4-oxo-3,4-dihydroquinazolinone compounds for the treatment of BRAF-related diseases and disorders

Abstract

This disclosure provides compounds of Formula I or pharmaceutically acceptable salts thereof for treating BRAF-related diseases and disorders, including BRAF-related tumors: wherein R<supgt;1< / supgt>, R<supgt;2< / supgt>, R<supgt;3< / supgt>, R<supgt;4< / supgt>, R<supgt;5< / supgt>, R<supgt;6< / supgt>, R<supgt;7< / supgt> and L are as defined herein.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the priority benefit of U.S. Provisional Application No. 63 / 036,522, filed Jun. 9, 2020, U.S. Provisional Application No. 63 / 116,204, filed Nov. 20, 2020, and U.S. Provisional Application No. 63 / 175,655, filed Apr. 16, 2021, the content of each of which is hereby incorporated by reference in its entirety. Field of the Invention

[0003] The present disclosure relates to novel quinazolinone compounds or pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts, and compositions to treat abnormal cell growth (including cancer) in a subject.

[0004] Background

[0005] The present disclosure relates to quinazolinones for the treatment of BRAF-related diseases and disorders, including BRAF-related tumors, including malignant and benign BRAF-related tumors of the CNS and malignant extracranial BRAF-related tumors.

[0006] The BRAF protein (a member of the RAF family of serine / threonine kinases) is involved in the Ras-Raf-MEK-extracellular signal-regulated kinase (ERK) pathway or the mitogen-activated protein kinase (MAPK) / ERK signaling cascade that affects cell division and differentiation. Mutations in the BRAF gene can lead to uncontrolled growth and subsequent tumor formation. More than 100 unique mutations in the BRAF gene have been identified in cancers (Cerami, E. et al., Cancer Discov. 2012, 2, 401-404). These mutations lead to ERK activation through different functional mechanisms and have been classified into three classes based on their dependence on dimerization and RAS activation for their activity, two of which are referred to as class I and class II mutations; these properties determine their sensitivity to RAF inhibitors (Yao, A. et al., Cancer Cell 2015, 28, 370-383).

[0007] Activating class I BRAF mutations such as V600E and / or V600K have been found in human cancers such as melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, renal cell carcinoma, and their metastatic cancers and primary brain tumors. Class I mutations such as the BRAF V600 mutants signal as RAS-independent active monomers.

[0008] Class II BRAF mutations include non-V600 mutations, which activate MEK through dimerization but do not require RAS (Yao, A. et al., Cancer Cell 2015, 28, 370-383). These class II mutations undergo constitutive, RAS-independent dimerization, leading to increased ERK activation and low RAS activity due to negative feedback. Common class II point mutations include G469A / V / R, K601E / N / T, and L597Q / V. Non-V600 mutants are resistant to class I BRAF inhibitors such as vemurafenib. Non-V600 BRAF mutants have also been found in many cancers and are more prevalent than V600 mutations in certain tumor types. Non-V600 BRAF mutations have been found in 5-16% of melanomas and in multiple other tumor types (Siroy AE et al., J Invest Dermatol. 2015;135:508-515; Dahlman KB et al., Cancer Discov. 2012;2:791-797). Approximately 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% of BRAF mutations in colorectal cancer encode non-V600 mutations (Jones JC et al., J Clin Oncol. 2017;35:2624-2630; Paik PK et al., J Clin Oncol. 2011;29:2046-2051). Class II BRAF mutations such as G469A, G469R, G469V, K601E, K601N, K601T, L597Q, and L597V have been identified in gliomas (Schreck, K.C. et al., Cancers (2019) 11:1262) and in other tumors such as breast cancer, small cell lung cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendiceal cancer, small intestine cancer, head and neck squamous cell carcinoma, and angiosarcoma (Sullivan, R.J., Cancer Discov February 1, 2018 (8)(2) 184-195). Class II BRAF mutations have also been identified in metastatic cancers (Dagogo-Jack, I., Clin Cancer Res. September 2018; Schirripa, M., Clin Cancer Res., May 2019; Menzer, C., J Clin Oncol 2019, 37(33):3142-3151).

