or "substituents," means at least one. For example, if a compound is substituted with "an" alkyl or aryl, the compound may be substituted with at least one alkyl and / or at least one aryl, where each alkyl and / or aryl is optionally different. In another example, if a compound is substituted with "a" substituents, the compound is substituted with at least one substituent, where each substituent is optionally different.

[0076] III. Method In one aspect, provided herein is a method for treating birthmarks, comprising administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound represented by Formulas (I), (II), (III), (IV), and (V): TIFF0007651101000011.tif94128 or an N-oxide, stereoisomer, mixture of stereoisomers and / or pharmaceutically acceptable salt thereof; During the ceremony, X 1 -CR 13b or N;X 2 is C1-C6 alkyl; X 3 is S or O; The subscript n is an integer from 0 to 2; The bond "a" is a single or double bond; R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 is an N-linked heterocycloalkyl substituted with; R 2 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; R 4 , R 5 and R 5b are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl, and each of the C3-C8 cycloalkyl group and heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is replaced by; R 5ais hydrogen or C1-C6 alkyl; Each R 6 are independently halo, hydroxy, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl or di-(C1-C6 alkyl)amino-C1-C6 alkyl; R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino; R 13 , R 13a and R 13b are each independently hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 23 , 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; R 33 , 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; R 43 is cyano, -C(O)NR 48 R 48a or -C(O)R 46 and; R 43a is hydrogen, halo, C1-C6 alkyl; or R 43 and R 43a together form —CH2CH2C(O)— or —CH2CH2CH2C(O)—, each of which is unsubstituted or contains one or two R49 is replaced by; R 46 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or heterocycloalkyl; R 48 and R 48a are independently hydrogen or C1-C6 alkyl; and Each R 49 are independently C1-C6 alkyl, C3-C8 cycloalkyl, or C3-C8 cycloalkyl-C1-C6 alkyl; R 51 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, R 7 -C(O)-C1-C6 alkyl or -OR 54 wherein each of the C3-C8 cycloalkyl group and the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is replaced by; Each R 53 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 R 54 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, or R 7-C(O)-C1-C6 alkyl, and each of the C3-C8 cycloalkyl group and heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is replaced by .

[0077] In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound disclosed herein, including a single enantiomer, a mixture of enantiomeric pairs, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers, or a tautomeric form of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, prodrug, phosphate, or active metabolite of a compound disclosed herein, e.g., a compound having any one of Formulas (I), (II), (III), (IV), and (V), and a compound of Tables 1-5.

[0078] In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound having formula (I) and a compound in Table 1, including a single enantiomer, a mixture of enantiomeric pairs, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers, or a tautomeric form of a compound having formula (I) and a compound in Table 1, or a pharmaceutically acceptable salt or solvate of a compound having formula (I) and a compound in Table 1.

[0079] In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound having formula (II) and a compound in Table 2, including a single enantiomer, a mixture of enantiomeric pairs, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers, or a tautomeric form of a compound having formula (II) and a compound in Table 2, or a pharmaceutically acceptable salt or solvate of a compound having formula (II) and a compound in Table 2.

[0080] In some embodiments, the method includes administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound having formula (III) and a compound in Table 3, including a single enantiomer, a mixture of enantiomeric pairs, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers, or a tautomeric form of a compound having formula (III) and a compound in Table 3, or a pharmaceutically acceptable salt or solvate of a compound having formula (III) and a compound in Table 3.

[0081] In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound having formula (IV) and a compound in Table 4, including a single enantiomer, a mixture of enantiomeric pairs, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers, or a tautomeric form of a compound having formula (IV) and a compound in Table 4, or a pharmaceutically acceptable salt or solvate of a compound having formula (IV) and a compound in Table 4.

[0082] In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount or an effective amount of a compound having formula (V) and a compound in Table 5, including a single enantiomer, a mixture of enantiomeric pairs, an individual diastereomer, a mixture of diastereomers, an individual stereoisomer, a mixture of stereoisomers, or a tautomeric form of a compound having formula (V) and a compound in Table 5, or a pharmaceutically acceptable salt or solvate of a compound having formula (V) and a compound in Table 5.

[0083] In some embodiments, the birthmark is a port wine stain (capillary malformation). In some embodiments, provided herein are methods of treating a port wine stain (capillary malformation) birthmark to reduce cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein are methods of prophylactically treating a port wine stain (capillary malformation) birthmark to delay the onset of the birthmark or slow the progression of the birthmark, thereby preventing the progression of the birthmark.

[0084] In some embodiments, the birthmark is an epidermal nevus. In some embodiments, provided herein are methods for treating epidermal nevus to reduce cosmetic appearance or progression of the birthmark. In some embodiments, provided herein are methods for prophylactically treating epidermal nevus to prevent progression of the birthmark, delay the onset of the birthmark, or slow the progression of the birthmark.

[0085] In some embodiments, the birthmark is a sebaceous nevus. In some embodiments, provided herein are methods of treating a birthmark that is a sebaceous nevus to reduce cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein are methods of prophylactically treating a birthmark that is a sebaceous nevus to prevent progression of the birthmark, delay the onset of the birthmark, or slow the progression of the birthmark.

[0086] In some embodiments, the birthmark is a nevus cytoid nevi. In some embodiments, provided herein are methods of treating nevus cytoid nevi to reduce cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein are methods of prophylactically treating nevus cytoid nevi to prevent progression of the birthmark, delay the onset of the birthmark, or slow the progression of the birthmark.

[0087] In some embodiments, the birthmark is a dysplastic nevus. In some embodiments, provided herein are methods of treating a dysplastic nevus to reduce cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein are methods of prophylactically treating a dysplastic nevus to prevent progression of the birthmark, delay the onset of the birthmark, or slow the progression of the birthmark.

[0088] In some aspects, the birthmark is a flat nevus. In some aspects, provided herein are methods of treating a birthmark that is a flat nevus to reduce cosmetic disfigurement or progression of the birthmark. In some aspects, provided herein are methods of prophylactically treating a birthmark that is a flat nevus to prevent progression of the birthmark, delay the onset of the birthmark, or slow the progression of the birthmark.

[0089] In some aspects, the birthmark is an intracutaneous arteriovenous malformation. In some aspects, provided herein are methods of treating the arteriovenous malformation to reduce cosmetic disfigurement or progression of the birthmark. In some aspects, provided herein are methods of prophylactically treating the arteriovenous malformation to prevent progression of the birthmark, delay the onset of the birthmark, or slow the progression of the birthmark.

[0090] In some aspects, the birthmark is a lymphatic malformation. In some aspects, provided herein are methods of treating lymphatic malformations to reduce the risk of cosmetic disfigurement or progression of the birthmark. In some aspects, provided herein are methods of prophylactically treating lymphatic malformations to prevent progression of the birthmark, delay the onset of the birthmark, or slow the progression of the birthmark.

[0091] In some embodiments, the birthmark is a congenital melanocytic nevus. In some embodiments, provided herein are methods of treating a congenital melanocytic nevus to reduce the risk of cosmetic disfigurement or progression of the birthmark. In some embodiments, provided herein are methods of prophylactically treating a congenital melanocytic nevus to prevent progression of the birthmark, delay the onset of the birthmark, or slow the progression of the birthmark.

[0092] In some aspects, the compounds described herein are used to reduce bruising in a subject in need thereof.

[0093] In some aspects, the compounds described herein are used to improve bruising in a subject in need thereof.

[0094] In some embodiments, the compounds described herein are used to prevent bruising (e.g., MEK inhibitor-responsive or MEK-mediated bruising) and / or prevent worsening of bruising (e.g., where bruising may progress to a proliferative disorder) in a subject in need thereof.

[0095] In some embodiments, the subject in need thereof is a human.

[0096] The birthmark is not a cafe au lait spot.

[0097] In some embodiments, administering comprises contacting the soft MEK inhibitor with the subject's skin, eg, an affected area of ​​the skin, eg, an area of ​​the skin having a birthmark.

[0098] In some embodiments, the appearance of the birthmark is reduced by at least about 15%, e.g., the size, volume, or total surface area, compared to a reference standard (e.g., the size of the birthmark before treatment begins), thereby treating the subject. In some embodiments, the size, volume, or total surface area on the skin is reduced by at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% compared to the reference standard. In some embodiments, the reference standard is the size of the birthmark before treatment begins.

[0099] Assay Method When a subject is in need of treatment for a bruise, the compound can be assayed for effectiveness in treating the bruise (e.g., a MEK inhibitor-responsive or MEK-mediated bruise) according to any assay known to one of skill in the art. Exemplary assay methods are provided elsewhere herein.

[0100] IV. Compound The present invention provides a compound for use in a method of treating a birthmark as defined and described herein, wherein the compound is represented by formula (I), (II), (III), (IV) and (V): TIFF0007651101000012.tif94128 or an N-oxide, stereoisomer, mixture of stereoisomers and / or pharmaceutically acceptable salt thereof; During the ceremony, X 1 -CR 13bor N;X 2 is C1-C6 alkyl; X 3 is S or O; The subscript n is an integer from 0 to 2; The bond "a" is a single or double bond; R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 is an N-linked heterocycloalkyl substituted with; R 2 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; R 4 , R 5 and R 5b are each independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl, and each of the C3-C8 cycloalkyl group and heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is replaced by; R 5a is hydrogen or C1-C6 alkyl; Each R 6are independently halo, hydroxy, oxo, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl or di-(C1-C6 alkyl)amino-C1-C6 alkyl; R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino or N-C1-C6 alkylhydroxyamino; R 8 is hydroxy, C1-C3 alkyl, or C1-C3 alkoxy; R 13 , R 13a and R 13b are each independently hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 23 , 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; R 33 , 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; R 43 is cyano, -C(O)NR 48 R 48a or -C(O)R 46 and; R 43a is hydrogen, halo, C1-C6 alkyl; or R 43 and R 43atogether form —CH2CH2C(O)— or —CH2CH2CH2C(O)—, each of which is unsubstituted or contains one or two R 49 is replaced by; R 46 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or heterocycloalkyl; R 48 and R 48a are independently hydrogen or C1-C6 alkyl; and Each R 49 are independently C1-C6 alkyl, C3-C8 cycloalkyl, or C3-C8 cycloalkyl-C1-C6 alkyl; R 51 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, R 7 -C(O)-C1-C6 alkyl or -OR 54 wherein each of the C3-C8 cycloalkyl group and the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is replaced by; Each R 53 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 R 54is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, di-(C1-C6 alkyl)amino-C1-C6 alkyl, heterocycloalkyl, heterocycloalkyl-C1-C6 alkyl, or R 7 -C(O)-C1-C6 alkyl, and each of the C3-C8 cycloalkyl group and heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 has been replaced by A compound is provided.

[0101] In some embodiments, the cycloalkyl groups provided in formulas (I), (II), (III), (IV), and (V) are saturated monocyclic C3-C8 cycloalkyl. In some embodiments, the C3-C8 cycloalkyl group, alone or as part of a C3-C8 cycloalkyl-C1-C6 alkyl, is cyclopropyl or cyclobutyl. In some embodiments, the C3-C8 cycloalkyl group, alone or as part of a C3-C8 cycloalkyl-C1-C6 alkyl, is unsubstituted. In some embodiments, the C3-C8 cycloalkyl group, alone or as part of a C3-C8 cycloalkyl-C1-C6 alkyl, is substituted with 1 to 6 R 6 is substituted with R 6 is as defined and described herein.

[0102] R as one or more substituents of a C3-C8 cycloalkyl group 6 In some embodiments, each R 6are independently halo, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, or di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, each R 6 is independently halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, or di-(C1-C6 alkyl)amino. 6 is independently halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or amino. In some embodiments, each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, each R 6 is independently hydroxy or amino.

[0103] In some embodiments, the heterocycloalkyl groups provided in Formulas (I), (II), (III), (IV), and (V) are 3-8 membered heterocycloalkyls having 1-3 ring heteroatoms selected from N, O, and S. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl having 1-2 heteroatoms of N or O. In some embodiments, the heterocycloalkyl group, alone or as part of a heterocycloalkyl-C1-C6 alkyl, is unsubstituted. In some embodiments, the heterocycloalkyl group, alone or as part of a heterocycloalkyl-C1-C6 alkyl, is selected from 1-6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, an N-linked heterocycloalkyl group is a substituted heterocycloalkyl group having one or two R 6 and R 6 is as defined and described herein.

[0104] R as one or more substituents of a heterocycloalkyl group or an N-linked heterocycloalkyl 6 In some embodiments, each R 6 are independently halo, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6-hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, amino-C1-C6 alkyl, C1-C6 alkylamino-C1-C6 alkyl, or di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, each R 6 is independently halo, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, amino, C1-C6 alkylamino, or di-(C1-C6 alkyl)amino. 6 is independently halo, hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, or amino. In some embodiments, each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, each R 6 is independently hydroxy, oxo, or amino. In some embodiments, each R 6 is independently hydroxy or amino.

[0105] In some embodiments, the compound useful in the present methods is a compound of formula (I).

[0106] With respect to formula (I), in some embodiments, X 1 Ha-CR 13b and the compound has formula (Ia): Represented by TIFF0007651101000013.tif29128, In the formula, R 1 , R 2 , R 2a , R 13 , R 13a and R 13b is as defined herein in any aspect or embodiment described herein.

[0107] In some embodiments of Formula (Ia), R 13 , R 13a and R 13b are each independently hydrogen, halo, or C1-C6 alkyl.

[0108] In some embodiments of Formula (Ia), R 13 is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is halo. In some embodiments, R 13 is fluoro, chloro, bromo, or iodo. In some embodiments, R 13 is fluoro. In some embodiments, R 13 is C1-C6 alkyl. In some embodiments, R 13 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. 13 is methyl.

[0109] In some embodiments of Formula (Ia), R 13a 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 13a is fluoro, chloro, bromo, or iodo. In some embodiments, R 13a is fluoro. In some embodiments, R 13a is C1-C6 alkyl. In some embodiments, R 13a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. 13a is methyl.

[0110] In some embodiments of Formula (Ia), R13b is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R 13b is hydrogen. In some embodiments, R 13b is halo. In some embodiments, R 13b is fluoro, chloro, bromo, or iodo. In some embodiments, R 13b is fluoro. In some embodiments, R 13b is C1-C6 alkyl. In some embodiments, R 13b is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. 13b is methyl.

[0111] In some embodiments of Formula (Ia), R 13 , R 13a and R 13b are each hydrogen. In some embodiments of Formula (Ia), R 13 and R 13a are hydrogen, and R 13b is halo. In some embodiments of Formula (Ia), R 13 and R 13a are hydrogen, and R 13b is fluoro.

[0112] Returning to formula (I), in some embodiments, X 1 is N and the compound has formula (Ib): Represented by TIFF0007651101000014.tif29128, In the formula, R 1 , R 2 , R 2a , R 13 and R 13a is as defined herein in any aspect or embodiment described herein.

[0113] In some embodiments of Formula (Ib), R 13 and R 13aare each independently hydrogen, halo, or C1-C6 alkyl.

[0114] In some embodiments of Formula (Ib), R 13 is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is halo. In some embodiments, R 13 is fluoro, chloro, bromo, or iodo. In some embodiments, R 13 is fluoro. In some embodiments, R 13 is C1-C6 alkyl. In some embodiments, R 13 is methyl.

[0115] In some embodiments of Formula (Ib), R 13a 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 13a is fluoro, chloro, bromo, or iodo. In some embodiments, R 13a is fluoro. In some embodiments, R 13a is C1-C6 alkyl. In some embodiments, R 13a is methyl.

[0116] In some embodiments of Formula (Ib), R 13 and R 13a are each independently hydrogen or halo. 13 and R 13a are each hydrogen. In some embodiments, R 13 and R 13a One of R is hydrogen and the other is halo. 13 and R 13a One of the groups is hydrogen and the other is fluoro.

[0117] With respect to any one of formulas (I), (Ia) and (Ib), in some embodiments, R 1 -OR 4 , -NR 5 R 5a OR-N(OR 5b )R 5a is.

[0118] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 1 HA-OR 4 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is a C3-C8 cycloalkyl-C1-C6 alkyl, and the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6is as defined and described herein. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is C1-C6 hydroxyalkyl. In some embodiments, R 4 is C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 4 is amino-C1-C6 alkyl. In some embodiments, R 4 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 4 is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 4 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 4 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0119] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 1 is -OH, TIFF0007651101000015.tif50128.

[0120] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 1 Ha-NR 5 R 5a In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is C1-C6 hydroxyalkyl. In some embodiments, R 5 is C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 5 is amino-C1-C6 alkyl. In some embodiments, R 5 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5 is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6is as defined and described herein. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 5 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 5 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0121] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 1 Ha-NR 5 R 5a and R 5 is hydrogen, TIFF0007651101000016.tif40128.

[0122] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 1 -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 unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5b is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5bis cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 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-C1-C6 alkyl. In some embodiments, R 5b is amino-C1-C6 alkyl. In some embodiments, R 5b is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5b is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5bis oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 5b is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 5b is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0123] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 1 is -N(OR 5b )R 5a and -OR 5b is -OH, TIFF0007651101000017.tif77128.

[0124] In some embodiments of any one of Formulas (I), (Ia) and (Ib), 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. 5a is methyl.

[0125] With respect to any one of formulas (I), (Ia) and (Ib), in some embodiments, R 1 is unsubstituted or contains one or two R6 is an N-linked heterocycloalkyl substituted with R 6 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, R 1 is unsubstituted or contains one or two R 6 is an N-linked azetidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked pyrrolidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked piperidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked isoxazolidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked morpholinyl substituted with R 6 is as defined and described herein.

[0126] R as one or two substituents of an N-linked heterocycloalkyl in any one of formulas (I), (Ia) and (Ib) 6 In some embodiments, each R 6 is independently hydroxyl, oxo, or amino. In some embodiments, each R 6 is hydroxy. In some embodiments, each R 6 is oxo. In some embodiments, each R 6 is amino. In some embodiments, R 6 One of the groups is hydroxy and the other R 6 is an amino.

[0127] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 1 is an N-linked heterocycloalkyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked azetidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked pyrrolidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked piperidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked isoxazolidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked morpholinyl that is unsubstituted or substituted with hydroxy, oxo, or amino.

[0128] With respect to any one of formulas (I), (Ia) and (Ib), in some embodiments, R 2 is halo, C1-C6 alkyl, —S—C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R 2 is halo or C1-C6 alkyl. In some embodiments, R 2is halo, -CH3, -SCH3, C2-C3 alkenyl, or C2-C3 alkynyl.

[0129] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 2 is halo. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is iodo. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo.

[0130] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0131] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 2 is -S-C1-C6 alkyl. In some embodiments, R 2 is -S-C1-C3 alkyl. In some embodiments, R 2 is -SCH3.

[0132] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 2 is C3-C8 cycloalkyl. In some embodiments, R 2 is cyclopropyl.

[0133] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 2 is C2-C6 alkenyl. In some embodiments, R 2 is C2-C4 alkenyl. In some embodiments, R 2 is vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, or butadienyl.2 is vinyl.