[0009] In addition, deletions within the BRAF framework can function as class II mutations. For example, acquired resistance has been observed in patients being treated with BRAF V600 inhibitors. Mechanisms of acquired resistance include alternative splicing. Splice variants of BRAF encode an active kinase but lack the full RAS-binding domain. Cells resistant to vemurafenib have been found to express variant forms of BRAF V600E that lack exons encompassing the RAS-binding domain, specifically exons 4-10, exons 4-8, exons 2-8, or exons 2-10 (Poulikakos, P.I. et al., Nature, 480(7377):387-390).

[0010] Currently, there is no effective targeted therapy for patients carrying non-V600 BRAF alterations or BRAF inhibitor-resistant mutations.

[0011] Although some inhibitors of BRAF V600 mutations produce excellent extracranial responses, cancer may still develop brain metastases during or following therapy with BRAF inhibitors (Oliva I.C.G. et al., Annals of Oncology, 29:1509-1520 (2018)). It is estimated that 20% of all subjects with cancer will develop brain metastases, with the majority of brain metastases occurring in those with melanoma, colorectal cancer, lung cancer, and renal cell carcinoma (Achrol A.S. et al., Nature Reviews (2019), 5:5, pages 1-26). Although these are the most likely types to develop brain metastases, any type of cancer can spread to the brain. The development of brain metastases remains an important factor in the overall cancer mortality of subjects with advanced cancer, as the prognosis remains poor despite the availability of multiple treatment modalities and advances in systemic therapies (including combinations of surgery, radiotherapy, chemotherapy, immunotherapy, and / or targeted therapy).

[0012] BRAF has also been identified as a potential target for the treatment of primary brain tumors. The prevalence of BRAF-V600E mutations in primary brain tumors has been reported: Schindler et al. analyzed 1,320 central nervous system (CNS) tumors (Acta Neuropathol 121(3): 397-405, 2011); and Behling et al. analyzed 969 CNS tumors in pediatric and adult populations (Diagn Pathol 11(1): 55, 2016). These studies, combined with other studies, have reported the presence of BRAF-V600E mutations in various cancers, including papillary craniopharyngioma, pleomorphic xanthoastrocytoma (PXA), ganglioglioma, astroblastoma, etc. (Behling et al., Diagn Pathol 11(1): 55, 2016; Brastianos et al., Nat Genet 46(2): 161-165, 2014; Dougherty et al., Neuro Oncol 12(7): 621-630, 2010; Lehman et al., Neuro Oncol 19(1): 31-42, 2017; Mordechai et al., Pediatr Hematol Oncol 32(3): 207-211, 2015; Myung et al., Transl Oncol 5(6): 430-436, 2012; Schindler et al., Acta Neuropathol 121(3): 397-405, 2011).

[0013] Cancers with BRAF-fusion proteins have also been described, including metastatic cancers (J.S. Ross et al., Int. J. Cancer: 138, 881-890 (2016)).

[0014] The blood-brain interface includes the brain microvascular endothelium that forms the blood-brain barrier (BBB) and the choroid plexus epithelium that forms the blood-CSF barrier (BCSFB). The blood-brain barrier (BBB) is a highly selective physical, transport, and metabolic barrier that separates the CNS from the blood. The BBB can prevent certain drugs from entering the brain tissue and is a limiting factor for the delivery of many peripherally administered agents to the CNS. Many drugs commonly used to treat cancer cannot cross the BBB. This means that these drugs cannot penetrate the brain and thus cannot effectively kill cancer cells in the brain. Current treatments for subjects with brain tumors include surgical resection, radiotherapy, and / or chemotherapy using agents such as temozolomide and / or bevacizumab. However, treating brain cancer surgically is not always possible or desirable. For example, the tumor may be inaccessible, or the subject may not tolerate the trauma of neurosurgery. Additionally, radiotherapy and treatment with cytotoxic agents are known to have undesirable side effects. For example, there is increasing evidence that the use of temozolomide itself may induce mutations and worsen the prognosis in a large portion of subjects (B.E. Johnson et al., Science 343:189-193 (2014)), and the bevacizumab label has black box warnings regarding gastrointestinal perforation, surgical and wound healing complications, and bleeding. Kinase inhibitors can be used to treat many peripheral cancers. However, due to their structural characteristics, many kinase inhibitors such as BRAF inhibitors (e.g., vemurafenib and dabrafenib) are substrates of active transporters such as P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). For example, dabrafenib has been reported to have an MDR1 efflux ratio of 11.4, a BCRP efflux ratio of 21.0, and a total brain-to-plasma ratio of 0.023; the free brain-to-plasma ratio was not reported (Mittapalli, R.K. et al., J Pharmacol. Exp Ther 344:655-664, March 2013), and vemurafenib has been reported to have an MDR1 efflux rate of 83, a BCRP efflux rate of 495, and a total brain-to-plasma ratio of 0.004; the free brain-to-plasma ratio was not reported (Mittapalli, R.K. et al., J Pharmacol. Exp Ther 342:33-40 (March 2012).

[0015] Given that both P-gp and BCRP are expressed in the endothelial cells lining the blood-brain capillaries, the activities of both P-gp and BCRP in the BBB play a key role in preventing the distribution of most kinase inhibitors into the brain parenchyma. Thus, kinase inhibitors are generally not suitable for treating tumors or cancers in the brain (which is protected by the BBB).

[0016] Accordingly, there is still a need to treat tumors carrying BRAF mutations (including class I and class II mutations, including resistant mutations). In addition, the treatment of CNS tumors (including CNS tumors carrying BRAF mutations (including resistant mutations)) remains an unmet need. Summary of the Invention

[0018] Accordingly, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0019]

[0020] Wherein:

[0021] L is NH or O;

[0022] R 1 is C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C1-C6 alkoxy)C1-C6 alkyl-, Ar 1 , Ar 1 CH2-, hetAr 1 or hetCyc 1 ;

[0023] Ar 1 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

[0024] hetAr 1 is a 5-6 membered heteroaryl ring having 1 or 2 ring nitrogen atoms and optionally substituted with 1, 2 or 3 substituents independently selected from halogen and C1-C3 alkyl;

[0025] hetCyc 1 is a 4-6 membered saturated monocyclic heterocycle having one epoxy atom;

[0026] R 2 is -CH3, -CH2CH3, -CH=CH2, F, Cl, Br or CN;

[0027] R 3 is F or Cl;

[0028] R 4 is H or F;

[0029] R 5 is H, F or Cl;

[0030] R 6 is C1-C6 alkyl, and

[0031] R7 is a C1-C6 alkyl, hetCyc 2 or a C3-C6 cycloalkyl,

[0032] or R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, (ii) a 6-7 membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spiro ring; and

[0033] hetCyc 2 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0034] provided that the compound is not:

[0035] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide,

[0036] (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide, or

[0037] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-N-ethyl-N-methylamino-1-sulfonamide.

[0038] This text also provides a compound of formula I-A or a pharmaceutically acceptable salt thereof

[0039]

[0040] wherein:

[0041] L is NH or O;

[0042] R 1is C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C1-C6 alkoxy)C1-C6 alkyl-, Ar 1 、Ar 1 CH2-, hetAr 1 or hetCyc 1 ;

[0043] Ar 1 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

[0044] hetAr 1 is a 5-6 membered heteroaryl ring having 1 or 2 ring nitrogen atoms and optionally substituted with 1, 2 or 3 substituents independently selected from halogen and C1-C3 alkyl;

[0045] hetCyc 1 is a 4-6 membered saturated monocyclic heterocycle having one epoxy atom;