[0134] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 2 is C2-C6 alkynyl. In some embodiments, R 2 is C2-C3 alkynyl. In some embodiments, R 2 is acetylenyl or propynyl. In some embodiments, R 2 is acetylenyl.

[0135] With respect to any one of formulas (I), (Ia) and (Ib), in some embodiments, R 2a is halo or C1-C3 alkyl. In some embodiments, R 2a is halo or CH. In some embodiments, R 2a is fluoro or CH. In some embodiments, R 2a is iodo or CH. In some embodiments, R 2a is chloro or CH. In some embodiments, R 2a is bromo or CH3.

[0136] In some embodiments of any one of Formulas (I), (Ia) and (Ib), 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.

[0137] In some embodiments of any one of Formulas (I), (Ia) and (Ib), R 2a is C1-C6 alkyl. In some embodiments, R 2a is C1-C3 alkyl. In some embodiments, R 2a is CH3.

[0138] With respect to any one of formulas (I), (Ia) and (Ib), in some embodiments, R 2 and R 2a and R are each halo. 2 is the halo and R 2a is C1-C6 alkyl. In some embodiments, R 2 is C1-C6 alkyl, and R 2a is halo. In some embodiments, R 2 is -S-C1-C6 alkyl, and R 2a is halo. In some embodiments, R 2 is -SCH3 and R 2a is halo. In some embodiments, R 2 is a C3-C8 cycloalkyl, and R 2a is halo. In some embodiments, R 2 is cyclopropyl and R 2a is halo. In some embodiments, R 2 is C2-C6 alkenyl, and R 2a is halo. In some embodiments, R 2 is C2-C6 alkynyl, and R 2a is halo. In some embodiments, R 2 is acetylenyl and R 2a is halo. In some embodiments, R 2 and R 2a are each independently fluoro, chloro, bromo, or iodo. 2 is iodine and R 2a is fluoro. In some embodiments, R 2 is the halo and R 2a is —CH3. In some embodiments, R 2 is bromo and R 2a is —CH3. In some embodiments, R 2 is iodine and R 2a is —CH3. In some embodiments, R 2 is -SCH3 and R 2a is fluoro. In some embodiments, R 2 is acetylenyl and R2a is fluoro.

[0139] In some embodiments, the compound of formula (I) has the following formula: It is represented by one of TIFF0007651101000018.tif37147TIFF0007651101000019.tif173147TIFF0007651101000020.tif192147TIFF0007651101000021.tif50146, In the formula, X 1 , R 2 , R 2a , R 13 and R 13a is as defined herein in any aspect or embodiment described herein.

[0140] In some embodiments of the above structure having formula (I), X 1 Ha-CR 13b and R 13b is as defined herein in any aspect or embodiment described herein. In some embodiments of the above structure having formula (I), X 1 is N.

[0141] In some embodiments of the above structure having formula (I), R 2 is iodine and R 2a is fluoro. In some embodiments of the above structure, R 2 is iodine and R 2a is methyl. In some embodiments of the above structure, R 2 is acetylenyl and R 2a is fluoro. In some embodiments of the above structure, R 2 is acetylenyl and R 2a is methyl. In some embodiments of the above structure, R 2 is -SCH3 and R 2a is fluoro. In some embodiments of the above structure, R 2 is -SCH3 and R 2a is methyl.

[0142] In some embodiments of the above structure having formula (I), X 1 Ha-CR 13b and R 13 , R 13a and R 13b are each hydrogen. In some embodiments of the above structure having formula (I), X 1 Ha-CR 13b and R 13 and R 13a are hydrogen, and R 13b In some embodiments of the above structure having formula (I), X 1 Ha-CR 13b and R 13 and R 13a are hydrogen, and R 13b is fluoro.

[0143] In some embodiments of the above structure having formula (I), X 1 is N and R 13 and R 13a are hydrogen atoms.

[0144] In some embodiments, the compound useful in the present methods is a compound of formula (II).

[0145] With respect to formula (II), in some embodiments, X 2 is C1-C3 alkyl. In some embodiments, X 2 is methyl, ethyl, propyl, or isopropyl. 2 is methyl and the compound has the formula (IIa): Represented by TIFF0007651101000022.tif27128, In the formula, R 1 , R 2 , R 2a , R 23 , R 23a and R 23b is as defined herein in any aspect or embodiment described herein.

[0146] In some embodiments of Formula (II) or (IIa), R 23 , R 23a and R 23b are each independently hydrogen, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0147] In some embodiments of Formula (II) or (IIa), R 23 is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R 23 is hydrogen. In some embodiments, R 23 is halo. In some embodiments, R 23 is fluoro, chloro, bromo, or iodo. In some embodiments, R 23 is fluoro. In some embodiments, R 23 is C1-C6 alkyl. In some embodiments, R 23 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. 23 is methyl.

[0148] In some embodiments of Formula (II) or (IIa), R 23a is hydrogen, halo, C1-C6 alkyl, or C1-C6 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. 23a is methyl. In some embodiments, R 23ais 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. 23a is methoxy.

[0149] In some embodiments of Formula (II) or (IIa), 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. 23b is methyl.

[0150] In some embodiments of Formula (II) or (IIa), R 23 , R 23a and R 23b are each hydrogen. In some embodiments of Formula (II) or (IIa), R 23 and R 23b are hydrogen, and R 23a is halo, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments of Formula (II) or (IIa), R 23 and R 23b are hydrogen, and R 23a is fluoro, methyl or methoxy.

[0151] With respect to formula (II) or (IIa), in some embodiments, R 1 -OR 4 , -NR5 R 5a OR-N(OR 5b )R 5a is.

[0152] In some embodiments of Formula (II) or (IIa), R 1 HA-OR 4 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is a C3-C8 cycloalkyl-C1-C6 alkyl, and the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is C1-C6 hydroxyalkyl. In some embodiments, R 4 is C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 4 is amino-C1-C6 alkyl. In some embodiments, R 4 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 4 is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 4 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 4 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0153] In some embodiments of Formula (II) or (IIa), R 1 is -OH, TIFF0007651101000023.tif21128.

[0154] In some embodiments of Formula (II) or (IIa), R 1 Ha-NR 5 R 5a In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is C1-C6 hydroxyalkyl. In some embodiments, R 5 is C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 5 is amino-C1-C6 alkyl. In some embodiments, R 5 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5 is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6is as defined and described herein. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 5 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 5 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0155] In some embodiments of Formula (II) or (IIa), R 5 is hydrogen, TIFF0007651101000024.tif16128.

[0156] In some embodiments of Formula (II) or (IIa), R 1 -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 unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5b is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5bis cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 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-C1-C6 alkyl. In some embodiments, R 5b is amino-C1-C6 alkyl. In some embodiments, R 5b is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5b is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5bis oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 5b is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 5b is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0157] In some embodiments of Formula (II) or (IIa), R 1 is -N(OR 5b )R 5a and -OR 5b is -OH, TIFF0007651101000025.tif21128.

[0158] In some embodiments of Formula (II) or (IIa), 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 can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. 5a is methyl.

[0159] With respect to formula (II) or (IIa), in some embodiments, R 1 is unsubstituted or contains one or two R 6is an N-linked heterocycloalkyl substituted with R 6 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, R 1 is unsubstituted or contains one or two R 6 is an N-linked azetidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked pyrrolidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked piperidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked isoxazolidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked morpholinyl substituted with R 6 is as defined and described herein.

[0160] R as one or two substituents of N-linked heterocycloalkyl in formula (II) or (IIa) 6 In some embodiments, each R 6 is independently hydroxyl, oxo, or amino. In some embodiments, each R 6 is hydroxy. In some embodiments, each R 6 is oxo. In some embodiments, each R 6 is amino. In some embodiments, R 6 One of the groups is hydroxy and the other R 6 is an amino.

[0161] In some embodiments of Formula (II) or (IIa), R 1 is an N-linked heterocycloalkyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked azetidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked pyrrolidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked piperidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked isoxazolidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked morpholinyl that is unsubstituted or substituted with hydroxy, oxo, or amino.

[0162] With respect to formula (II) or (IIa), in some embodiments, R 2 is halo, C1-C6 alkyl, —S—C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R 2 is halo or C1-C6 alkyl. In some embodiments, R 2is halo, -CH3, -SCH3, C2-C3 alkenyl, or C2-C3 alkynyl.

[0163] In some embodiments of Formula (II) or (IIa), R 2 is halo. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is iodo. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo.

[0164] In some embodiments of Formula (II) or (IIa), R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0165] In some embodiments of Formula (II) or (IIa), R 2 is -S-C1-C6 alkyl. In some embodiments, R 2 is -S-C1-C3 alkyl. In some embodiments, R 2 is -SCH3.

[0166] In some embodiments of Formula (II) or (IIa), R 2 is C3-C8 cycloalkyl. In some embodiments, R 2 is cyclopropyl.

[0167] In some embodiments of Formula (II) or (IIa), R 2 is C2-C6 alkenyl. In some embodiments, R 2 is C2-C4 alkenyl. In some embodiments, R 2 is vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, or butadienyl. 2 is vinyl.

[0168] In some embodiments of Formula (II) or (IIa), R 2 is C2-C6 alkynyl. In some embodiments, R 2 is C2-C3 alkynyl. In some embodiments, R 2 is acetylenyl or propynyl. In some embodiments, R 2 is acetylenyl.

[0169] With respect to formula (II) or (IIa), in some embodiments, R 2a is halo or C1-C3 alkyl. In some embodiments, R 2a is halo or CH. In some embodiments, R 2a is fluoro or CH. In some embodiments, R 2a is iodo or CH. In some embodiments, R 2a is chloro or CH. In some embodiments, R 2a is bromo or CH3.

[0170] In some embodiments of Formula (II) or (IIa), 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.

[0171] In some embodiments of Formula (II) or (IIa), R 2a is C1-C6 alkyl. In some embodiments, R 2a is C1-C3 alkyl. In some embodiments, R 2a is CH3.

[0172] With reference to Formula (II) or (IIa), in some embodiments, R 2 and R 2a and R are each halo. 2 is the halo and R 2ais C1-C6 alkyl. In some embodiments, R 2 is C1-C6 alkyl, and R 2a is halo. In some embodiments, R 2 is -S-C1-C6 alkyl, and R 2a is halo. In some embodiments, R 2 is -SCH3 and R 2a is halo. In some embodiments, R 2 is a C3-C8 cycloalkyl, and R 2a is halo. In some embodiments, R 2 is cyclopropyl and R 2a is halo. In some embodiments, R 2 is C2-C6 alkenyl, and R 2a is halo. In some embodiments, R 2 is C2-C6 alkynyl, and R 2a is halo. In some embodiments, R 2 is acetylenyl and R 2a is halo. In some embodiments, R 2 and R 2a are each independently fluoro, chloro, bromo, or iodo. 2 is iodine and R 2a is fluoro. In some embodiments, R 2 is the halo and R 2a is —CH3. In some embodiments, R 2 is bromo and R 2a is —CH3. In some embodiments, R 2 is iodine and R 2a is —CH3. In some embodiments, R 2 is -SCH3 and R 2a is fluoro. In some embodiments, R 2 is acetylenyl and R 2a is fluoro.

[0173] In some embodiments, the compound of Formula (II) or Formula (IIa) has the following formula: It is represented by one of the following: TIFF0007651101000026.tif77155, TIFF0007651101000027.tif164155, or TIFF0007651101000028.tif46155. In the formula, R 2 , R 2a , R 23 , R 23a and R 23b is as defined herein in any aspect or embodiment described herein.

[0174] In some embodiments of the above structures having formula (II) or (IIa), R 2 is iodine and R 2a is fluoro. In some embodiments of the above structure, R 2 is iodine and R 2a is methyl. In some embodiments of the above structure, R 2 is acetylenyl and R 2a is fluoro. In some embodiments of the above structure, R 2 is acetylenyl and R 2a is methyl. In some embodiments of the above structure, R 2 is -SCH3 and R 2a is fluoro. In some embodiments of the above structure, R 2 is -SCH3 and R 2a is methyl.

[0175] In some embodiments of the above structures having formula (II) or (IIa), R 23 , R 23a and R 23b are each hydrogen. In some embodiments of the above structure, R 23 and R 23b are hydrogen, and R 23a is fluoro. In some embodiments of the above structure, R 23 and R 23b are hydrogen, and R 23a is methoxy.

[0176] In some embodiments, the compound useful in the present methods is a compound of formula (III).

[0177] With respect to formula (III), in some embodiments, X 3 is S and the compound has formula (IIIa): Represented by TIFF0007651101000029.tif27128, In the formula, R 2 , R 2a , R 33 , R 33a and R 33b is as defined herein in any aspect or embodiment described herein.

[0178] In some embodiments of Formula (III), X 3 is O and the compound has formula (IIIb): Represented by TIFF0007651101000030.tif27128, In the formula, R 2 , R 2a , R 33 , R 33a and R 33b is as defined herein in any aspect or embodiment described herein.

[0179] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33 , R 33a and R 33b are each independently hydrogen, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0180] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33 is hydrogen, halo, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, R 33 is hydrogen. In some embodiments, R 33 is halo. In some embodiments, R 33is fluoro, chloro, bromo, or iodo. In some embodiments, R 33 is fluoro. In some embodiments, R 33 is C1-C6 alkyl. In some embodiments, R 33 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. 33 is methyl. In some embodiments, R 33 is C1-C6 alkoxy. In some embodiments, R 33 is methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy. 33 is methoxy.

[0181] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33a is hydrogen, halo, C1-C6 alkyl, or C1-C6 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. 33a is methyl. In some embodiments, R 33a is C1-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.33a is methoxy.

[0182] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33b is hydrogen, halo, C1-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 C1-C6 alkyl. In some embodiments, R 33b is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. 33b is methyl. In some embodiments, R 33b is C1-C6 alkoxy. In some embodiments, R 33b is methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, or hexoxy. 33b is methoxy.

[0183] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33 , R 33a and R 33b and R are each hydrogen. In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33a and R 33b are hydrogen, and R 33 is halo, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33 and R 33b are hydrogen, and R 33ais fluoro, methyl, or methoxy. In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33 and R 33a are hydrogen, and R 33b is halo, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33a and R 33b are hydrogen, and R 33 is fluoro, methyl, or methoxy. In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33 and R 33b are hydrogen, and R 33a is fluoro, methyl, or methoxy. In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 33 and R 33a are hydrogen, and R 33b is fluoro, methyl or methoxy.

[0184] With respect to any one of formulas (III), (IIIa), and (IIIb), in some embodiments, R 1 -OR 4 , -NR 5 R 5a OR-N(OR 5b )R 5a is.

[0185] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 1 HA-OR 4 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 4is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is a C3-C8 cycloalkyl-C1-C6 alkyl, and the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is C1-C6 hydroxyalkyl. In some embodiments, R 4 is C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 4 is amino-C1-C6 alkyl. In some embodiments, R 4 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 4is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 4 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 4 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0186] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 1 is -OH, TIFF0007651101000031.tif21128.

[0187] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 1 Ha-NR 5 R 5a In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R6 is as defined and described herein. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is C1-C6 hydroxyalkyl. In some embodiments, R 5 is C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 5 is amino-C1-C6 alkyl. In some embodiments, R 5 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5 is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 5 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 5 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0188] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 5 is hydrogen, TIFF0007651101000032.tif16128.

[0189] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 1 -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 unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5b is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 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-C1-C6 alkyl. In some embodiments, R 5b is amino-C1-C6 alkyl. In some embodiments, R 5b is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5b is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 5b is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 5b is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0190] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 1 is -N(OR5b )R 5a and -OR 5b is -OH, TIFF0007651101000033.tif21128.

[0191] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), 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. 5a is methyl.

[0192] With respect to any one of formulas (III), (IIIa), and (IIIb), in some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked heterocycloalkyl substituted with R 6 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, R 1 is unsubstituted or contains one or two R 6 is an N-linked azetidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1is unsubstituted or contains one or two R 6 is an N-linked pyrrolidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked piperidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked isoxazolidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked morpholinyl substituted with R 6 is as defined and described herein.

[0193] R as one or two substituents of an N-linked heterocycloalkyl in any one of formulas (III), (IIIa) and (IIIb) 6 In some embodiments, each R 6 is independently hydroxy, oxo, or amino. In some embodiments, each R 6 is hydroxy. In some embodiments, each R 6 is oxo. In some embodiments, each R 6 is amino. In some embodiments, R 6 One of the groups is hydroxy and the other R 6 is an amino.

[0194] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 1 is an N-linked heterocycloalkyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked azetidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino.1 is an N-linked pyrrolidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked piperidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked isoxazolidinyl that is unsubstituted or substituted with hydroxy, oxo, or amino. 1 is an N-linked morpholinyl that is unsubstituted or substituted with hydroxy, oxo, or amino.

[0195] With respect to any one of formulas (III), (IIIa), and (IIIb), in some embodiments, R 2 is halo, C1-C6 alkyl, —S—C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R 2 is halo or C1-C6 alkyl. In some embodiments, R 2 is halo, -CH3, -SCH3, C2-C3 alkenyl, or C2-C3 alkynyl.

[0196] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 2 is halo. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is iodo. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo.

[0197] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0198] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 2 is -S-C1-C6 alkyl. In some embodiments, R 2 is -S-C1-C3 alkyl. In some embodiments, R 2 is -SCH3.

[0199] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 2 is C3-C8 cycloalkyl. In some embodiments, R 2 is cyclopropyl.

[0200] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 2 is C2-C6 alkenyl. In some embodiments, R 2 is C2-C4 alkenyl. In some embodiments, R 2 is vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, or butadienyl. 2 is vinyl.

[0201] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 2 is C2-C6 alkynyl. In some embodiments, R 2 is C2-C3 alkynyl. In some embodiments, R 2 is acetylenyl or propynyl. In some embodiments, R 2 is acetylenyl.

[0202] With respect to any one of formulas (III), (IIIa), and (IIIb), in some embodiments, R 2a is halo or C1-C3 alkyl. In some embodiments, R 2a is halo or CH. In some embodiments, R 2a is fluoro or CH. In some embodiments, R 2ais iodo or CH. In some embodiments, R 2a is chloro or CH. In some embodiments, R 2a is bromo or CH3.

[0203] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), 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.

[0204] In some embodiments of any one of Formulas (III), (IIIa), and (IIIb), R 2a is C1-C6 alkyl. In some embodiments, R 2a is C1-C3 alkyl. In some embodiments, R 2a is CH3.