[0046] R 2 is -CH3, -CH2CH3, -CH=CH2, F, Cl, Br or CN;

[0047] R 3 is F or Cl;

[0048] R 4 is H or F;

[0049] R 5 is H, F or Cl;

[0050] R 6 is C1-C6 alkyl, and

[0051] R 7 is C1-C6 alkyl, hetCyc 2 or C3-C6 cycloalkyl,

[0052] or R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4-6 membered monocyclic ring optionally having a second ring heteroatom which is O, wherein the ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCF2H, -OCD3, -CH3 and -CH2CH3, (ii) a 6-7 membered fused bicyclic ring optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6-7 membered bridged ring, and (iv) a 7 membered spiro ring; and

[0053] hetCyc 2 is a 5- or 6-membered saturated monocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0054] provided that the compound is not:

[0055] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide,

[0056] (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide, or

[0057] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-N-ethyl-N-methylamino-1-sulfonamide.

[0058] The present invention also provides a compound of formula II or a pharmaceutically acceptable salt thereof:

[0059]

[0060] wherein:

[0061] L is NH or O;

[0062] R 1 is C1-C6 alkyl or C1-C6 fluoroalkyl;

[0063] R 2 is -CH3, -CH2CH3, -CH=CH2, F, Cl, Br or CN;

[0064] R 3 is F or Cl;

[0065] R 4 is H or F;

[0066] R 5 is H, F or Cl;

[0067] R 6 is C1-C6 alkyl, and

[0068] R 7 is C1-C6 alkyl, hetCyc 2 or C3-C6 cycloalkyl,

[0069] or R 6 and R 7Together with the nitrogen atom to which they are attached, form a saturated ring system selected from the following: (i) a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, (ii) a 6-7 membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spiro ring; and

[0070] hetCyc 2 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0071] provided that the compound is not:

[0072] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide,

[0073] (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide, or

[0074] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-N-ethyl-N-methylamino-1-sulfonamide.

[0075] The present invention also provides a compound of formula III or a pharmaceutically acceptable salt thereof

[0076]

[0077] wherein:

[0078] L is NH or O;

[0079] R 1 is C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C1-C6 alkoxy)C1-C6 alkyl-, Ar 1 、Ar 1 CH2-, hetAr 1 or hetCyc 1 ;

[0080] Ar1 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

[0081] hetAr 1 is a 5- or 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms and optionally substituted with 1, 2 or 3 substituents independently selected from halogen and C1-C3 alkyl;

[0082] hetCyc 1 is a 4- to 6-membered saturated monocyclic heterocycle having one epoxy atom;

[0083] R 2 is -CH2CH3, -CH=CH2, F, Cl, Br or CN;

[0084] R 3 is F or Cl;

[0085] R 4 is H or F;

[0086] R 5 is H, F or Cl;

[0087] R 6 is C1-C6 alkyl, and

[0088] R 7 is C1-C6 alkyl, hetCyc 2 or C3-C6 cycloalkyl,

[0089] or R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4- to 6-membered monocyclic ring optionally having a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, (ii) a 6- to 7-membered fused bicyclic ring optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6- to 7-membered bridged ring, and (iv) a 6- to 8-membered spiro ring; and

[0090] hetCyc 2 is a 5- or 6-membered saturated monocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O.

[0091] Also provided herein are compounds of formula IV or pharmaceutically acceptable salts thereof

[0092]

[0093] Wherein:

[0094] L is NH or O;

[0095] R 1 is C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C1-C6 alkoxy)C1-C6 alkyl-, Ar 1 、Ar 1 CH2-, hetAr 1 or hetCyc 1 ;

[0096] Ar 1 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

[0097] hetAr 1 is a 5-6 membered heteroaryl ring having 1 or 2 ring nitrogen atoms and optionally substituted with 1, 2 or 3 substituents independently selected from halogen and C1-C3 alkyl;

[0098] hetCyc 1 is a 4-6 membered saturated monocyclic heterocycle having one epoxy atom;

[0099] R 2 is -CH3, -CH2CH3, -CH=CH2, F, Cl, Br or CN;

[0100] R 3 is F or Cl;

[0101] R 4 is H or F;

[0102] R 5 is H, F or Cl;

[0103] R 6 is C1-C6 alkyl, and

[0104] R 7 is C1-C6 alkyl, hetCyc 2 or C3-C6 cycloalkyl,

[0105] or R 6 and R 7Together with the nitrogen atom to which they are attached, form a saturated ring system selected from the following: (i) a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, (ii) a 6-7 membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spiro ring; and

[0106] hetCyc 2 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0107] wherein when R 1 is methyl, L is NH, R 3 is Cl, R4 is F, R 5 is H and R 6 is methyl and R 7 is ethyl, or R 6 and R 7 together with the nitrogen atom to which they are attached form a pyrrolidinyl or 3-fluoropyrrolidinyl, then R 2 is -CH2CH3, -CH=CH2, F, Cl, Br or CN.

[0108] This disclosure also provides a compound of formula V or a pharmaceutically acceptable salt thereof

[0109]

[0110] wherein:

[0111] L is NH;

[0112] R 1 is a C1-C6 alkyl;

[0113] R 2 is F or Cl;

[0114] R 3 is Cl;

[0115] R 4 is F;

[0116] R 5 is H;

[0117] R 6 and R 7Together with the nitrogen atom to which they are attached, form a saturated ring system selected from the following: (i) a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, and (iii) a 6-7 membered bridged ring.

[0118] The present invention also provides a pharmaceutical composition comprising a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0119] The present invention also provides a method for treating BRAF-related tumors in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof. The compounds of the present invention can be administered as a single agent, or can be administered in combination with other anti-cancer therapies, said other anti-cancer therapies being one or more additional anti-cancer therapies such as independently selected from one or more anti-cancer agents and / or surgery and / or radiotherapy.

[0120] The present invention also provides a method for inhibiting metastasis associated with BRAF-related tumors in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof.

[0121] The present invention also provides a method for inhibiting BRAF kinase activity in vitro or in vivo, said method comprising contacting cells with a therapeutically effective amount of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof.

[0122] The present invention also provides a method for inhibiting cell proliferation in vitro or in vivo, said method comprising contacting cells with a therapeutically effective amount of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof.

[0123] The present invention also provides a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof for use in therapy.

[0124] The present invention also provides a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof for use in treating tumors.

[0125] The present invention also provides a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof, which is used for inhibiting metastasis associated with BRAF-related tumors.

[0126] The present invention also provides a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof, which is used for inhibiting BRAF kinase activity.

[0127] The present invention also provides a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof, which is used for treating BRAF-related diseases or disorders (e.g., BRAF-related tumors).

[0128] The present invention also provides the use of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof as defined herein in the preparation of a medicament for treating BRAF-related tumors (e.g., BRAF-related malignant tumors or BRAF-related benign tumors).

[0129] The present invention also provides the use of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof as defined herein in the preparation of a medicament for inhibiting metastasis associated with BRAF-related tumors.

[0130] The present invention also provides the use of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof as defined herein in the preparation of a medicament for inhibiting BRAF kinase activity.

[0131] The present invention also provides the use of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof as defined herein in the preparation of a medicament for treating BRAF-related diseases or disorders.

[0132] The present invention also provides a method for treating BRAF-related tumors in a subject in need thereof, the method comprising (a) determining that the tumor is associated with a BRAF mutation; and (b) administering to the subject a therapeutically effective amount of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0133] The present invention also provides a pharmaceutical combination for treating BRAF-related tumors in subjects in need thereof, which comprises (a) a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof and (b) an additional anti-cancer agent, wherein the compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof and the additional anti-cancer agent are formulated as separate compositions or dosages for separate or sequential use for treating BRAF-related tumors, and wherein the amount of the compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof and the amount of the additional anti-cancer agent together effectively treat BRAF-related tumors. The present invention also provides the use of such a combination for treating BRAF-related tumors. The present invention also provides a commercial package or product which comprises such a combination as a combined preparation for separate or sequential use for treating BRAF-related tumors in a subject in need thereof.