[0205] With respect to any one of formulas (III), (IIIa), and (IIIb), in some embodiments, R 2 and R 2a and R are each halo. 2 is the halo and R 2a is C1-C6 alkyl. In some embodiments, R 2 is C1-C6 alkyl, and R 2a is halo. In some embodiments, R 2 is -S-C1-C6 alkyl, and R 2a is halo. In some embodiments, R 2 is -SCH3 and R 2a is halo. In some embodiments, R 2 is a C3-C8 cycloalkyl, and R 2a is halo. In some embodiments, R 2 is cyclopropyl and R 2a is halo. In some embodiments, R 2is C2-C6 alkenyl, and R 2a is halo. In some embodiments, R 2 is C2-C6 alkynyl, and R 2a is halo. In some embodiments, R 2 is acetylenyl and R 2a is halo. In some embodiments, R 2 and R 2a are each independently fluoro, chloro, bromo, or iodo. 2 is iodine and R 2a is fluoro. In some embodiments, R 2 is the halo and R 2a is —CH3. In some embodiments, R 2 is bromo and R 2a is —CH3. In some embodiments, R 2 is iodine and R 2a is —CH3. In some embodiments, R 2 is -SCH3 and R 2a is fluoro. In some embodiments, R 2 is acetylenyl and R 2a is fluoro.

[0206] In some embodiments, the compound of formula (III) has the following formula: TIFF0007651101000034.tif159155TIFF0007651101000035.tif126155, wherein X 3 , R 2 , R 2a , R 33 , R 33a and R 33b is as defined herein in any aspect or embodiment described herein.

[0207] In some embodiments of the above structures having any one of formulas (III), (IIIa) and (IIIb), R 2 is iodine and R 2a is fluoro. In some embodiments of the above structure, R2 is iodine and R 2a is methyl. In some embodiments of the above structure, R 2 is acetylenyl and R 2a is fluoro. In some embodiments of the above structure, R 2 is acetylenyl and R 2a is methyl. In some embodiments of the above structure, R 2 is -SCH3 and R 2a is fluoro. In some embodiments of the above structure, R 2 is -SCH3 and R 2a is methyl.

[0208] In some embodiments of the above structures having any one of formulas (III), (IIIa) and (IIIb), R 33 , R 33a and R 33b are each hydrogen. In some embodiments of the above structure, R 33 and R 33b are hydrogen, and R 33a is fluoro. In some embodiments of the above structure, R 33 and R 33b are hydrogen, and R 33a is methyl. In some embodiments of the above structure, R 33 and R 33b are hydrogen, and R 33a is methoxy. In some embodiments of the above structure, R 33 and R 33a are hydrogen, and R 33b is methyl. In some embodiments of the above structure, R 33 and R 33a are hydrogen, and R 33b is methoxy. In some embodiments of the above structure, R 33a and R 33b are hydrogen, and R 33 is methyl.

[0209] In some embodiments, the compound useful in the present methods is a compound of formula (IV).

[0210] With respect to formula (IV), in some embodiments, R 43 is cyano, -C(O)NR 48 R 48a or -C(O)R 46 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 C1-C6 alkyl. In some embodiments, R 43a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. 43a is methyl.

[0211] In some embodiments of Formula (IV), R 43 is cyano and the compound has formula (IVa): TIFF0007651101000036.tif26128, where R 1 , R 2 , R 2a and R 43a is as defined herein in any aspect or embodiment described herein.

[0212] In some embodiments of Formula (IVa), 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.

[0213] With respect to formula (IV), in some embodiments, R 43 is -C(O)NR 48 R 48aand the compound has formula (IVb): TIFF0007651101000037.tif29128, where R 1 , R 2 , R 2a , R 43a , R 48 and R 48a is as defined herein in any aspect or embodiment described herein.

[0214] 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.

[0215] In some embodiments of Formula (IVb), R 48 and R 48a are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 48 and R 48a are each hydrogen. In some embodiments, R 48 and R 48a are each independently C1-C6 alkyl. In some embodiments, R 48 and R 48a One of them is hydrogen and the other is C1-C6 alkyl.

[0216] In some embodiments of Formula (IV), R 43 is -C(O)NH2 and R 43a is methyl.

[0217] With respect to formula (IV), in some embodiments, R 43 HA-C(O)R 46 and the compound has formula (IVc): TIFF0007651101000038.tif26128, where R 1 , R 2 , R 2a , R 43a and R46 is as defined herein in any aspect or embodiment described herein.

[0218] In some embodiments of Formula (IVc), 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.

[0219] In some embodiments of Formula (IVc), R 46 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 46 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein said haloalkyl is alkyl substituted with 1, 2 or 3 fluoro.

[0220] In some embodiments of Formula (IVc), R 46 is hydrogen. In some embodiments of Formula (IVc), R 46 is C1-C6 alkyl. In some embodiments, R 46 is C1-C4 alkyl. In some embodiments, R 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl.

[0221] In some embodiments of Formula (IVc), R 46 is a C1-C6 haloalkyl, wherein the haloalkyl is an alkyl substituted with 1, 2, or 3 fluoro. 46 is a C1-C4 haloalkyl, wherein said C1-C4 haloalkyl is a C1-C4 alkyl substituted with 1, 2, or 3 fluoro. 46 is trifluoromethyl, fluoromethyl or 2,2,2-trifluoroethyl.

[0222] In some embodiments of Formula (IVc), R 46is C-C cycloalkyl or heterocycloalkyl. In some embodiments, R 46 is C3-C8 cycloalkyl. In some embodiments, R 46 is cyclopropyl or cyclobutyl. In some embodiments, R 6 is heterocycloalkyl. In some embodiments, R 46 is a 3-8 membered heterocycloalkyl having 1-3 heteroatoms of N, O, or S. In some embodiments, R 46 is a 3-6 membered heterocycloalkyl having 1-2 heteroatoms of N or O. In some embodiments, R 46 is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, isoxazolidinyl or morpholinyl.

[0223] Returning to formula (IV), in some embodiments, R 43 and R 43a together form —CH2CH2C(O)— or —CH2CH2CH2C(O)—, each of which is unsubstituted or contains one or two R 49 In some embodiments, R 43 and R 43a together form -CH2CH2C(O)- or -CH2CH2CH2C(O)-.

[0224] In some embodiments of Formula (IV), the compound has the formula (IVd-1) or (IVd-2): TIFF0007651101000039.tif28128, where R 1 , R 2 , R 2a and R 49 is as defined herein in any aspect or embodiment described herein.

[0225] In some embodiments of Formula (IV), the compound has the formula (IVe-1) or (IVe-2): TIFF0007651101000040.tif27128, where R 1 , R 2 , R 2a and R 49 is as defined herein in any aspect or embodiment described herein.

[0226] In some embodiments of any one of Formulas (IVd-1), (IVd-2), (IVe-1), and (IVe-2), each R 49 is independently C1-C6 alkyl. In some embodiments of any one of Formulas (IVd-1), (IVd-2), (IVe-1) and (IVe-2), R 49 does not exist.

[0227] In relation to any one of formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1) and (IVe-2), in some embodiments, R 1 -OR 4 , -NR 5 R 5a OR-N(OR 5b )R 5a is.

[0228] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 HA-OR 4 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is a C3-C8 cycloalkyl-C1-C6 alkyl, and the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is C1-C6 hydroxyalkyl. In some embodiments, R 4 is C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 4 is amino-C1-C6 alkyl. In some embodiments, R 4 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 4 is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 4 is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 4 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 4 is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 4 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 4 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0229] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 is -OH, TIFF0007651101000041.tif49128.

[0230] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 is -NR 5 R 5a In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is C1-C6 hydroxyalkyl. In some embodiments, R 5 is C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 5 is amino-C1-C6 alkyl. In some embodiments, R 5 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5 is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 5 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 5 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0231] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 Ha-NR 5 R 5a and R 5 is hydrogen, TIFF0007651101000042.tif40128.

[0232] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 -N(OR 5b )R 5a In some embodiments, R 5b is hydrogen. In some embodiments, R5b is C1-C6 alkyl. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5b is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5b is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is C1-C6 hydroxyalkyl. In some embodiments, R 5bis C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 5b is amino-C1-C6 alkyl. In some embodiments, R 5b is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 5b is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 5b is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5b is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5b is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 5b is R 7 -C(O)-C1-C6 alkyl, and R 7is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 5b is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0233] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 -N(OR 5b )R 5a and -OR 5b -OH, TIFF0007651101000043.tif77128.

[0234] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-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 5a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. 5a is methyl.

[0235] With respect to any one of formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), in some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked heterocycloalkyl substituted with R 6is 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, R 1 is unsubstituted or contains one or two R 6 is an N-linked azetidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked pyrrolidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked piperidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked isoxazolidinyl substituted with R 6 is as defined and described herein. In some embodiments, R 1 is unsubstituted or contains one or two R 6 is an N-linked morpholinyl substituted with R 6 is as defined and described herein.

[0236] R as one or two substituents of an N-linked heterocycloalkyl in any one of formulae (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1) and (IVe-2) 6 In some embodiments, each R 6 is independently hydroxyl, oxo, or amino. In some embodiments, each R 6 is hydroxy. In some embodiments, each R 6 is oxo. In some embodiments, each R 6 is amino. In some embodiments, R 6 One of the groups is hydroxy and the other R 6 is an amino.

[0237] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 1 is an N-linked heterocycloalkyl that is unsubstituted or substituted with hydroxyl, oxo, or amino. In some embodiments, R 1 is an N-linked azetidinyl that is unsubstituted or substituted with hydroxyl, oxo, or amino. 1 is an N-linked pyrrolidinyl that is unsubstituted or substituted with hydroxyl, oxo, or amino. 1 is an N-linked piperidinyl that is unsubstituted or substituted with hydroxyl, oxo, or amino. 1 is an N-linked isoxazolidinyl that is unsubstituted or substituted with hydroxyl, oxo, or amino. 1 is an N-linked morpholinyl that is unsubstituted or substituted with hydroxyl, oxo, or amino.

[0238] With respect to any one of formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), in some embodiments, R 2is halo, C1-C6 alkyl, —S—C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R 2 is halo or C1-C6 alkyl. In some embodiments, R 2 is R 2 is halo, -CH3, -SCH3, C2-C3 alkenyl, or C2-C3 alkynyl.

[0239] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 is halo. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is iodo. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo.

[0240] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0241] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 is -S-C1-C6 alkyl. In some embodiments, R 2 is -S-C1-C3 alkyl. In some embodiments, R 2 is -SCH3.

[0242] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 is C3-C8 cycloalkyl. In some embodiments, R 2 is cyclopropyl.

[0243] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 is C2-C6 alkenyl. In some embodiments, R 2 is C2-C4 alkenyl. In some embodiments, R 2 is vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, or butadienyl. 2 is vinyl.

[0244] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2 is C2-C6 alkynyl. In some embodiments, R 2 is C2-C3 alkynyl. In some embodiments, R 2 is acetylenyl or propynyl. In some embodiments, R 2 is acetylenyl.

[0245] With respect to any one of formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (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 CH. In some embodiments, R 2a is fluoro or CH. In some embodiments, R 2a is iodo or CH. In some embodiments, R 2ais chloro or CH. In some embodiments, R 2a is bromo or CH3.

[0246] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (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.

[0247] In some embodiments of any one of Formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), R 2a is C1-C6 alkyl. In some embodiments, R 2a is C1-C3 alkyl. In some embodiments, R 2a is CH3.

[0248] With respect to any one of formulas (IV), (IVa), (IVb), (IVc), (IVd-1), (IVd-2), (IVe-1), and (IVe-2), in some embodiments, R 2 and R 2a and R are each halo. 2 is the halo and R 2a is C1-C6 alkyl. In some embodiments, R 2 is C1-C6 alkyl, and R 2a is halo. In some embodiments, R 2 is -S-C1-C6 alkyl, and R 2a is halo. In some embodiments, R 2 is -SCH3 and R 2a is halo. In some embodiments, R 2 is a C3-C8 cycloalkyl, and R 2a is halo. In some embodiments, R2 is cyclopropyl and R 2a is halo. In some embodiments, R 2 is C2-C6 alkenyl, and R 2a is halo. In some embodiments, R 2 is C2-C6 alkynyl, and R 2a is halo. In some embodiments, R 2 is acetylenyl and R 2a is halo. In some embodiments, R 2 and R 2a are each independently fluoro, chloro, bromo, or iodo. 2 is iodine and R 2a is fluoro. In some embodiments, R 2 is the halo and R 2a is —CH3. In some embodiments, R 2 is bromo and R 2a is —CH3. In some embodiments, R 2 is iodine and R 2a is —CH3. In some embodiments, R 2 is -SCH3 and R 2a is fluoro. In some embodiments, R 2 is acetylenyl and R 2a is fluoro.

[0249] In some embodiments, the compound of formula (IV) has the following formula: It is represented by one of TIFF0007651101000044.tif29151, TIFF0007651101000045.tif182152, and TIFF0007651101000046.tif103151. In the formula, R 2 , R 2a , R 43 and R 43a is as defined herein in any aspect or embodiment described herein.

[0250] In some embodiments of the above structure having formula (IV), R2 is iodine and R 2a is fluoro. In some embodiments of the above structure, R 2 is iodine and R 2a is methyl. In some embodiments of the above structure, R 2 is acetylenyl and R 2a is fluoro. In some embodiments of the above structure, R 2 is acetylenyl and R 2a is methyl. In some embodiments of the above structure, R 2 is -SCH3 and R 2a is fluoro. In some embodiments of the above structure, R 2 is -SCH3 and R 2a is methyl.

[0251] In some embodiments of the above structure having formula (IV), R 43 is cyano, -C(O)NR 48 R 48a or -C(O)R 46 and R 43a is C1-C6 alkyl. In some embodiments of the above structure, R 43 is cyano and R 43a is methyl. In some embodiments of the above structure, R 43 is -C(O)NR 48 R 48a and R 48 and R 48a are hydrogen, and R 43a is methyl. In some embodiments of the above structure, R 43 HA-C(O)R 46 and R 46 is C1-C4 alkyl, and R 43a is C1-C4 alkyl. In some embodiments of the above structure, R 43 HA-C(O)R 46 and R 46 is C1-C4 alkyl, and R 43a is methyl. In some embodiments of the above structure, R 43 and R 43atogether form -CH2CH2C(O)- or -CH2CH2CH2C(O)-.

[0252] In some embodiments, the compound useful in the present methods is a compound of formula (V).

[0253] With respect to formula (V), in some embodiments, bond "a" is a double bond and the compound has formula (Va): Represented by TIFF0007651101000047.tif26128, where the subscripts n, R 2 , R 2a , R 51 , R 53 , R 53a and R 53b is as defined herein in any aspect or embodiment described herein.

[0254] In some embodiments of Formula (V), bond "a" is a single bond and the compound has the formula (Vb): Represented by TIFF0007651101000048.tif26128, where the subscripts n, R 2 , R 2a , R 51 , R 53 , R 53a and R 53b is as defined herein in any aspect or embodiment described herein.

[0255] In some embodiments of any one of Formulas (V), (Va), and (Vb), each R 53 is independently halo or C1-C3 alkyl. In some embodiments, each R 53 is independently fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, or isopropyl. 53 is methyl.

[0256] In some embodiments of any one of formulas (V), (Va) and (Vb), the subscript n is 0 or 1. In some embodiments, the subscript n is 0 and the compound has formula (Va-1) or (Vb-1): Represented by TIFF0007651101000049.tif26128, In the formula, R 2 , R 2a , R 51 , R 53a and R 53b is as defined herein in any aspect or embodiment described herein.

[0257] With respect to any one of formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 53a and R 53b are each independently hydrogen, halo, or C1-C6 alkyl.

[0258] In some embodiments of any one of Formulas (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. 53a is methyl.

[0259] In some embodiments of any one of Formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 53b is hydrogen, halo, or C1-C6 alkyl. In some embodiments, R53b 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 can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. 53b is methyl.

[0260] In some embodiments of any one of Formulas (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.

[0261] With respect to any one of formulas (V), (Va), (Vb), (Va-1) and (Vb-1), in some embodiments, R 51 is C1-C6 alkyl. In some embodiments, R 5 is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 51 is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 51 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R6 is as defined and described herein. In some embodiments, R 51 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 51 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 51 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 51 is C1-C6 hydroxyalkyl. In some embodiments, R 51 is C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 51 is amino-C1-C6 alkyl. In some embodiments, R 51 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 51 is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 51 is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 51 is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6is independently hydroxy or C1-C6 alkyl. In some embodiments, R 5 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 51 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 51 is oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 51 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 51 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0262] In some embodiments of any one of Formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 51 is hydrogen, TIFF0007651101000050.tif62128.

[0263] In some embodiments of any one of Formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 51 is OR 54In some embodiments, R 54 is hydrogen. In some embodiments, R 54 is C1-C6 alkyl. In some embodiments, R 54 is unsubstituted or 1 to 6 R 6 C3-C8 cycloalkyl substituted with R 6 is as defined and described herein. In some embodiments, R 54 is unsubstituted or 1 to 6 R 6 and each R is a C3-C8 cycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 54 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 54 is a C3-C8 cycloalkyl-C1-C6 alkyl, wherein the C3-C8 cycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 54 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of the cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopropyl-C1-C6 alkyl, or cyclobutyl-C1-C6 alkyl; each of said cyclopropyl and cyclobutyl groups is unsubstituted or contains 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 54is C1-C6 hydroxyalkyl. In some embodiments, R 54 is C1-C6 alkoxy-C1-C6 alkyl. In some embodiments, R 54 is amino-C1-C6 alkyl. In some embodiments, R 54 is C1-C6 alkylamino-C1-C6 alkyl. In some embodiments, R 54 is di-(C1-C6 alkyl)amino-C1-C6 alkyl. In some embodiments, R 54 is unsubstituted or 1 to 6 R 6 and R is a heterocycloalkyl substituted with 6 is as defined and described herein. In some embodiments, R 54 is unsubstituted or 1 to 6 R 6 and each R is a heterocycloalkyl substituted with 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 54 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 is substituted with R 6 is as defined and described herein. In some embodiments, R 54 is heterocycloalkyl-C1-C6 alkyl, wherein the heterocycloalkyl group is unsubstituted or has 1 to 6 R 6 and each R 6 is independently hydroxy or C1-C6 alkyl. In some embodiments, R 54 is oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl-C1-C6 alkyl, azetidinyl-C1-C6 alkyl, pyrrolidinyl-C1-C6 alkyl, piperidinyl-C1-C6 alkyl, or 2,2-dimethyl-1,3-dioxolan-4-yl-C1-C6 alkyl. 54 is R 7 -C(O)-C1-C6 alkyl, and R 7is hydroxy, C1-C6 alkoxy, amino, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, hydroxyamino, or N-C1-C6 alkylhydroxyamino. In some embodiments, R 54 is R 7 -C(O)-C1-C6 alkyl, and R 7 is hydroxy, C1-C6 alkoxy, amino or hydroxyamino.

[0264] In some embodiments of any one of Formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 51 is -OH, TIFF0007651101000051.tif73128.

[0265] With respect to any one of formulas (V), (Va), (Vb), (Va-1) and (Vb-1), in some embodiments, R 2 is halo, C1-C6 alkyl, —S—C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, R 2 is halo or C1-C6 alkyl. In some embodiments, R 2 is halo, -SCH3, -CH3, C2-C3 alkenyl, or C2-C3 alkynyl.

[0266] In some embodiments of any one of Formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 2 is halo. In some embodiments, R 2 is fluoro. In some embodiments, R 2 is iodo. In some embodiments, R 2 is chloro. In some embodiments, R 2 is bromo.

[0267] In some embodiments of any one of Formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 2is C1-C6 alkyl. In some embodiments, R 2 is C1-C3 alkyl. In some embodiments, R 2 is methyl.

[0268] In some embodiments of any one of Formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 2 is -S-C1-C6 alkyl. In some embodiments, R 2 is -S-C1-C3 alkyl. In some embodiments, R 2 is -SCH3.

[0269] In some embodiments of any one of Formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 2 is C3-C8 cycloalkyl. In some embodiments, R 2 is cyclopropyl.

[0270] In some embodiments of any one of Formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 2 is C2-C6 alkenyl. In some embodiments, R 2 is C2-C4 alkenyl. In some embodiments, R 2 is vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, or butadienyl. 2 is vinyl.

[0271] In some embodiments of any one of Formulas (V), (Va), (Vb), (Va-1) and (Vb-1), R 2 is C2-C6 alkynyl. In some embodiments, R 2 is C2-C3 alkynyl. In some embodiments, R 2 is acetylenyl or propynyl. In some embodiments, R 2 is acetylenyl.

[0272] With respect to any one of formulas (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 CH. In some embodiments, R 2a is fluoro or CH. In some embodiments, R 2a is iodo or CH. In some embodiments, R 2a is chloro or CH. In some embodiments, R 2a is bromo or CH3.

[0273] In some embodiments of any one of Formulas (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.

[0274] In some embodiments of any one of Formulas (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.

[0275] With respect to any one of formulas (V), (Va), (Vb), (Va-1) and (Vb-1), in some embodiments, R 2 and R 2a and R are each halo. 2 is the halo and R 2a is C1-C6 alkyl. In some embodiments, R 2 is C1-C6 alkyl, and R 2a is halo. In some embodiments, R 2 is -S-C1-C6 alkyl, and R2a is halo. In some embodiments, R 2 is -SCH3 and R 2a is halo. In some embodiments, R 2 is a C3-C8 cycloalkyl, and R 2a is halo. In some embodiments, R 2 is cyclopropyl and R 2a is halo. In some embodiments, R 2 is C2-C6 alkenyl, and R 2a is halo. In some embodiments, R 2 is C2-C6 alkynyl, and R 2a is halo. In some embodiments, R 2 is acetylenyl and R 2a is halo. In some embodiments, R 2 and R 2a are each independently fluoro, chloro, bromo, or iodo. 2 is iodine and R 2a is fluoro. In some embodiments, R 2 is the halo and R 2a is —CH3. In some embodiments, R 2 is bromo and R 2a is —CH3. In some embodiments, R 2 is iodine and R 2a is —CH3. In some embodiments, R 2 is -SCH3 and R 2a is fluoro. In some embodiments, R 2 is acetylenyl and R 2a is fluoro.

[0276] In some embodiments, the compound of formula (V) has the following formula: It is represented by one of TIFF0007651101000052.tif150155, TIFF0007651101000053.tif159155, and TIFF0007651101000054.tif44154. In the formula, bond "a", R 2 , R2a , R 53a and R 53b is as defined herein in any aspect or embodiment described herein.

[0277] In some embodiments of the above structure having formula (V), bond "a" is a double bond. In some embodiments of the above structure having formula (V), bond "a" is a single bond.

[0278] In some embodiments of the above structure having formula (V), R 2 is iodine and R 2a is fluoro. In some embodiments of the above structure, R 2 is iodine and R 2a is methyl. In some embodiments of the above structure, R 2 is acetylenyl and R 2a is fluoro. In some embodiments of the above structure, R 2 is acetylenyl and R 2a is methyl. In some embodiments of the above structure, R 2 is -SCH3 and R 2a is fluoro. In some embodiments of the above structure, R 2 is -SCH3 and R 2a is methyl.

[0279] In some embodiments of the above structure having formula (V), R 53a and R 53b are each hydrogen. In some embodiments of the above structure, R 53a is hydrogen and R 53b is halo. In some embodiments of the above structure, R 53a is hydrogen and R 53b is fluoro.

[0280] Exemplary compounds having any one of formulas (I), (II), (III), (IV) and (V) are listed in Tables 1-5.

[0281] Table 1: Compounds of formula (I) TIFF0007651101000055.tif162133TIFF0007651101000056.tif195134TIFF0007651101000057.tif19413 3TIFF0007651101000058.tif177133TIFF0007651101000059.tif164133TIFF0007651101000060.tif48133

[0282] Table 2: Compounds of formula (II) TIFF0007651101000061.tif120130TIFF0007651101000062.tif187131TIFF0007651101000063.tif19113 0TIFF0007651101000064.tif188130TIFF0007651101000065.tif201130TIFF0007651101000066.tif87130

[0283] Table 3: Compounds of formula (II) TIFF0007651101000067.tif83128TIFF0007651101000068.tif193128TIFF0007651101000069.tif179128TIFF0007651101000070.tif111128

[0284] Table 4: Compounds of formula (IV) TIFF0007651101000071.tif70128TIFF0007651101000072.tif187128TIFF00076511010 00073.tif201126TIFF0007651101000074.tif195126TIFF0007651101000075.tif127128

[0285] Table 5: Compounds of formula (V) TIFF0007651101000076.tif43128TIFF0007651101000077.tif180128

[0286] The compounds of the present invention may exist as salts. The present invention includes such salts. Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Acceptable acid addition salts include: Examples of salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as those derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galactunoric acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, which allow the compounds to be converted into either base or acid addition salts.

[0287] Other salts include the acid or basic salts of the compounds used in the method of the present invention.Examples of pharmaceutically acceptable salts include mineral acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.).It is understood that pharmaceutically acceptable salts are non-toxic.Additional information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the contents of which are incorporated herein by reference.

[0288] Pharmaceutically acceptable salts include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein.When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound 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 salts, or similar salts.When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound 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 such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunoric acid (see, e.g., 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 functional groups, which allow the compounds to be converted into either base or acid addition salts.

[0289] The neutral forms of the compounds may preferably 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.

[0290] Certain compounds of the present invention can exist in non-solvated form as well as solvated form, including hydrated form.In general, solvated form is equivalent to non-solvated form and is included 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 use contemplated by the present invention and are intended to be within the scope of the present invention.

[0291] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms which may be defined with respect to absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, (D)- or (L)-, and individual isomers are included within the scope of the present invention. Compounds of the present invention do not include those known in the art to be too unstable to synthesize and / or isolate. The present invention is intended to encompass compounds in racemic and optically pure form. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0292] Isomers include compounds that have the same number and kind of atoms, and hence the same molecular weight, but differ with regard to the structural arrangement or configuration of the atoms.

[0293] It will be apparent to those skilled in the art that certain compounds of this invention may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the invention. A tautomer refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0294] Unless otherwise stated, structures depicted herein are also intended 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.

[0295] Unless otherwise specified, the compounds of the present invention may 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 contain isotopes of, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), fluorine-18( 18 F), nitrogen-15( 15 N), oxygen-17( 17 O), oxygen-18( 18 O), carbon-13( 13 C), or carbon-14 ( 14 The compounds may be labeled with radioactive or stable isotopes, such as C. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0296] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can also 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 containing a suitable enzyme or chemical reagent.

[0297] The compounds of the present application are designed for topical, subcutaneous, intradermal, or intralesional application, and result in the inhibition of MEK activity in the dermal and epidermal layers (i.e., within the bruise) for the treatment of bruises. In some embodiments, the compounds are designed to be metabolically unstable to limit systemic toxicity after topical, subcutaneous, transdermal, intradermal, or intralesional application by limiting the time the compound remains in the peripheral circulation after acting to treat the bruise. The present application provides a solution for the treatment of bruises with compounds that penetrate the skin and exhibit the ability to inhibit phospho-ERK.

[0298] V. Composition The present invention provides a pharmaceutical composition comprising a compound having any one of formulas (I)-(V), as defined and described herein, and a pharmaceutically acceptable carrier, for use in a method for treating a birthmark.

[0299] The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and disclosed herein. Any of the compounds disclosed herein can be provided in a suitable pharmaceutical composition and administered by a suitable route of administration.

[0300] The compounds described herein can be administered to a subject locally or non-systemically, for example, topically, subcutaneously, intradermally, or intralesionally. In some embodiments, the compounds can be administered topically. In some embodiments, the compounds can be administered intradermally. In some embodiments, the compounds can be administered intralesionally, for example, by intralesional injection.

[0301] The methods provided herein include administering to a subject in need thereof a pharmaceutical composition containing at least one compound described herein, including a compound having any one of Formulas (I)-(V), optionally in salt form, used alone or in combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or in combination with another agent for the treatment of bruising (e.g., MEK inhibitor-responsive or MEK-mediated bruising).

[0302] In some embodiments, the second agent can be formulated or packaged together with the compound provided herein.Of course, the second agent will only be formulated together with the compound provided herein if, according to the judgment of those skilled in the art, such co-formulation will not interfere with the activity of either the agent or the administration method.In some embodiments, the compound provided herein and the second agent will be formulated separately.The compound provided herein and the second agent can be packaged together or packaged separately for the convenience of those skilled in the art.

[0303] In clinical practice, the active agents provided herein can be administered by any conventional route, particularly topically, subcutaneously, intradermally, or intralesionally. In some embodiments, the compounds provided herein are administered topically. In some embodiments, the compounds provided herein are administered subcutaneously. In some embodiments, the compounds provided herein are administered intradermally. In some embodiments, the compounds provided herein are administered intralesionally.

[0304] The composition for topical administration may be a paste, lotion, tincture, emulsion, spray, ointment, cream, or gel. In another embodiment, topical administration may be achieved in the form of a patch containing an active substance, which is in contact with the affected area on the skin. In a further embodiment, topical administration may be achieved in the form of a liquid paint that dries on the skin after application to the affected area. In some of these embodiments, the composition may contain a skin penetrating agent so that the active substance penetrates the epidermis and is delivered transdermally. In a further embodiment, the composition is formulated for intradermal injection. In another embodiment, the composition is formulated for intralesional injection.

[0305] Compositions for topical administration may be used as pastes, lotions, tinctures, emulsions, sprays, ointments, creams, or gels. In these compositions, the active product is mixed with one or more inert excipients, including water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof. Topical compositions (e.g., gels, creams, ointments, lotions) may contain a pharmaceutically acceptable polymer. Creams and ointments may contain a paraffin base. For active agents delivered transdermally, topical compositions may further contain a skin penetration enhancer (e.g., DMSO, pyrrolidinone). Emollients (e.g., glycerin, cocoa butter) may be present in compositions containing a compound having any one of formulas (I) to (V) described herein.

[0306] Compositions for topical, subcutaneous, intradermal, or intralesional administration may be emulsions or sterile solutions. Propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, or injectable organic esters, in some embodiments, ethyl oleate, may be used as solvents or vehicles. These compositions may also contain auxiliary agents, particularly wetting agents, isotonicity adjusting agents, emulsifying agents, dispersing agents, and stabilizers. Sterilization can be achieved in several ways, in some embodiments by using a bacterial filter, irradiation, or heat. These compositions may also be prepared in the form of sterile solid compositions that can be dissolved in sterile water or any other injectable sterile medium at the time of use.

[0307] Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides, or polyethylene glycols.

[0308] This composition can be in the form of aerosol, and can be sprayed on the affected area.When used in the form of liquid aerosol, this composition can be a stable sterile solution, or a solid composition that dissolves in non-pyrogenic sterile water, physiological saline, or any other pharmaceutically acceptable vehicle when used.When used in the form of dry aerosol that is intended to be directly inhaled, the active ingredient is micronized and combined with a water-soluble solid diluent or vehicle, in some embodiments, dextran, mannitol, or lactose.

[0309] In some embodiments, the compositions provided herein are pharmaceutical compositions or single-unit dosage forms. The pharmaceutical compositions and single-unit dosage forms provided herein comprise an effective, prophylactically effective, or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a compound provided herein or other prophylactic or therapeutic agent), typically accompanied by one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, more specifically in humans. The term "carrier" includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle through which a therapeutic agent is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. When a pharmaceutical composition is administered intravenously, water can be used as a carrier. Physiological saline, and aqueous dextrose and glycerin solutions may be used as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd Edition (September 15, 2012).

[0310] Typical pharmaceutical compositions and dosage forms contain one or more excipients.Suitable excipients are well known to those skilled in the art of pharmacy, and in some embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, nonfat dry milk, glycerin, propylene, glycol, water, ethanol, etc.Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or unit dosage form depends on various factors well known in the art, including, but not limited to, the manner in which the unit dosage form is administered to a subject and the specific active ingredient in the dosage form.If desired, the composition or single unit dosage form may contain minor amounts of wetting or emulsifying agents or pH buffering agents.

[0311] The lactose-free compositions provided herein may contain excipients well known to those skilled in the art and, in some embodiments, listed in the United States Pharmacopoeia (USP 36-NF 31 S2). Generally, lactose-free compositions contain an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. An exemplary lactose-free dosage form contains an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0312] Because water can promote the decomposition of some compounds, anhydrous pharmaceutical compositions and dosage forms containing active ingredients are also included herein.For example, the addition of water (for example, 5%) is widely accepted in the pharmaceutical field as a means to promote long-term storage in order to determine the properties of formulations, such as shelf life or stability over time.See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, New York, 1995, pp. 379-80.In fact, water and heat promote the decomposition of some compounds.Therefore, the effect of water on formulations can be very important, since moisture and / or humidity are usually encountered during the production, handling, packaging, storage, transportation and use of formulations.

[0313] The anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine can be anhydrous if significant contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage.

[0314] Anhydrous pharmaceutical compositions should be prepared and stored so that their anhydrous nature is maintained.Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water, so that they can be included in suitable formulation kits.In some embodiments, suitable packaging includes, but is not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0315] Pharmaceutical compositions and dosage forms are further provided that contain one or more compounds that reduce the rate at which the active ingredient decomposes. These compounds, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0316] The pharmaceutical composition can be in the form of a solution, suspension, emulsion, gel, cream, ointment, or aerosol formulation. In some embodiments, the composition is impregnated into a suitable matrix to form a patch. In some embodiments, the composition is a sustained-release formulation. The formulation should be suitable for the mode of administration (e.g., topical, subcutaneous, intradermal, or intralesional administration). In some embodiments, the pharmaceutical composition or single unit dosage form is sterile and in a form suitable for administration to a subject, in some embodiments, an animal subject, for example, a mammalian subject, and in some embodiments, a human subject.

[0317] Pharmaceutical compositions are formulated to be compatible with their intended route of administration. In some embodiments, routes of administration include, but are not limited to, parenteral administration, e.g., intradermal, subcutaneous, intramuscular, inhalation, intranasal, intrasynovial, rectal, topical, intralesional, and transmucosal administration. In some embodiments, the route of administration is subcutaneous, intradermal, topical, or intralesional. In some embodiments, the route of administration is non-systemic. In some embodiments, the composition is formulated according to routine procedures as a pharmaceutical composition adapted for subcutaneous or topical administration to humans. In some embodiments, the pharmaceutical composition is formulated according to routine procedures for intradermal or intralesional administration to humans. Typically, compositions for injectable administration (e.g., intradermal or subcutaneous injection) are solutions, emulsions, or suspensions in sterile isotonic aqueous buffer. If necessary, the composition may also include a solubilizing agent and a local anesthetic, such as lignocaine, to ease pain at the injection site.

[0318] In some embodiments, dosage forms include, but are not limited to, ointments; poultices (compresses); pastes; bandages; creams; plasters; solutions; patches; aerosols (e.g., nasal drops, inhalants, skin sprays); gels; liquid dosage forms suitable for dermal administration to a subject, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and lotions; liquid dosage forms suitable for mucosal administration to a subject, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral (e.g., subcutaneous or intradermal) administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject.

[0319] The composition, shape and type of dosage forms provided herein typically vary depending on their use.In some embodiments, the dosage form used in the initial treatment of bruising (for example, MEK inhibitor-responsive or MEK-mediated bruising) can contain a larger amount of one or more of the active ingredients contained in the dosage form used in the initial treatment than the dosage form used in the maintenance treatment of the same disorder or disease.Similarly, a parenteral (intradermal) dosage form can contain a smaller amount of one or more of the active ingredients contained in the parenteral (intradermal) dosage form than the external application form used to treat the same disease or disorder.These and other ways in which specific dosage forms included herein differ from each other will be obvious to those skilled in the art.See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).

[0320] Generally, the components of the composition are supplied separately or mixed together in a unit dosage form, and in some embodiments are supplied as a dry lyophilized powder or anhydrous concentrate in a sealed container such as an ampoule or sachet indicating the amount of active substance.When the composition is administered by injection, the composition can be dispensed with an infusion bottle containing sterile pharmaceutical-grade water or saline.When the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the components can be mixed before administration.

[0321] Typical dosage forms include a compound provided herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the range of about 0.1 mg to about 1000 mg per day, given as a single dose once daily in the morning or as divided doses throughout the day taken with food. Specific dosage forms can have about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1.0 mg, 2.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, 25.0 mg, 50.0 mg, 100 mg, 200 mg, 250 mg, 500 mg, or 1000 mg of active compound.

[0322] In some embodiments, the compositions described herein contain a lubricant.Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof.In some embodiments, additional lubricants include syloid silica gel (AEROSIL 200 manufactured by WR Grace Co., Baltimore, Maryland), coagulated aerosol of synthetic silica (sold by Degussa Co., Plano, Texas), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co., Boston, Massachusetts), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

[0323] Delayed-Release Dosage Forms Active ingredients, such as the compounds provided herein, can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. In some embodiments, the present invention is directed to compounds such as those disclosed in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,923,567; and 6,699,500, each of which is incorporated herein by reference in its entirety. In some embodiments, such dosage forms can be used to provide desired release characteristics at various rates, such as hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, to provide slow or controlled release of one or more active ingredients.Suitable controlled-release formulations known to those skilled in the art, including the controlled-release formulations described herein, can be easily selected for use with the active ingredients provided herein, and can be incorporated into, for example, bandages or patches.Therefore, the present invention encompasses single-unit dosage forms suitable for dermal administration, such as, but not limited to, gels, ointments, patches, creams, and wound dressings, which are adapted for controlled release.

[0324] All controlled-release pharmaceuticals share the common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of optimally designed controlled-release preparations in medical treatment is characterized by the minimum amount of drug substance utilized to cure or control a disease or disorder in the shortest time. The advantages of controlled-release formulations include prolonging the activity of the drug, reducing the frequency of administration, and increasing subject compliance. Furthermore, controlled-release formulations can be used to affect other characteristics, such as the onset of action or blood levels of the drug, thereby affecting the occurrence of one or more side effects (e.g., adverse effects).

[0325] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that rapidly produces the desired therapeutic effect, and then gradually and continuously release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug being metabolized and excreted from the body. Controlled-release of the active ingredient can be stimulated by various physiological factors, including, but not limited to, pH, temperature, enzymes, water, or other physiological factors associated with the bruise or compound.