[0134] The present invention also provides a method for treating a subject suffering from a BRAF-related tumor, the method comprising administering a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof before, during or after administering another anti-cancer therapy (e.g., surgery, radiotherapy and / or another anti-cancer drug).

[0135] The present invention also provides a method for preparing a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof.

[0136] The present invention also provides a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof obtained by a method for preparing a compound as defined herein.

[0137] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for the present invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods and examples are merely exemplary and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0138] Other features and advantages of the present invention will be apparent from the following detailed description and the drawings and from the claims. Brief Description of the Drawings

[0140] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline form (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidine-1-sulfonamide form A. Detailed Description of the Invention

[0142] This disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0143]

[0144] Wherein:

[0145] L is NH or O;

[0146] R 1 is C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C1-C6 alkoxy)C1-C6 alkyl-, Ar 1 , Ar 1 CH2-, hetAr 1 or hetCyc 1 ;

[0147] Ar 1 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

[0148] hetAr 1 is a 5-6 membered heteroaryl ring having 1 or 2 ring nitrogen atoms and optionally substituted with 1, 2 or 3 substituents independently selected from halogen and C1-C3 alkyl;

[0149] hetCyc 1 is a 4-6 membered saturated monocyclic heterocycle having one ring oxygen atom;

[0150] R 2 is -CH3, -CH2CH3, -CH=CH2, F, Cl, Br or CN;

[0151] R 3 is F or Cl;

[0152] R 4 is H or F;

[0153] R 5 is H, F or Cl;

[0154] R 6 is C1-C6 alkyl, and

[0155] R7 is a C1-C6 alkyl, hetCyc 2 or a C3-C6 cycloalkyl,

[0156] or R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCF2H, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, (ii) a 6-7 membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spiro ring; and

[0157] hetCyc 2 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0158] provided that the compound is not:

[0159] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide,

[0160] (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide, or

[0161] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-N-ethyl-N-methylamino-1-sulfonamide.

[0162] In one embodiment, there is provided a compound of formula I-A or a pharmaceutically acceptable salt thereof

[0163]

[0164] wherein:

[0165] L is NH or O;

[0166] R 1is a C1-C6 alkyl group, a C1-C6 deuterated alkyl group, a C1-C6 fluoroalkyl group, a C3-C6 cycloalkyl group, (C3-C6 cycloalkyl)CH2-, (C1-C6 alkoxy)C1-C6 alkyl-, Ar 1 、Ar 1 CH2-, hetAr 1 or hetCyc 1 ;

[0167] Ar 1 is a phenyl group optionally substituted by 1, 2, 3, 4 or 5 substituents, said substituents being independently selected from halogen and C1-C3 alkyl groups;

[0168] hetAr 1 is a 5- or 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms, and is optionally substituted by 1, 2 or 3 substituents, said substituents being independently selected from halogen and C1-C3 alkyl groups;

[0169] hetCyc 1 is a 4- to 6-membered saturated monocyclic heterocycle having one epoxy atom;

[0170] R 2 is -CH3, -CH2CH3, -CH=CH2, F, Cl, Br or CN;

[0171] R 3 is F or Cl;

[0172] R 4 is H or F;

[0173] R 5 is H, F or Cl;

[0174] R 6 is a C1-C6 alkyl group, and

[0175] R 7 is a C1-C6 alkyl group, hetCyc 2 or a C3-C6 cycloalkyl group,

[0176] or R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4- to 6-membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted by 1 or 2 substituents which are independently selected from F, -OH, -OCH3, -OCF2H, -OCD3, -CH3 and -CH2CH3, (ii) a 6- to 7-membered fused bicyclic ring which is optionally substituted by 1 or 2 substituents which are independently selected from F and -CH3, (iii) a 6- to 7-membered bridged ring, and (iv) a 7-membered spiro ring; and

[0177] hetCyc 2 is a 5- or 6-membered saturated monocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0178] provided that the compound is not:

[0179] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide,

[0180] (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide, or

[0181] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-N-ethyl-N-methylamino-1-sulfonamide.