[0326] In some embodiments, drugs can be administered using transdermal patches, liposomes, or other modes of administration. In some embodiments, polymeric materials can be used. In some embodiments, controlled-release systems can be placed in a subject at appropriate sites determined by those skilled in the art, i.e., sites that therefore require only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled-release systems are discussed in a review by Langer (Science 249:1527-1533 (1990)). The active ingredient is contained in an outer polymeric membrane that is insoluble in body fluids, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer. The active ingredient can be dispersed in a solid inner matrix surrounded by a hydrophilic polymer such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of acrylic and methacrylic acid esters, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.The active ingredient then diffuses through the outer polymer membrane in a release rate-controlling process.The percentage of active ingredient in such parenteral (e.g., intradermal) compositions largely depends on the specific nature of the composition as well as the needs of the patient.

[0327] Parenteral (intramuscular, subcutaneous, intralesional, intradermal) dosage forms In some embodiments, parenteral dosage forms are provided. In some embodiments, parenteral dosage forms can be administered to a subject by various routes, including but not limited to subcutaneous, intramuscular, and intradermal. In some embodiments, parenteral dosage forms can be administered to a subject by various routes, including but not limited to subcutaneous, intramuscular, intradermal, or intralesional. Because administration of parenteral dosage forms typically bypasses the subject's natural defenses against contaminants, parenteral dosage forms are typically sterile or can be sterilized before administration to a subject. In some embodiments, parenteral dosage forms include, but are not limited to, ready-to-inject solutions, dry products that are ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, ready-to-inject suspensions, and emulsions.

[0328] Suitable vehicles that can be used to obtain parenteral dosage forms are well known to those skilled in the art.In some embodiments, suitable vehicles include but are not limited to: water for injection USP; aqueous vehicles such as but not limited to sodium chloride injection, Ringer's solution, dextrose injection, dextrose sodium chloride injection, and lactated Ringer's solution; water-miscible vehicles such as but not limited to ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0329] Compounds that increase the solubility of one or more of the active ingredients disclosed herein may also be incorporated into the parenteral dosage forms.

[0330] Topical and mucosal dosage forms Topical dosage forms and mucosal dosage forms are also provided. Transdermal dosage forms, mucosal dosage forms, and topical dosage forms include, but are not limited to, pastes, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd Edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues in the oral cavity can be formulated as mouthwashes or oral gels. Furthermore, transdermal dosage forms include "reservoir-type" or "matrix-type" patches, which can be applied to the skin and worn for a specific period of time to allow the desired amount of active ingredient to penetrate.

[0331] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting any subject composition or its components. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components and not harmful to the patient. Suitable carriers (e.g., excipients and diluents) and other materials that can be used to obtain transdermal, topical, and in some embodiments, mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that in mind, typical carriers for forming non-toxic and pharmaceutically acceptable lotions, tinctures, creams, emulsions, gels, or ointments include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof.In some embodiments, materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; and (16) pyrogen-free water. (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances used in pharmaceutical preparations. If desired, humectants or humectants may be added to pharmaceutical compositions and dosage forms. Examples of these additional ingredients are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd Edition (September 15, 2012).

[0332] According to the specific tissue to be treated, additional components can be used before, at the same time, or after the treatment with the provided active ingredient.In some embodiments, permeation enhancer can be used to help deliver active ingredient to tissue.Suitable permeation enhancer includes but is not limited to acetone; various alcohols such as ethanol, oleyl and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grade (povidone, polyvidone); urea; and various water-soluble or water-insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

[0333] In addition, the pH of pharmaceutical compositions or dosage forms, or the pH of the tissue to which the pharmaceutical compositions or dosage forms are applied, can be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity, ionic strength, or isotonicity of solvent carriers can be adjusted to improve delivery.Compounds such as stearic acid esters can be added to pharmaceutical compositions or dosage forms to advantageously modify the hydrophilicity or lipophilicity of one or more active ingredients to improve delivery.In this regard, stearic acid esters can serve as lipid vehicles for formulations, as emulsifiers or surfactants, and as delivery enhancers or penetration enhancers.Different salts, hydrates, or solvates of active ingredients can be used to further adjust the properties of the resulting composition.

[0334] Dosage and unit dosage form In human therapy, a physician will determine the dosage regimen he or she deems most appropriate depending on whether the treatment is prophylactic or therapeutic, and on the age, weight, stage of the disorder or disease, and other factors specific to the subject being treated. In some embodiments, the dosage is about 1 to about 1000 mg per adult per day, or about 5 to about 250 mg per adult per day, or about 10 to 50 mg per adult per day. In some embodiments, the dosage is about 5 to about 400 mg per adult per day, or 25 to 200 mg per adult per day. In some embodiments, a dosage of about 50 to about 500 mg per day is also contemplated.

[0335] In a further aspect, a method for treating bruising (e.g., MEK inhibitor-responsive or MEK-mediated bruising) in a subject is provided by administering a therapeutically effective or effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof to a subject in need thereof.The therapeutically effective or effective amount of the compound or composition in treating bruising or one or more symptoms thereof depends on the nature and severity of the disease or condition and the route by which the active ingredient is administered.Frequency and dosage also vary depending on factors specific to each subject, which depend on the specific therapeutic agent (e.g., therapeutic or preventive agent) administered, the severity of the disorder, disease, or condition, the route of administration, and the subject's age, physical condition, weight, response, and medical history.Effective amounts can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0336] In some embodiments, exemplary dosages of the compositions include milligram or microgram amounts of active compound per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 micrograms per kilogram to about 10 milligrams per kilogram). For the compositions provided herein, in some embodiments, the dosage administered to a subject is 0.140 mg to 3 mg per kg of the subject's body weight, based on the weight of the active compound. In some embodiments, the dosage administered to a subject is 0.20 mg to 2.00 mg, 0.30 mg to 1.50 mg, 1 mg to 100 mg, 5 mg to 50 mg, 10 mg to 50 mg, 20 mg to 50 mg, 15 mg to 40 mg, 15 mg to 35 mg, 15 mg to 30 mg, 25 mg to 35 mg, 10 mg to 30 mg, 10 mg to 20 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg per kg of the subject's body weight.

[0337] In some embodiments, the recommended daily dose range of the compositions provided herein for a disease or disorder described herein ranges from about 0.1 mg to about 1000 mg per day, given as a single dose once daily or as divided doses throughout the day. In some embodiments, the daily dose is administered twice daily in equally divided doses. In some embodiments, the daily dose range should be about 10 mg to about 200 mg per day, in some embodiments about 10 mg to about 150 mg per day, and in further embodiments about 25 mg to about 100 mg per day. As will be apparent to those skilled in the art, in some cases it may be necessary to use dosages of the active ingredients outside the ranges disclosed herein. Furthermore, it should be noted that the clinician or treating physician will know when and how to interrupt, adjust, or terminate treatment in relation to the subject's response.

[0338] As those skilled in the art will readily understand, different therapeutically effective amounts or effective amounts may be applicable to different diseases and conditions.Similarly, the dosage and administration frequency schedule described herein also encompasses an amount that is sufficient to prevent, manage, treat, or alleviate the disease, but is insufficient to cause or reduce the adverse effects associated with the compositions provided herein.Furthermore, when administering multiple doses of the compositions administered herein to a subject, all doses do not need to be the same.In some embodiments, the dose administered to a subject may be increased to improve the preventive or therapeutic effect of the composition, or may be decreased to reduce one or more side effects experienced by a particular subject.

[0339] In some embodiments, the dosage of the compositions provided herein administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is 0.1 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 10 mg, or 15 mg or more per kg of the subject's body weight, based on the weight of the active compound. In some embodiments, the dosage of the compositions provided herein administered to prevent, treat, manage, or ameliorate a disorder or one or more symptoms thereof in a subject is a unit dose of 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg ~7.5mg, 0.1mg~5mg, 0.1mg~2.5mg, 0.25mg~20mg, 0.25~15mg, 0.25~12mg, 0.25~10mg, 0.25mg~7.5mg, 0.25mg~5mg, 0.5mg~2.5mg, 1mg~20mg, 1mg~15mg, 1mg~12mg, 1mg~10mg, 1mg~7.5mg, 1mg~5mg, or 1mg~2.5mg.

[0340] In some embodiments, treatment or prophylaxis can be initiated with one or more initial loading doses of a compound or composition provided herein, followed by one or more maintenance doses. In such embodiments, the initial loading dose can be, for example, about 60 to about 400 mg per day or about 100 to about 200 mg per day for one day to five weeks. The initial loading dose can be followed by one or more maintenance doses. In some embodiments, each maintenance dose is independently about 10 mg to about 200 mg per day, about 25 mg to about 150 mg per day, or about 25 mg to about 80 mg per day. The maintenance dose can be administered daily and can be administered as a single dose or in divided doses.

[0341] In some embodiments, a compound or composition provided herein can be administered in a dose that achieves a steady-state concentration of the active ingredient in the subject's blood or serum. The steady-state concentration can be determined by measurements available to those of skill in the art and can be based on the subject's physical characteristics, such as height, weight, and age. In some embodiments, a compound or composition provided herein is administered in an amount sufficient to achieve a steady-state concentration in the subject's blood or serum of about 300 to about 4000 ng / mL, about 400 to about 1600 ng / mL, or about 600 to about 1200 ng / mL. In some embodiments, a loading dose can be administered for 1 to 5 days to achieve a steady-state blood or serum concentration of about 1200 to about 8000 ng / mL or about 2000 to about 4000 ng / mL. In some embodiments, a maintenance dose can be administered to achieve a steady-state concentration in the subject's blood or serum of about 300 to about 4000 ng / mL, about 400 to about 1600 ng / mL, or about 600 to about 1200 ng / mL.

[0342] In some embodiments, administration of the same composition can be repeated, and administration can occur at intervals of 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 prophylactic or therapeutic agent can be repeated, and administration can occur at intervals of 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.

[0343] In certain aspects, provided herein are unit dosage forms containing a compound or a pharmaceutically acceptable salt thereof in a form suitable for administration. Such forms are described in detail herein. In some embodiments, the unit dosage form contains 1-1000 mg, 5-250 mg, or 10-50 mg of the active ingredient. In certain embodiments, the unit dosage form contains about 1, 5, 10, 25, 50, 100, 125, 250, 500, or 1000 mg of the active ingredient. These dosage forms can be prepared according to techniques known to those skilled in the art.

[0344] Dosages can vary within a range depending on the dosage form used and the route of administration utilized. For any compound, the therapeutically effective amount or effective dose can be initially estimated by cell culture assays. The IC determined in cell culture media in skin with a birthmark, such as any of the birthmarks described herein, is 50 Doses can be formulated in animal models to achieve levels that include (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms). This information can be used to more accurately determine useful doses in humans. Additionally, plasma levels can be measured, for example, by high performance liquid chromatography, to confirm systemic exposure.

[0345] It should also be understood that the specific dosage and treatment regimen in any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, size of the lesion, number of lesions, general health, sex, diet, time of administration, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a soft MEK inhibitor, such as a soft MEK inhibitor described herein, in the composition will also depend on the particular soft MEK inhibitor in the composition.

[0346] In some embodiments, the topical, subcutaneous, intradermal, or intralesional amount is about 0.01 μg / cm 2 , about 0.05μg / cm 2 , about 0.1μg / cm 2 , about 0.15μg / cm 2 , about 0.2μg / cm 2 , about 0.3μg / cm 2 , about 0.4μg / cm 2 , about 0.5μg / cm 2 , about 0.6μg / cm 2 , about 0.7μg / cm 2 , about 0.8μg / cm 2 , or approximately 0.9 μg / cm 2 or about 0.01 to 0.03 μg / cm 2 , about 0.03~0.05μg / cm 2 , about 0.05~0.1μg / cm 2 , about 0.1~0.3μg / cm 2 , about 0.3~0.5μg / cm 2 , about 0.5~0.8μg / cm 2 , about 0.8~1.0μg / cm 2 , about 1~10μg / cm 2 , about 10~20μg / cm 2 , about 20~30μg / cm 2 , about 30~40μg / cm 2 , about 40~50μg / cm 2 , about 50~60μg / cm 2 , about 60~70μg / cm 2 , about 70~80μg / cm 2 , about 80~90μg / cm 2 , about 90~100μg / cm2 , about 100~125μg / cm 2 , about 125~150μg / cm 2 , about 150~175μg / cm 2 , about 175~200μg / cm 2 , about 200~250μg / cm 2 , about 250~300μg / cm 2 , about 300~350μg / cm 2 , about 350~400μg / cm 2 , about 400~450μg / cm 2 , about 450~500μg / cm 2 , about 500~550μg / cm 2 , about 550~600μg / cm 2 , about 600~650μg / cm 2 , about 650~700μg / cm 2 , about 700~750μg / cm 2 , about 750~800μg / cm 2 , about 800~850μg / cm 2 , about 850~900μg / cm 2 , about 900~950μg / cm 2 , or approximately 950-1000 μg / cm 2 is within the range.

[0347] In some embodiments, the topical, subcutaneous, intradermal, or intralesional amount is about 0.5-1.0 mg / cm 2 , 1.0-1.5mg / cm 2 , 1.5-2.0mg / cm 2 , 2.5-2.5mg / cm 2 , 3.0-3.5mg / cm 2 , 3.5-5.0mg / cm 2 , 5.0-7.5mg / cm 2 , 7.5-10mg / cm 2 , 1-10mg / cm 2 , about 10~20mg / cm 2 , about 20~30mg / cm 2 , about 30~40mg / cm 2 , about 40~50mg / cm 2 , about 50~60mg / cm 2 , about 60~70mg / cm2 , about 70~80mg / cm 2 , about 80~90mg / cm 2 , about 90~100mg / cm 2 , about 100~125mg / cm 2 , about 125~150mg / cm 2 , about 150~175mg / cm 2 , about 175~200mg / cm 2 , about 200~250mg / cm 2 , about 250~300mg / cm 2 , about 300~350mg / cm 2 , about 350~400mg / cm 2 , about 400~450mg / cm 2 , about 450~500mg / cm 2 , about 500~550mg / cm 2 , about 550~600mg / cm 2 , about 600~650mg / cm 2 , about 650~700mg / cm 2 , about 700~750mg / cm 2 , about 750~800mg / cm 2 , about 800~850mg / cm 2 , about 850~900mg / cm 2 , about 900~950mg / cm 2 , or approximately 950-1000 mg / cm 2 is within the range.

[0348] VI. Kits Also provided are kits for use in methods of treating bruises (e.g., MEK inhibitor-responsive or MEK-mediated bruises) when a subject is in need of bruise treatment. The kits can include a compound or composition provided herein, a second agent or composition, and instructions providing a healthcare provider with information regarding use to treat bruises (e.g., MEK inhibitor-responsive or MEK-mediated bruises). The instructions can be provided in printed form, or in the form of electronic media such as a floppy disk, CD, or DVD, or in the form of a website address from which such instructions can be obtained. A unit dose of a compound or composition or second agent or composition provided herein can include an amount such that, when administered to a subject, a therapeutically effective plasma level of the compound or composition can be maintained in the subject for at least one day. In some embodiments, the compound or composition can be included as a sterile aqueous pharmaceutical composition or a dry powder (e.g., lyophilized) composition.

[0349] In some embodiments, suitable packaging is provided.As used herein, "packaging" refers to the solid matrix or material that is conventionally used in systems and can hold the compound provided herein and / or the second agent suitable for administration to subject within a certain range.Such materials include glass and plastic (for example, polyethylene, polypropylene and polycarbonate) bottles, vials, paper, plastic, and plastic foil laminated packages, etc.When electron beam sterilization technology is used, packaging should have a sufficiently low density to allow sterilization of contents.

[0350] VII. Combination Therapy In some embodiments, the compounds and compositions provided herein are useful in methods for treating birthmarks (e.g., MEK inhibitor-responsive or MEK-mediated birthmarks), including the further administration of a second agent effective in treating the birthmark, when the subject is in need of such treatment. The second agent can be any agent known to those skilled in the art to be effective in treating skin disorders or diseases, including those currently approved by the U.S. Food and Drug Administration or other similar agencies in countries other than the United States.

[0351] In some embodiments, the compounds provided herein are administered in combination with one second agent. In further embodiments, the compounds provided herein are administered in combination with two second agents. In yet further embodiments, the compounds provided herein are administered in combination with two or more second agents.

[0352] In some embodiments, the method includes administering (e.g., topically, subcutaneously, intradermally, or intralesionally) to a subject in need thereof an amount of a compound effective to treat a bruise (e.g., a MEK inhibitor-responsive or MEK-mediated bruise) when the subject is in need of bruise treatment, in combination with a second agent effective to treat or prevent a bruise (e.g., a MEK inhibitor-responsive or MEK-mediated bruise) when the subject is in need of bruise treatment. The compound can be any compound described herein, and the second agent can be any second agent described in the art or herein. In some embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.

[0353] As used herein, the term "in combination" includes the use of more than one therapies (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 treatment (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), concurrently with, or after (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 treatment (e.g., a prophylactic or therapeutic agent) to a subject with a disorder.

[0354] As used herein, the term "synergistic" includes a combination of a compound provided herein with another therapy (e.g., a prophylactic or therapeutic agent) that has been or is currently being used to prevent, manage, or treat a disorder, which is more effective than the additive effect of the therapies. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may allow for the use of lower dosages of one or more therapies and / or less frequent administration of the therapy to a subject with a disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and / or administer the therapy less frequently reduces the toxicity associated with administering the therapy to a subject without reducing the effectiveness of the therapy in preventing or treating a disorder. Furthermore, a synergistic effect may result in improved efficacy of agents in preventing or treating a disorder. Finally, the 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 undesirable side effects associated with the use of either therapy alone.

[0355] The active compounds provided herein can be administered in combination or alternation with another therapeutic agent, particularly an agent effective in treating bruises (e.g., MEK inhibitor-responsive or MEK-mediated bruises) when the subject requires treatment for bruises. In combination therapy, effective dosages of two or more agents are administered together, whereas in alternation therapy or sequential step therapy, effective dosages of each agent are administered sequentially or sequentially. The dosage given depends on the absorption, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​also vary depending on the severity of the bruise to be alleviated. It should be further understood that for any particular subject, specific administration regimens and schedules should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0356] In some embodiments, the dosage of the second agent to be used in the combination therapy is provided herein. In some embodiments, a lower dosage than that which has been or is currently used to treat MEK inhibitor-responsive or MEK-mediated skin conditions is used in the combination therapy provided herein. The recommended dosage of the second agent can be obtained from the knowledge of those skilled in the art. For second agents approved for clinical use, the recommended dosage can be found, for example, in 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 is incorporated herein by reference in its entirety.

[0357] The present disclosure provides combination treatments by administering a MEK inhibitor, e.g., a soft MEK inhibitor, described herein with one or more additional agents. In some embodiments, the one or more additional agents are selected from the following: Agents to treat acne (e.g., Accutane, azelaic acid, benzoyl peroxide, salicylic acid); analgesics (e.g., acetaminophen, capsaicin), such as Cox2 inhibitors, e.g., celecoxib); Anesthetics (e.g., benzocaine, benzocaine / menthol, dibucaine, diperodone, lidocaine, lidocaine / prilocaine, pramoxine); anti-infective drugs (e.g., crotamiton); antipruritic drugs (e.g., ammonium lactate, benzocaine, ascomycin macrolactams, e.g., pimecrolimus); antipruritic / 5HT3 receptor antagonists (e.g., ondansetron); antibiotics (e.g., clindamycin, doxycycline, erythromycin, tetracycline); anticholinergic antiemetics (e.g., diphenhydramine); antifibrotic drugs (e.g., collagenase, pirfenidone); Antihistamines (e.g., triprolidine (Actifed®), fexofenadine (Allergra®, Allegra® D-12, Allegra®-24), Astepro / Astelin nasal spray (azelastine) (Dymista®), hydroxyzine hydrochloride (Atarax®), diphenhydramine hydrochloride (Benadryl®), brompheniramine (Dimetapp® Cold and Allergy Elixir), Zyrtec® (cetirizine), Chlor-Trimeton® (chlorpheniramine), desloratadine (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®), levocetirizine (Xyzal®); Mast cell stabilizers (e.g., β2-adrenergic agonists, cromoglycate, cromolyn sodium, Gastrocrom®, ketotifen, methylxanthines, omalizumab, pemirolast, quercetin, ketotifen (Zaditen®); Anti-inflammatory drugs (e.g., NSAIDs (e.g., aspirin, choline salicylate and magnesium salicylate), diclofenac potassium (Cataflam®), diclofenac sodium (Voltaren®, Voltaren® XR), diclofenac sodium misoprostol (Arthrotec®), diflunisal (Dolobid®), etodolac (Lodine®, Lodine® XL), fenoprofen calcium (Nalfon®), Trademark), 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 inhibitors (e.g., sunitinib); alkylating agents (e.g., dacarbazine, carboplatin); CDK 4 / 6 inhibitors (e.g., LEE011); PKC inhibitors (e.g., AEB071); MAPK inhibitors (e.g., RAS inhibitors / farnesyltransferase inhibitors (e.g., tipifarnib), Raf kinase inhibitors (e.g., sorafenib (BAY 43-9006, Nexavar), vemurafenib, dabrafenib, LGX818, TAK-632, MLN2480, PLX-4720), ERK inhibitors (e.g., SCH772984, VTX11e); BRAF inhibitors (e.g., vemurafenib, dabrafenib); PI3K inhibitors (e.g., LY294002); AKT inhibitors (e.g., MK 2206); PI3K / AKT inhibitors (e.g., bupallisib, cizutumumab); 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 inhibitors (e.g., ranibizumab (Lucentis®), cediranib); immune response modifiers (e.g., topical imiquimod, interferon, PEG-interferon); calcium channel blockers (e.g., Avocil (Mederma) / 15% verapamil, separate vitamin D, doxycycline injection); statins (e.g., lovastatin, methotrexate, vinblastine, pregabalin, temozolomide, PLX3397); HDAC inhibitors (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, augmented betamethasone dipropionate, budesonide, clobetasol propionate, cortisone, desonide, dexamethasone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halobetasol propionate, halcinonide, 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 (topical Levulan Kerastick + light), electrodesiccation (ED), YAG laser).

[0358] In various embodiments, the therapeutic agents (e.g., a compound provided herein and a second agent) are administered at intervals of less than 5 minutes, less than 30 minutes, 1 hour, about 1 hour, about 1 hour to about 2 hours, about 2 hours to about 3 hours, about 3 hours to about 4 hours, about 4 hours to about 5 hours, about 5 hours to about 6 hours, about 6 hours to about 7 hours, about 7 hours to about 8 hours, about 8 hours to about 9 hours, about 9 hours. The therapeutic agents may be administered at intervals of about 10 hours, about 10 hours to about 11 hours, about 11 hours to about 12 hours, about 12 hours to 18 hours, 18 hours to 24 hours, 24 hours to 36 hours, 36 hours to 48 hours, 48 ​​hours to 52 hours, 52 hours to 60 hours, 60 hours to 72 hours, 72 hours to 84 hours, 84 hours to 96 hours, or 96 hours to 120 hours. In various embodiments, the therapeutic agents are administered at intervals of 24 hours or less or 48 hours or less. In some embodiments, two or more therapeutic agents are administered within the same patient visit. In some embodiments, the compound provided herein and the second agent are administered simultaneously.

[0359] In some embodiments, the compound provided herein and the second agent are administered about 2-4 days apart, about 4-6 days apart, about 1 week apart, about 1-2 weeks apart, or more than 2 weeks apart.

[0360] In some embodiments, administration of the same agent can be repeated and administration can occur at intervals of 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 can be repeated and administration can occur at intervals of 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.

[0361] In some embodiments, the compound provided herein and the second agent are administered to a patient, in some embodiments a mammal, for example, a human, in an order and time interval that allows them to act together to provide increased benefit compared to when the compound provided herein and the other agent are administered separately.In some embodiments, the second active substance can be administered simultaneously or at different times in any order, but if not administered simultaneously, they should be administered with a sufficiently short time interval to achieve the desired therapeutic or prophylactic effect.In some embodiments, the compound provided herein and the second active substance exert their effects at overlapping times.Each second active substance can be administered separately in any suitable form and by any suitable route.In some embodiments, the compound provided herein is administered before, simultaneously with, or after the administration of the second active substance.

[0362] In some embodiments, the compound provided herein and the second agent are administered to patients in cycles. Cycling therapy involves administering a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by administering a second agent and / or a third agent (e.g., a second and / or a 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 therapeutic agents, avoid or reduce one or more side effects of a therapeutic agent, and / or improve the effectiveness of treatment.

[0363] In some embodiments, the compound provided herein and the second active agent are administered in cycles of about once every three weeks, about once every two weeks, about once every ten days, or about once a week. One cycle can include administration of the compound provided herein and the second agent by infusion over about 90 minutes per cycle, about 1 hour per cycle, or about 45 minutes per cycle. Each cycle can include at least one week of rest, at least two weeks of rest, or at least three weeks of rest. The number of cycles performed is about 1 to about 12 cycles, more typically about 2 to about 10 cycles, and more typically about 2 to about 8 cycles.

[0364] In some embodiments, the treatment process is carried out simultaneously for patients, that is, each dose of the second agent is administered separately, but within a time interval that allows the compound provided herein to act together with the second active substance.In some embodiments, one component can be administered once a week, and other components can be administered once every two weeks or once every three weeks.In other words, even if the therapeutic agents are not administered at the same time or on the same day, the administration regimen will be carried out simultaneously.

[0365] The second agent may act additively or synergistically with the compound provided herein. In some embodiments, the compound provided herein is administered simultaneously with one or more second agents in the same pharmaceutical composition. In some embodiments, the compound provided herein is administered simultaneously with one or more second agents in separate pharmaceutical compositions. In some embodiments, the compound provided herein is administered before or after the administration of the second agent. The administration of the compound provided herein and the second agent by the same or different administration routes, for example, oral and parenteral routes, is also contemplated. In some embodiments, when the compound provided herein is administered simultaneously with a second agent that potentially causes one or more adverse side effects, including but not limited to toxicity, it may be advantageous to administer the second active substance at a dose below the threshold that induces adverse side effects. [Example]

[0366] VIII. Working Examples General synthesis method The compounds provided herein can be prepared, isolated or obtained by any method that is obvious to those skilled in the art.The compounds provided herein can be prepared according to the exemplary preparation schemes provided below.The reaction conditions, steps and reactants that are not provided in the exemplary preparation schemes will be obvious and known to those skilled in the art.The symbols and conventions used in these processes, schemes and examples used herein are consistent with those used in modern scientific literature, for example, Journal of the American Chemical Society or Journal of Biological Chemistry, regardless of whether specific abbreviations are specifically defined. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimolar); μM (micromolar); Hz (Hertz); MHz (Megahertz); mmol (millimolar); hr or hrs (hours); min (minutes); MS (Mass Spectrometry); ESI (Electrospray Ionization); TLC (Thin Layer Chromatography); HPLC (High Pressure Liquid Chromatography); THF (Tetrahydrofuran); CDCl3 (Deuterated Chloroform); AcOH (Acetic Acid); DCM (Dichloromethane); DMSO (Dimethyl Sulfoxide); DMSO-d6 (Deuterated Dimethyl Sulfoxide); EtOAc (Ethyl Acetate); MeOH (Methanol); Tces (2,2,2-Trichloroethoxysulfonyl); -Si(tert-Bu)(Ph)2 and -Si t BuPh2 (tert-butyl-diphenylsilyl); and BOC (t-butyloxycarbonyl).

[0367] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be used. Unless otherwise specified, all temperatures are in degrees Celsius. All reactions are carried out at room temperature unless otherwise specified. The synthetic methods exemplified herein are intended to illustrate the applicable chemistry through the use of specific examples and are not indicative of the scope of the present disclosure.

[0368] Compounds of formula (I) Compounds of formula (Ia) can be prepared according to Scheme I-1, as shown in FIG. 7, where R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 and X is an N-linked heterocycloalkyl substituted with 1 , R 2 , R 2a , R 13 , R 13a , R 4 , R 5 , R 5a , R 5b and R 6 is as defined in any aspect, embodiment, or claim described herein. In some embodiments, R 13 and R 13a are hydrogen atoms.

[0369] Starting from a commercially available or routinely obtainable acid of formula (I-101) and a commercially available or routinely obtainable aniline of formula (I-102), compounds of formula (I-103) can be prepared by methods readily apparent to those skilled in the art. The acid-containing compound of formula (I-103) can be activated with a number of reagents readily apparent to those skilled in the art to produce a compound having a suitable leaving group attached to the carbonyl of the C(O)OH acid group, for example, an acid chloride produced from reaction of (I-103) with thionyl chloride or an activated ester produced from reaction of (I-103) with a reagent such as EDCI or HOBt. The acid chloride or activated ester can then be converted to a compound of formula R 4 OH, HNR 5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof to produce a compound of formula (Ia).

[0370] Compounds of formula (Ia) can be prepared according to Scheme I-2, as shown in FIG. 8, where R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 is an N-linked heterocycloalkyl substituted with R 2 is iodine; R 13b is fluoro; R 2a , R 13 , R 13a , R 4 , R 5 , R 5a , R 5b and R 6 is as defined in any aspect, embodiment, or claim described herein. In some embodiments, R 13and R 13a are hydrogen atoms.

[0371] Starting from a commercially available or routinely obtainable acid of formula (I-104) and a commercially available or routinely obtainable aniline of formula (I-105), compounds of formula (I-106) can be prepared by methods readily apparent to those skilled in the art. Compounds of formula (I-106) are then treated with Zn(CN) in the presence of a catalyst such as Pd(PPh) . Compounds of formula (I-108) are prepared by treating I-107 with iodine in the presence of silver trifluoroacetate or iodine monochloride. Acid-containing compounds of formula (I-108) can be activated using a number of reagents readily apparent to those skilled in the art to produce compounds bearing a suitable leaving group attached to the carbonyl of the C(O)OH acid group, such as an acid chloride produced by reaction of I-108 with thionyl chloride, or an activated ester produced by reaction of I-108 with a reagent such as EDCI or HOBt. The acid chloride or activated ester is then reacted with a compound of formula R 4 OH, HNR 5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof, to form R 2 is iodine, and R 13b Compounds of formula (Ia) can be produced in which is fluoro.

[0372] Compounds of formula (Ib) can be prepared according to Scheme I-3, as shown in FIG. 9, where R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6is an N-linked heterocycloalkyl substituted with R 2 is iodine; R 3b is fluoro; R 2a , R 13 , R 13a , R 4 , R 5 , R 5a , R 5b and R 6 is as defined in any aspect, embodiment, or claim described herein. In some embodiments, R 13 and R 13a are each hydrogen. In some embodiments, R 3 is hydrogen and R 13a is fluoro.

[0373] Starting from a commercially available or routinely obtainable acid of formula (I-109) and a commercially available or routinely obtainable aniline of formula (I-105), a compound of formula (I-110) can be prepared by methods apparent to those skilled in the art. Alternatively, the compound of formula (I-110) can be converted to a methyl ester of formula (I-111) by methods known in the art. The compound of formula (I-110) or formula (I-111) is then treated with Zn(CN) in the presence of a catalyst such as Pd(PPh). The compound of formula (I-114) or formula (I-115) is prepared by treating the compound of formula (I-110) or formula (I-111) with iodine in the presence of silver trifluoroacetate or with iodine monochloride. In the case of the compound of formula (I-115), the methyl ester is then hydrolyzed to the corresponding acid. The acid-containing compound of formula (I-114) can be activated with a number of reagents readily apparent to those skilled in the art to produce a compound having a suitable leaving group attached to the carbonyl of the C(O)OH acid group, for example, an acid chloride produced from reaction of (I-114) with thionyl chloride or an activated ester produced from reaction of (I-114) with a reagent such as EDCI or HOBt. The acid chloride or activated ester can then be converted to a compound of formula R 4 OH, HNR5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof to produce a compound of formula (Ib).

[0374] Compound of formula (II) Compounds of formula (II) can be prepared according to any one of Schemes II-1, II-2, II-3, II-4, and II-5, as shown in Figures 10-14, respectively. As shown in Schemes II-1, II-2, II-3, II-4, and II-5, R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 and X is an N-linked heterocycloalkyl substituted with 2 , R 2 , R 2a , R 23 , R 23a , R 23b , R 4 , R 5 , R 5a , R 5b and R 6 is as defined in any aspect, embodiment or claim described herein. In some embodiments, X 2 is methyl. In some embodiments, X 2 is methyl and R 23 and R 23b are hydrogen, and R 23a is fluoro, methyl, or methoxy. 2 is methyl and R 23 , R 23a and R 23b are hydrogen atoms.

[0375] Compounds of formula (II) can be prepared according to Scheme II-1 shown in Figure 10, starting from commercially available intermediate (II-101). Compounds of formula (II-102) can be prepared by the reaction of X of intermediate (II-101). 2 The compound of formula (II-103) can be prepared by alkylation with -LG, where LG is a suitable leaving group. The compound of formula (II-103) can be prepared by methods readily apparent to those skilled in the art and is converted to a compound of formula (II-104) by iodination. The compound of formula (II-104) is then reacted with aniline in the presence of a Pd catalyst to give a compound of formula (II-105). The compound of formula (II-106) is prepared by treating (II-106) with iodine in the presence of silver trifluoroacetate or with iodine monochloride. The acid-containing compound of formula (II-106) can be activated using a number of reagents readily apparent to those skilled in the art to produce a compound with a suitable leaving group attached to the carbonyl of the C(O)OH acid group, for example, the acid chloride produced from the reaction of (II-106) with thionyl chloride. The acid chloride can then be converted to a compound of formula R 4 OH, HNR 5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof, to form R 2 Compounds of formula (II) can be produced in which is iodo.

[0376] Compounds of formula (II) can be prepared according to Scheme II-2 shown in Figure 11 starting from commercially available or readily obtainable intermediates of formula (II-107). Compounds of formula (II-108) can be prepared by the reaction of X of intermediate (II-107). 2The compound of formula (II-109) can be prepared by alkylation with -LG, where LG is a suitable leaving group. Compounds of formula (II-109) can be prepared by methods obvious to those skilled in the art by chlorination. Compounds of formula (II-109) are then reacted with aniline to give compounds of formula (II-110), which are further converted to acids of formula (II-111). The acid-containing compound of formula (II-111) can be activated with a number of reagents obvious to those skilled in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(O)OH acid group, for example, the acid chloride produced from the reaction of (II-111) with thionyl chloride. The acid chloride can then be converted to a compound of formula R 4 OH, HNR 5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof to produce a compound of formula (II).

[0377] Compounds of formula (II) can be prepared according to Scheme II-3 shown in Figure 12, starting from commercially available or readily obtainable intermediates of formula (II-107). Compounds of formula (II-108) can be prepared by reacting X of intermediate (II-107). 2The compound of formula (II-112) can be prepared by alkylation with -LG, where LG is a suitable leaving group. Compounds of formula (II-112) can be prepared by methods obvious to those skilled in the art by hydrolysis of the nitrile group to an acid, protection of the acid group, and chlorination. Compounds of formula (II-112) are then reacted with aniline to give compounds of formula (II-113), which are further hydrolyzed to acids of formula (II-114). The acid-containing compounds of formula (II-114) can be activated using a number of reagents obvious to those skilled in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(O)OH acid group, such as the acid chloride produced from the reaction of (II-114) with thionyl chloride. Alternatively, compounds of formula (II-113) can be directly converted to acid chlorides or activated esters, as described in Schemes II-4 or II-5. The acid chlorides or activated esters can then be converted to compounds of formula R 4 OH, HNR 5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof to produce a compound of formula (II).

[0378] Compounds of formula (II) can be prepared according to Scheme II-4 shown in Figure 13, starting from a commercially available or readily obtainable intermediate of formula (II-115). Intermediate (II-116), prepared by N-alkylation on the pyrrole nitrogen of (II-115), is readily converted to the trifluoromethyl ketone intermediate (II-117), which is hydrolyzed to the corresponding acid (II-118) and converted to the tert-butyl ester (II-119) by esterification using methods obvious to those skilled in the art. Treatment of (II-119) with a base such as LDA, followed by chlorination at the 2-position of intermediate (II-119) with a chlorinating agent such as perchloroethane, affords the chlorinated intermediate (II-120). Displacement of the chlorine of intermediate (II-120) with an appropriate aniline in the presence of base gives intermediate (II-121), which can be easily converted to the corresponding acid chloride (II-122) by treatment with thionyl chloride with or without the addition of 4N HCl in dioxane (J. Org. Chem., 2017, 82(6), pp3245-3251). Alternatively, intermediate (II-122) can be converted to an activated ester by treatment with an alcohol such as pentafluorophenol. The acid chloride or activated ester can then be converted to a compound of formula R 4 OH, HNR 5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof to produce a compound of formula (II).

[0379] Furthermore, compounds of formula (II) can be prepared by the synthetic route shown in Scheme II-5, as shown in Figure 14. Nitrile (II-108), prepared by N-alkylation on the pyrrole nitrogen of (II-107), can be hydrolyzed to the corresponding acid and esterified to form t-butyl ester (II-120). Compounds of formula (II) can then be prepared according to the sequence in Scheme II-4.

[0380] Compound of formula (III) Compounds of formula (IIIa) can be prepared according to Schemes III-1 or III-2, as shown in Figures 15-16, respectively. As shown in Schemes III-1 or III-2, R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 is an N-linked heterocycloalkyl substituted with R 2 , R 2a , R 33 , R 33a , R 33b , R 4 , R 5 , R 5a , R 5b and R 6 is as defined in any aspect, embodiment, or claim described herein. In some embodiments, R 33a and R 33b are hydrogen, and R 33 is fluoro, methyl, or methoxy. In some embodiments, R 33 and R 33b are hydrogen, and R 33a is fluoro, methyl, or methoxy. In some embodiments, R 33 and R 33a are hydrogen, and R 33b is fluoro, methyl, or methoxy. 2 is methyl and R33 , R 33a and R 33b are hydrogen atoms.

[0381] Compounds of formula (IIIa) can be prepared according to Scheme III-1, as shown in Figure 15. Starting from commercially available or routinely obtainable substituted phenyl isothiocyanates (III-101) and intermediates (III-102), intermediates (III-103) can be prepared by methods readily apparent to those skilled in the art. Intermediate (III-103) can be readily hydrolyzed to intermediate (III-104) by contact with a suitable acid, such as hydrochloric acid or trifluoroacetic acid, in a suitable solvent, such as dichloromethane or dioxane. The acid intermediate (III-104) can be activated with a number of reagents readily apparent to those skilled in the art to produce compounds bearing a suitable leaving group attached to the carbonyl, for example, an acid chloride, generated from reaction of (III-104) with thionyl chloride, or an activated ester, generated from reaction of (III-104) with a reagent such as EDCI or HOBt. The acid chloride or activated ester can then be converted to a compound of formula R 4 OH, HNR 5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof to produce a compound of formula (IIIa).

[0382] Alternatively, R 2 The compound of formula (IIIa) in which R is a C2-C6 alkynyl group can be prepared according to Scheme III-2 as shown in FIG. 2can be prepared from a compound of formula (IIIa) (i.e., formula III-105) in which is initially an iodo group. The conversion of the aromatic iodo group to an alkyne can be achieved using reaction conditions similar to those published in Journal of Medicinal Chemistry 2007, 50, 5090-5102. Intermediate (IIIa-107) can be converted to a compound of formula (IIIa) using the procedures described herein and above for Scheme III-1.

[0383] Compound of formula (IV) Compounds of any one of formulas (IVa), (IVb), and (IVc) can be prepared according to Scheme IV-1, as shown in FIG. 17, where R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 is an N-linked heterocycloalkyl substituted with R 2 , R 2a , R 43a , R 4 , R 5 , R 5a , R 5b , R 6 , R 46 , R 48 and R 48a is as defined in any aspect, embodiment or claim described herein.

[0384] Starting from commercially available or routinely obtainable aniline of formula (IV-101) and thiophosgene, intermediate (IV-102) can be prepared by methods obvious to those skilled in the art. Intermediate (IV-102) can be readily condensed with intermediate of formula (IV-103) in the presence of a base and a solvent, followed by treatment with intermediate of formula (IV-104) to give intermediate of formula (IV-105). Intermediate (IV-105) is then hydrolyzed by contact with a suitable base, such as LiOH, in a suitable solvent, such as THF and / or ethanol and / or water, to give intermediate (IV-106). The acid intermediate (IV-106) can be activated with a number of reagents readily apparent to those skilled in the art to produce a compound having a suitable leaving group attached to the carbonyl, such as an acid chloride produced from reaction of intermediate (IV-106) with thionyl chloride or an activated ester produced from reaction of intermediate (IV-106) with a reagent such as EDCI or HOBt. The acid chloride or activated ester can then be converted to a compound of formula R 4 OH, HNR 5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof, to form R 43 is cyano, -C(O)NR 48 R 48a or -C(O)R 46 Any one of formulas (IVa), (IVb) and (IVc) can be produced, wherein

[0385] R 3a and R 3Compounds of formula (IV), e.g., compounds of formula (IVe-1), in which R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 is an N-linked heterocycloalkyl substituted with R 2a , R 4 , R 5 , R 5a , R 5b and R 6 is as defined in any aspect, embodiment, or claim described herein. In some embodiments, R 2a is fluoro.

[0386] Starting from a commercially available or routinely obtainable compound of formula (IV-108) and a commercially available or routinely obtainable aniline of formula (IV-109), a compound of formula (IV-110) can be prepared by methods readily apparent to those skilled in the art. Compounds of formula (IV-111) are prepared by treating (IV-110) with iodine in the presence of silver trifluoroacetate or with iodine monochloride. Compounds of formula (IV-111) are then subjected to ester hydrolysis to yield acid-containing compounds of formula (IV-112). The acid group of compound (IV-112) can be activated using a number of reagents readily apparent to those skilled in the art to produce compounds with a suitable leaving group attached to the carbonyl of the C(O)OH acid group, such as an acid chloride produced from reaction of (IV-112) with thionyl chloride or an activated ester produced from reaction of (IV-112) with a reagent such as EDCI or HOBt. The acid chloride or activated ester is then reacted with a compound of formula R 4 OH, HNR5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof, to form R 2 Similarly, compounds of formula (IVe-1) can be prepared in which R 2 Compounds of any one of formulae (IVd-1), (IVd-2) and (IVe-2), in which is iodo, can be prepared according to Scheme IV-2 starting from the corresponding starting material.

[0387] Compounds of formula (IVa) can be prepared according to Scheme IV-3, as shown in Figure 19, where R 1 -OR 4 , -NR 5 R 5a , -N(OR 5b )R 5a or unsubstituted or one or two R 6 is an N-linked heterocycloalkyl substituted with R 2a , R 43a , R 4 , R 5 , R 5a , R 5b and R 6 is as defined in any aspect, embodiment, or claim described herein. In some embodiments, R 2a is fluoro. In some embodiments, R 43a is methyl.

[0388] Starting from a commercially available or routinely obtainable compound of formula (IV-113), a compound of formula (IV-115) can be prepared by methods known in the art. From a compound of formula (IV-115) and a commercially available or routinely obtainable aniline of formula (IV-109), a compound of formula (IV-116) can be prepared by methods obvious to those skilled in the art. A compound of formula (IV-117) is prepared by treating (IV-116) with iodine in the presence of silver trifluoroacetate or with iodine monochloride. The compound of formula (IV-117) is then subjected to ester hydrolysis to obtain an acid-containing compound of formula (IV-118). The acid group of compound (IV-118) can be activated with a number of reagents readily apparent to those skilled in the art to produce compounds bearing a suitable leaving group attached to the carbonyl of the C(O)OH acid group, such as an acid chloride produced from reaction of (IV-118) with thionyl chloride or an activated ester produced from reaction of (IV-118) with a reagent such as EDCI or HOBt. The acid chloride or activated ester can then be converted to a compound of formula R 4 OH, HNR 5 R 5a , HN(OR 5b )R 5a , R a -H(wherein, R a is unsubstituted or contains one or two R 6 or a suitable protected form thereof, to form R 2 Compounds of formula (IVa) can be produced in which is iodo.

[0389] Compound of formula (V) Compounds of formula (Va) can be prepared according to Scheme V-1, as shown in Figure 20, where subscript n is 0; 51 HA-OR 54 Other than but containing -OH; R 2 , R 2a , R 51 , R 53a and R 53bis as defined in any aspect, embodiment, or claim described herein. In some embodiments, R 53a and R 53b are hydrogen atoms.

[0390] Starting from commercially available or routinely obtainable pyridine of formula (V-101) and commercially available methyl chloroformate, the compound of formula (V-102) can be prepared by methods obvious to those skilled in the art. The compound of formula (V-102) is then reacted with a compound of formula (V-103) in the presence of CsCO and a catalyst such as PdXPhos G2, which is prepared from pinacolborane and ethyl vinyl ether. Cyclization of the compound of formula (V-104) under acidic conditions gives the intermediate of formula (V-105). The compound of formula (V-105) can be prepared from commercially available or routinely obtainable R 51 Various amines or protected amines of NH can be reacted with the intermediate of formula (V-105) to give compounds of formula (V-106). Compounds of formula (Va) can be prepared by coupling the compound of formula (V-106) with commercially available or routinely obtainable anilines, followed by optional deprotection, by methods obvious to those skilled in the art. 51 In some embodiments of compounds of Formula (Va) where R is HOC(O)-C1-C6 alkyl, after further activation of the -C(O)OH group by methods known in the art, these compounds can be converted to R 51 R 7 is converted to a compound of formula (Va), which is C(O)—C1-C6 alkyl.

[0391] Compounds of formula (Va) can be prepared according to Scheme V-2, as shown in Figure 21, where subscript n is 0; 51 HA-OR 54 and;R 2 , R 2a , R 53a , R 53b and R 54is as defined in any aspect, embodiment, or claim described herein. In some embodiments, R 53a and R 53b are hydrogen atoms.

[0392] Starting from a common intermediate of formula (V-104) shown in Scheme V-1, commercially available or routinely obtainable R 54 Various hydroxyamines or protected hydroxyamines of ONH2 can be reacted with compounds of formula (V-104) to give compounds of formula (V-107). Cyclization of compounds of formula (V-107) under base gives compounds of formula (V-108) (R 51 (Note that any ester group in R is also hydrolyzed to the corresponding acid.) Compounds of formula (Va) can be prepared by coupling a compound of formula (V-108) with a commercially available or routinely obtainable aniline, followed by optional deprotection, by methods readily apparent to those skilled in the art. 51 -OR 54 and R 54 In some embodiments of compounds of Formula (Va) where R is HOC(O)-C1-C6 alkyl, after further activation of the C(O)OH group by methods known in the art, these compounds can be converted to R 51 -OR 54 and R 54 R 7 In some embodiments, R 51 When is -OH, the corresponding compound of formula (Va) is prepared according to Scheme V-1.

[0393] Compounds of formula (Vb) can be prepared according to Scheme V-3, as shown in Figure 22, where subscript n is 0; 51 , R 2 , R 2a , R 53a and R 53bis as defined in any aspect, embodiment, or claim described herein. In some embodiments, R 53a and R 53b are hydrogen atoms.

[0394] Starting from a common intermediate of formula (V-104) shown in Scheme V-1, commercially available or routinely obtainable R 51 Various amines, hydroxyamines, protected amines, or protected hydroxyamines of NH can be reacted with compounds of formula (V-104) to give compounds of formula (V-109). Reductive cyclization of compounds of formula (V-109) in the presence of a reducing agent (e.g., NaCNBH) gives compounds of formula (V-110) (R 51 (Note that the ester group in R is also hydrolyzed to the corresponding acid.) Compounds of formula (Va) can be prepared by coupling a compound of formula (V-110) with a commercially available or routinely obtainable aniline, followed by optional deprotection, by methods readily apparent to those skilled in the art. 51 is HOC(O)-C1-C6 alkyl or -OR 54 and R 54 In some embodiments of compounds of Formula (Va) where R is HOC(O)-C1-C6 alkyl, after further activation of the C(O)OH group by methods known in the art, these compounds can be converted to R 51 R 7 C(O)-C1-C6 alkyl or -OR 54 and R 54 R 7 is converted to a compound of formula (Ia), which is C(O)—C1-C6 alkyl.

[0395] Using the exemplary preparative schemes provided herein and procedures known to one of ordinary skill in the art, the compounds in Tables 1-5 can be prepared.

[0396] Example 1: Human birthmark explant protocol This study establishes an in vitro birthmark explant model.

[0397] Study Objectives: The primary objective was to evaluate the efficacy of topically formulated compounds described herein in suppressing p-ERK, a downstream biomarker of RAS / MAPK signaling, in epidermal and sebaceous nevi. A secondary objective was to evaluate the permeability (when the compounds are applied topically) of birthmark explants treated with the compounds described herein.

[0398] Sample Collection and Eligibility: Discarded human birthmark (epidermal nevi and sebaceous nevi) samples were obtained from the Stanford Surgery Clinic using an approved human subjects protocol (Stanford IRB#18325). Specimens were identified under the direction of the investigator and placed in cell growth medium (DMEM / F12 containing penicillin / streptomycin (0.1%); fungizone (40 μg / mL); B27 (without vitamin A)).

[0399] Patients had the following data to be enrolled in the study: Patients must be over 18 years of age. The specimen must be a bruise at least 6 mm in size. The specimen is excised by slicing, punch biopsy or elliptical excision. Patients cannot receive chemotherapy treatment at the time of biopsy.

[0400] Study Procedures The samples were primary, untreated birthmarks at least 6 mm in size, excised by slicing, punch biopsy, or elliptical excision. The specimens were identified under the direction of the investigator. The specimens were minced into 2 mm fragments and placed in a 24-well plate containing cell growth medium (DMEM / F12 containing penicillin / streptomycin (0.1%); fungizone (40 μg / mL); and B27 (without vitamin A)) and submerged in the drug-containing medium. For topical gel application, the specimens were placed in a 96-well plate with the epidermal surface exposed to air.

[0401] For the data presented in Figure 1, explant samples were immersed in culture medium and 5 μL of Compound No. 2.003 in 100% DMSO was added to the medium to achieve the indicated concentration of 5 μM. Samples were harvested at 4 hours, one half was snap frozen in liquid nitrogen, and one half was fixed in 10% formalin and paraffin-embedded for histological analysis.

[0402] For the data presented in Figures 3 and 4, topical gel formulations of trametinib, Compound No. 2.003, Compound No. 4.029, or vehicle-only gel formulations were applied topically to the surface of birthmark explants for 4 hours for analysis. The gel formulation was 1% hydroxypropyl cellulose in DMSO / PEG 400 1:1 (v / v), and the test compound was 1% by weight in the gel formulation. Samples were collected at 4 hours for analysis. The collected tissues were bisected, one half flash frozen, and the other half fixed in 10% formalin and embedded in paraffin for further analysis.

[0403] For the data provided in Figure 5, a gelled topical gel formulation of Compound 2.003 or a vehicle-only gel formulation was applied topically to the surface of birthmark explants for 4 hours for analysis. The gel formulation was 1.5% hydroxypropyl cellulose in a base formulation, and the test compound was 0.01% by weight of the base formulation. The composition of the base formulation is listed below. Samples were collected at 4 hours for analysis. The collected tissue was bisected, one half flash frozen, and the other half fixed in 10% formalin and embedded in paraffin for further analysis. TIFF0007651101000078.tif68128

[0404] For the data presented in Figure 6, three gelled topical gel formulations of Compound 2.003 at different concentrations or vehicle-only gel formulations were applied topically to the surface of birthmark explants for 4 hours for analysis. The gel formulations were 1.5% hydroxypropyl cellulose in the base formulation as shown above, and the test compound was 0.01%, 0.15%, or 1.00% by weight of the base formulation. Samples were collected at 4 hours for analysis. The collected tissues were bisected, one half flash frozen, and the other half fixed in 10% formalin and embedded in paraffin for further analysis.

[0405] Western blot analysis: For immunoblotting, whole skin biopsies were lysed in lysis buffer and Western blots were performed. Antibodies used for immunoblotting included rabbit anti-phospho-p44 / 42 MAPK (1:3000, Cell Signaling), rabbit anti-p44 / 42 MAPK (1:3000, Cell Signaling), rabbit anti-phospho-Mek1 / 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 to HRP (1:40,000, Jackson ImmunoResearch).

[0406] Immunohistochemistry: Immunohistochemistry was performed on 5 μm paraffin sections. Antigen retrieval was performed by enzyme treatment (1:1000) using standard protocols. The antibody used was rabbit p-ERK (Cell Signaling, 4307S, 1:100). Bond Polymer Refine anti-rabbit HRP Detection (Leica Biosystems) was used according to the manufacturer's protocol. Sections were then counterstained with hematoxylin, dehydrated, and coverslipped using TissueTek-Prisma and Coverslipper (Sakura).

[0407] Data Analysis: Semi-quantitative Western blots were used to assess differences in p-ERK in samples treated with compounds described herein compared to vehicle controls.

[0408] Study Administration: This study was conducted under IRB oversight with patient informed consent and HIPAA certification.

[0409] Example 2: MEK Inhibition Assay-1 Biochemical activity can be measured using the following procedure. The MEK1 inhibitory activity of compounds was 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. reagent: Reaction buffer: 20mM Hepes (pH 7.5), 10mM MgCl2, 1mM EGTA, 0.02% Brij35, 0.02mg / mL BSA, 0.1mM Na3VO4, 2mM DTT, 1% DMSO Enzyme: MEK1, Invitrogen Catalog No. PV3303 N-terminal His-tagged recombinant human full-length protein, expressed in insect cells. In vitro activated by RAF1. MW=49.2 kDa, GenBank accession number NP_002746. Substrate: 5 μM ERK2(K52R), kinase-dead mutant, (GenBank accession number NM_0011949), N-terminally His6-tagged aa2-358, MW=43.63 kDa, expressed in E. coli.

[0410] A substrate solution was prepared in freshly prepared reaction buffer. The kinase was added to the substrate solution and mixed gently. A 100% DMSO solution of the test compound was added to the kinase reaction mixture using ultrasonic technology (Echo550; nanoliter range) and incubated at room temperature for 20 minutes. 33 The reaction was initiated by adding P-ATP to the reaction mixture. The reaction mixture was incubated at room temperature for 2 hours. Kinase activity was detected by the P81 filter binding method.

[0411] Example 3: MEK Inhibition Assay-2 Compounds were tested for MEK1 inhibitory activity 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%20assay%20conditions.pdf): The Z'-LYTE biochemical assay (ThermoFisher) uses a fluorescence-based coupled enzyme format and is based on the differential susceptibility of phosphorylated and non-phosphorylated peptides to proteolytic cleavage.

[0412] Wells were screened with 100% DMSO solutions of test compounds in 1% DMSO (final). 3-fold serial dilutions were made in a 10-point titration from a starting concentration of 30 μM.

[0413] The peptide / kinase mixture, i.e., MAP2K1 (MEK1) / inactive MAPK1 (ERK2) / Ser / Thr O3 ("peptide / kinase mixture"), was diluted to 2x working concentration in the following buffer ("kinase buffer"): 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. The final 10 μL kinase reaction solution consisted of 0.06–0.25 ng of MAP2K1 (MEK1), 105 ng of inactive MAPK1 (ERK2), and 2 μM Ser / Thr O3 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. After 1 h of incubation, 5 μL of a 1:1024 dilution of Chromogen Reagent A (available from Invitrogen, catalog number PV3295) was added.

[0414] The ATP solution was diluted to a 4x working concentration in kinase buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl, 1 mM EGTA). The apparent Km of ATP was previously determined using the Z'-LYTE assay. The color reagent was diluted in color development buffer (available from Invitrogen, catalog number P3127).

[0415] Assay protocol: 2.5 μL of 4x test compound or 100 nL of 100x test compound, 2.4 μL of kinase buffer, 5 μL of 2x peptide / kinase mixture, and 2.5 μL of 4x ATP solution were added to the plate and placed on a shaker plate for 30 seconds. The kinase reaction was allowed to proceed for 60 minutes at room temperature, after which 5 μL of color reagent solution was added and the mixture was agitated for 30 seconds on a shaker plate. The mixture was incubated for 60 minutes at room temperature. Fluorescence was measured using a plate reader, and data was analyzed.

[0416] The maximum emission ratio was determined by a 0% phosphorylation control (100% inhibition control), which did not contain ATP and therefore did not exhibit kinase activity. This control resulted in 100% cleaved peptide in the color reaction. A 100% phosphorylation control consisting of a synthetic phosphorylated peptide with the same sequence as the peptide substrate was designed to allow for calculation of the percentage of phosphorylation. This control resulted in a very low percentage of cleaved peptide in the color reaction. The 0% phosphorylation control and the 100% phosphorylation control allowed for calculation of the percentage of phosphorylation in a particular reaction well. The control wells did not contain kinase inhibitors.

[0417] The minimum emission ratio in the screen was established by a 0% inhibition control containing active kinase. This control was designed to generate 10-50% phosphorylated peptides in the kinase reaction. The cascade assay can generate peptides up to 70% phosphorylated.

[0418] A 10-point titration of known inhibitor control standard curves was performed for each individual kinase on the same plate as the kinase to obtain previously determined expected IC 50 It was ensured that the kinase was inhibited within the range.

[0419] The following controls were prepared for each concentration of test compound assayed: Colorimetric reaction interference was determined by comparing test compound control wells without ATP with a 0% phosphorylation control (no test compound). The expected value for a non-interfering compound should be 100%. All values ​​outside the range of 90%-110% were flagged. Fluorescence interference of test compound was determined by comparing test compound control wells without kinase / peptide mix (zero peptide control) with a 0% inhibition control. The expected value for a non-fluorescent compound should be 0%. All values ​​above 20% were flagged.

[0420] The data in Table A were calculated using IDBS XLfit. Dose-response curves were curve-fitted to model number 205 (sigmoidal dose-response model). If the minimum response in the curve did not fit between -20% and 20% inhibition, it was set to 0% inhibition. If the maximum response in the curve did not fit between 70% and 130% inhibition, it was set to 100% inhibition.

[0421] (Table A) TIFF0007651101000079.tif97146FI = Fluorescence Intensity C 100% = average coumarin luminescence signal of 100% phosphorylation control C 0% = average coumarin luminescence signal of 0% phosphorylation control F 100% = mean fluorescein emission signal of 100% phosphorylation control F 0% = mean fluorescein emission signal of 0% phosphorylation control DRI = chromogenic reaction interference TCFI = Fluorescence interference of test compound

[0422] Table 6 shows the MEK1 inhibition assay results for compounds selected according to the procedure described above. A indicates an IC of 150 nM or less. 50 B indicates IC > 150 nM and IC < 1.5 μM 50 and C has an IC of greater than 1.5 μM 50 Shows.

[0423] Table 6: MEK inhibition assay results TIFF0007651101000080.tif109136ND - Not measured

[0424] Example 4: Cell-based assay-1 Preparation of cell lines useful for testing soft MEK inhibitors in NF1-associated cell proliferation assays can be found in Basu et al. Nature 356: 713-715, 1992; and DeClue et al. Cell 69: 265-273, 1992. Additionally, exemplary in vitro and in vivo models for determining the 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.

[0425] Example 5: Cell-based assay-2 Alternatively, cell-based activity can be measured using the following procedure: Test compounds were dissolved in DMSO to a 10 mM stock. Cell Titer-Glo® 2.0 Luminescent Cell Viability Assay Reagent was purchased from Promega (Madison, Wisconsin). A375 and HCT116 cell lines were purchased from American Type Culture Collection (Manassas, Virginia). For A375 cells, the cell culture medium was DMEM + 10% FBS. The cell culture medium is listed in the table below. For HCT116 cells, the cell culture medium was McCoy's 5A + 10% FBS. All media were supplemented with 100 μg / mL penicillin and 100 μg / mL streptomycin. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air.

[0426] Test compounds were diluted in DMSO in the source plate at 10 doses in 3-fold dilutions starting at 10 mM. 25 nL of each test compound was added to each well of a 384-well cell culture plate (T = final) from the source plate using an Echo 550. 25 μL of medium containing 2000 A375 or HCT116 cells was added to each duplicate well of the cell culture plate (T = 0 and T = final). 25 μL of Cell Titer Glo 2.0 reagent was added to each well of the cell culture plate (T = 0). The contents were mixed on an orbital shaker for 2 minutes and incubated at room temperature for 15 minutes to stabilize the luminescence signal. Luminescence was recorded using an Envision 2104 multilabel reader (PerkinElmer, Santa Clara, CA). The number of viable cells in the culture was determined based on quantification of ATP present in each culture well. Cells in the cell culture plate (T = final) were incubated with the compounds at 37°C and 5% CO2 for 72 hours. 25 μL of Cell Titer Glo 2.0 reagent was added to each well. The contents were mixed on an orbital shaker for 2 minutes and incubated at room temperature for 15 minutes to stabilize the luminescence signal. Luminescence was recorded using an Envision 2104 multilabel reader (PerkinElmer, Santa Clara, CA). The number of viable cells in the culture was determined based on quantification of ATP present in each culture well. GI50 curves were plotted using the GraphPad Prism 4 program based on the sigmoidal dose-response equation Y = minimum response + (maximum response - minimum response) / (1 + 10^((LogEC50-X) * Hill slope)). All parameters in the equation were calculated using the GraphPad Prism 4 program. GI 50 That is, [(T i -T z ) / (C - T z )] * 100 = 50, where T i where T = the raw data of cells with test compound at the end; T zis the raw data for cells without compound at T = 0 h; C is the raw data for cells with the control compound staurosporine (Sigma-Aldrich) at T = 72 h. Therefore, GI 50 where X is calculated by the curve fitting formula using Excel, Y is 50, and Y is 10. X is the value.

[0427] Example 6: Assay results of tested compounds Tested compounds of formula (I) For the tested compounds of formula (I), the following applies in Table 7 below:

[0428] Assay 1 is the biochemical MEK IC assay described in Example 2. 50 (nM) assay. A1 is an IC less than or equal to 150 nM 50 B1 indicates an IC greater than 150 nM but less than or equal to 1.5 μM 50 Shows.

[0429] Assay 2 is the A375(BRAF) GI assay described in Example 5. 50 (nM) Cell-based assay. A2 is an IC less than or equal to 500 nM. 50 B2 indicates an IC greater than 500 nM but less than or equal to 1.5 μM. 50 Shows.

[0430] Assay 3 was performed using the HCT116(Kras) GI assay described in Example 5. 50 (nM) assay. A3 is an IC less than or equal to 750 nM. 50 B3 shows an IC of greater than 750 nM but less than or equal to 2 μM. 50 Shows.

[0431] Table 7: Assay results of tested compounds of formula (I) TIFF0007651101000081.tif56128

[0432] Tested compounds of formula (II) For tested compounds of formula (II), the following applies in Table 8 below: NT indicates that the compound was not tested in the particular assay. Assay 1 is the biochemical MEK IC described in Example 2 and was used for all tested compounds except for compounds 2.042, 2.044, 2.047 and 2.048, which were tested using Example 3. 50 Assay 2 is the A375(BRAF)GI assay described in Example 5. 50 (nM) Cell-based assay. Assay 3 is HCT116(Kras)GI as described in Example 5. 50 (nM) assay.

[0433] Table 8: Assay results of tested compounds of formula (II) TIFF0007651101000082.tif66128

[0434] Tested compounds of formula (III) For tested compounds of formula (III), the following applies in Table 9 below: NT indicates that the compound was not tested in the particular assay. Assay 1 is the biochemical MEK IC described in Example 2 and used for compounds 2 and 6. 50 (nM) assay, and compounds 1, 3, 5, and 7-8 were tested using Example 3. Assay 2 was performed using the A375(BRAF)GI 50 (nM) Cell-based assay. Assay 3 is HCT116(Kras)GI as described in Example 5. 50 (nM) assay.

[0435] Table 9: Assay results of tested compounds of formula (III) TIFF0007651101000083.tif65128

[0436] Tested compounds of formula (IV) For the tested compounds of formula (IV), the following applies in Table 10 below:

[0437] Assay 1 is the biochemical MEK IC assay described in Example 2. 50 (nM) assay. A1 has an IC of 500 nM or less. 50 B1 shows IC values ​​above 500 nM and below 1 μM 50 C1 shows IC > 1 μM and < 5 μM 50 and D1 has an IC of greater than 5 μM and less than or equal to 10 μM 50 Shows.

[0438] Assay 2 was performed using the A375(BRAF) GI assay described in Example 5. 50 (nM) Cell assay. A2 has an IC of 1 μM or less. 50 and B2 has an IC of greater than 1 μM and less than 2 μM. 50 Shows.

[0439] Assay 3 was performed using the HCT116(Kras) GI assay described in Example 5. 50 (nM) assay. A3 has an IC of 5 μM or less. 50 and B3 has an IC of greater than 5 μM and less than or equal to 10 μM. 50 Shows.

[0440] Table 10: Assay results for tested compounds TIFF0007651101000084.tif98128

[0441] Example 7: In vivo model Test Procedure Topical formulations of the compounds described herein and topical formulations of vehicle are applied in duplicate to the skin of nude mice. The skin is biopsied at different time intervals and bisected, with one half snap-frozen in liquid nitrogen and the other half formalin-fixed and paraffin-embedded. Proteins are isolated for Western blot analysis of p-ERK levels. FFPE sections are subjected to p-ERK immunostaining for cell-specific analysis of p-ERK levels. Further analysis includes H&E staining to examine skin integrity.

[0442] Compounds will be evaluated for the inhibition of p-ERK, a downstream biomarker of RAS / MAPK signaling in mouse skin. Additionally, mouse skin proliferation, mouse skin apoptosis, and mouse skin tissue integrity will also be evaluated.

[0443] mouse 129 8-week-old mice obtained from Jackson Laboratories are shaved prior to the start of the study. Approximately 21 mice are used in the study. Compounds are applied to the hairless dorsal skin of the mice at 12-hour intervals, and skin biopsies are obtained using a 6 mm punch biopsy before treatment, and 24, 72, and 96 hours after treatment.

[0444] Western blot analysis For immunoblotting, epidermis was snap-frozen in liquid nitrogen immediately after biopsy. The epidermis was then lysed in lysis buffer and subjected to Western blotting. Antibodies used for immunoblotting included rabbit anti-phosphorylated p44 / 42 MAPK (1:3000, Cell Signaling), rabbit anti-p44 / 42 MAPK (1:3000, Cell Signaling), mouse anti-actin (1:5,000, Sigma-Aldrich), donkey anti-mouse IgG-conjugated horseradish peroxidase (HRP; 1:40,000, Amersham Biosciences), and goat anti-rabbit IgG-conjugated HRP (1:40,000, Jackson ImmunoResearch).

[0445] Immunohistochemistry Immunohistochemistry is performed on 5 μm paraffin sections. Antigen retrieval is achieved by enzymatic treatment (1:1000) using standard protocols. The antibody used is rabbit p-ERK (Cell Signaling, 4307S, 1:100). The Bond Polymer Refine anti-rabbit HRP detection kit (Leica Biosystems) is used according to the manufacturer's protocol. Sections are then counterstained with hematoxylin, dehydrated, and coverslipped onto film using TissueTek-Prisma and Coverslipper (Sakura).

[0446] Histological analysis : Perform H&E on 5 µM paraffin sections and examine the tissue to assess for cytotoxicity, inflammation, or other changes in the integrity of the mouse skin.

[0447] Exogenous RAS activation in mouse skin Experiments are performed on untreated mouse skin. Alternatively, skin is pre-treated with TPA to increase p-ERK levels. TPA-induced RAS / MAPK activation is performed by applying 12.5 μG TPA in 100 μL of acetone to nude mouse skin for 96 hours. Tests are performed 48 hours after TPA exposure.

[0448] A t-test will be used to assess differences in p-ERK and Ki-67 in samples treated with topical MEK1 inhibitors versus vehicle controls.

[0449] Example 8: 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid A solution of 4-cyano-2-fluorobenzoic acid (3.0 g, 18.1 mmol) in THF (30 mL) stirred at -78 °C under TIFF0007651101000085.tif27128N2 was treated dropwise with LDA (2.0 M in THF, 27.2 mL, 54.5 mmol). After 20 min, a solution of 2-fluoro-4-iodoaniline (12.9 g, 54.5 mmol) in anhydrous THF (15 mL) was added dropwise, and the reaction mixture was further stirred and allowed to warm to room temperature. After 16 h, the reaction mixture was concentrated in vacuo, acidified with 1 M HCl, and extracted twice with EtO. The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude residue was purified by trituration with boiling DCM to give the product (1.57 g, 22.7%) as a yellow solid. TIFF0007651101000086.tif24147

[0450] Example 9: 4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid TIFF0007651101000087.tif33128 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), diisopropylethylamine (140 μL, 0.8 mmol), and N,N-dimethylformamide (6 mL) were added to a microwave vial. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The organics were washed with water, brine, and dried over sodium sulfate. The solvent was 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 pale yellow solid (71 mg, 41%). TIFF0007651101000088.tif24151

[0451] The following compounds were prepared as described in Example 9, substituting the appropriate amine for 3-hydroxyazetidine hydrochloride, which is either commercially available or prepared using conditions known to one skilled in the art. TIFF0007651101000089.tif171155TIFF0007651101000090.tif181155TIFF0007651101000091.tif199155TIFF0007651101000092.tif52155

[0452] Example 23: N-(azetidin-3-ylmethoxy)-4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamide TIFF0007651101000093.tif48128 Step 1: tert-butyl 3-(((4-cyano-2-((2-fluoro-4-iodophenyl)amino)benzamido)oxy)methyl)azetidine-1-carboxylate 4-Cyano-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (0.100 g, 0.3 mmol), tert-butyl 3-((aminooxy)methyl)azetidine-1-carboxylate, (60% pure) (0.13 g, 0.4 mmol), HATU (0.15 g, 0.4 mmol), and diisopropylethylamine (135 μL, 0.8 mm...

Claims

1. Formula (IV): or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, or combination thereof, and a pharmaceutically acceptable carrier, for the treatment of birthmarks associated with activation of p-ERK, wherein the birthmarks associated with activation of p-ERK are selected from the group consisting of port wine stain / capillary malformation, pigmented nevus, dysplastic nevus, epidermal nevus, sebaceous nevus, nevus spilus, arteriovenous malformation, lymphatic malformation, and congenital pigmented nevus; The pharmaceutical composition is administered to a patient in need thereof; During the ceremony, R 1 -NR 5 R 5a , or -N (OR 5b ) R 5a , and R 2 Halo, C 1 ~C 6 Alkyl, -SC 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 2 ~C 6 Alkenyl, or C 2 ~C 6 alkynyl; R 2a is halo or C 1 ~C 6 is alkyl; R 5 and R 5b are each independently 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl or amino-C 1 ~C 6 alkyl, 3 ~C 8 Cycloalkyl is unsubstituted or contains one to two R 6 is substituted with; R 5a is hydrogen; Each R 6 are independently halo, hydroxy, oxo, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 -Hydroxyalkyl, C 1 ~C 6 Haloalkyl, Amino, C 1 ~C 6 Alkylamino, di-(C 1 ~C 6 Alkyl)amino, amino-C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylamino-C 1 ~C 6 Alkyl or di-(C 1 ~C 6 Alkyl)amino-C 1 ~C 6 is alkyl; R 43 and R 43a Together, -CH 2 CH 2 CH 2 C(O)- or -CH 2 CH 2 C(O)-, each of which is unsubstituted or has one or two R 49 is replaced by; or R 43 is cyano, -C(O)NR 48 R 48a OR -C(O)R 46 and R 43a is hydrogen, halo, or C 1 ~C 6 is alkyl; R 46 is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 3 ~C 8 is cycloalkyl; R 48 and R 48a are independently hydrogen or C 1 ~C 6 is alkyl; and Each R 49 is independently 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyl-C 1 ~C 6 is alkyl, The pharmaceutical composition.

2. The compound is 2. The pharmaceutical composition of claim 1, having a formula selected from the group consisting of:

3. Each R 49 C 1 ~C 6 3. The pharmaceutical composition of claim 1 or 2, wherein said alkyl is aryl.

4. R 49 3. The pharmaceutical composition of claim 1 or 2, wherein:

5. R 1 -N (OR 5b ) R 5a The pharmaceutical composition according to any one of claims 1 to 4,

6. R 1 Ga-NR 5 R 5a R 5 But, C 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl or amino-C 1 ~C 6 alkyl; 3 ~C 8 The pharmaceutical composition of any one of claims 1 to 4, wherein the cycloalkyl is unsubstituted.

7. R 1 Ga-NR 5 R 5a R 5 but, The pharmaceutical composition of any one of claims 1 to 4 and 6, selected from the group consisting of:

8. R 1 -N (OR 5b ) R 5a R 5b But, C 3 ~C 8 Cycloalkyl-C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl or amino-C 1 ~C 6 alkyl; 3 ~C 8 The pharmaceutical composition of any one of claims 1 to 5, wherein the cycloalkyl is unsubstituted.

9. R 1 -N (OR 5b ) R 5a -OR 5b but, The pharmaceutical composition of any one of claims 1 to 5 and 8, wherein the pharmaceutical composition is selected from the group consisting of:

10. R 1 -N (OR 5b ) R 5a and R 5b C 1 ~C 6 The pharmaceutical composition of any one of claims 1 to 5 and 8 to 9, wherein the is hydroxyalkyl.

11. R 2 But, Halo, C 1 ~C 6 Alkyl, -SC 1 ~C 6 Alkyl, or C 2 ~C 6 The pharmaceutical composition of any one of claims 1 to 10, wherein said compound is alkynyl.

12. R 2 The pharmaceutical composition of any one of claims 1 to 11, wherein is halo.

13. R 2 13. The pharmaceutical composition of any one of claims 1 to 12, wherein is iodine.

14. R 2 C 1 ~C 6 The pharmaceutical composition of any one of claims 1 to 11, wherein said alkyl group is aryl.

15. R 2 CH 3 15. The pharmaceutical composition of any one of claims 1 to 11 and 14, wherein

16. R 2 Ga-SC 1 ~C 6 The pharmaceutical composition of any one of claims 1 to 11, wherein said alkyl group is aryl.

17. R 2 Ga-SCH 3 17. The pharmaceutical composition of any one of claims 1 to 11 and 16, wherein

18. R 2 C 2 ~C 6 The pharmaceutical composition of any one of claims 1 to 11, wherein said compound is alkynyl.

19. R 2 19. The pharmaceutical composition of any one of claims 1-11 and 18, wherein is acetylenyl.

20. R 2a The pharmaceutical composition of any one of claims 1 to 19, wherein is halo.

21. R 2a 21. The pharmaceutical composition of any one of claims 1 to 20, wherein is fluoro.

22. R 2a C 1 ~C 6 20. The pharmaceutical composition of any one of claims 1 to 19, wherein said alkyl group is aryl.

23. R 2a 23. The pharmaceutical composition of any one of claims 1-19 and 22, wherein is methyl.

24. The compound is 22. The pharmaceutical composition of any one of claims 1 to 13, 20, and 21, selected from the group consisting of:

25. The compound is selected from the group consisting of:

25. The pharmaceutical composition of any one of claims 1-13, 20, 21, and 24, having the structure:

26. 26. The pharmaceutical composition of any one of claims 1 to 25, wherein the birthmark associated with activation of p-ERK is selected from the group consisting of epidermal nevus, sebaceous nevus, nevus spilus, arteriovenous malformation, capillary malformation / port wine stain, congenital pigmented nevus and lymphatic malformation.

27. 27. The pharmaceutical composition of any one of claims 1 to 26, which is administered topically, subcutaneously, intradermally, or intralesionally.

28. 28. The pharmaceutical composition of any one of claims 1 to 27, administered as a lotion, spray, ointment, cream, gel, paste, or patch.

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