[0182] For complex chemical names used herein, substituents are generally named before the group to which they are attached. For example, methoxyethyl contains an ethyl backbone with a methoxy substituent.

[0183] The term "halogen" refers to -F (sometimes referred to herein as "fluoro" or "fluoride"), -Cl, -Br, and -I.

[0184] The terms "C1-C3 alkyl" and "C1-C6 alkyl" as used herein denote saturated straight-chain or branched-chain monovalent hydrocarbon radicals having 1 to 3 or 1 to 6 carbon atoms, respectively. Examples of alkyls include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

[0185] The term "C1-C6 fluoroalkyl" as used herein denotes a C1-C6 alkyl as defined herein, wherein 1 to 3 hydrogen atoms are each replaced by 1 to 3 fluorine atoms. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0186] The term "C1-C6 deuterated alkyl" as used herein denotes a C1-C6 alkyl as defined herein, which is substituted with 1 to 6 deuterium atoms. Examples include, but are not limited to, -CD3.

[0187] The term "C3-C6 cycloalkyl" refers to a saturated carbocyclic ring having 3 to 6 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl

[0188] The term "C1-C6 alkoxy" as used herein means a saturated straight-chain or branched-chain monovalent alkoxy having 1 to 6 carbon atoms, wherein the radical is on the oxygen atom. Examples of alkoxy include methoxy, ethoxy, propoxy, and isopropoxy.

[0189] The term "(C1-C6 alkoxy)C1-C6 alkyl" as used herein means a C1-C6 alkyl as defined herein, wherein one of the carbon atoms is substituted with a C1-C6 alkoxy. Examples of (C1-C6 alkoxy)C1-C6 alkyl include methoxymethyl (CH3OCH2-) and methoxyethyl (CH3OCH2CH2-).

[0190] The term "heteroaryl" as used herein means an aromatic molecule containing at least one heteroatom as part of the aromatic ring.

[0191] The term "heterocycle" as used herein means a saturated cycloalkyl, wherein one or more ring methylene groups (-CH2-) have been replaced by heteroatoms. For example, the term "hetCyc" 1 as used herein means a saturated 4-6 membered monocyclic cycloalkyl ring, wherein one of the methylene groups has been replaced by -O-, and the term "hetCyc" 2 as used herein means a 5-6 membered saturated monocyclic cycloalkyl ring, wherein one or two methylene groups have been independently replaced by a group selected from -O- and -N-, provided that the ring does not contain two adjacent ring heteroatoms.

[0192] Throughout the disclosure, it should be understood that the number and nature of optional substituents will be limited to the extent that such substitution is chemically meaningful.

[0193] The term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structures. A compound identified herein by name or structure as a particular tautomeric form is intended to include other tautomeric forms unless otherwise indicated.

[0194] In one embodiment of Formula I, L is NH.

[0195] In one embodiment of Formula I, L is O.

[0196] In one embodiment of Formula I, R 1 is C1-C6 alkyl. Non-limiting examples include methyl, ethyl, and isopropyl. In one embodiment of Formula I, R 1 is methyl.

[0197] In one embodiment of Formula I, R 1 is C1-C6 deuterated alkyl. Non-limiting examples include -CD3.

[0198] In one embodiment of formula I, R 1 is C1-C6 fluoroalkyl. In one embodiment of formula I, R 1 is fluoromethyl.

[0199] In one embodiment of formula I, R 1 is C3-C6 cycloalkyl. Non-limiting examples include cyclopropyl, cyclobutyl, and cyclopentyl.

[0200] In one embodiment of formula I, R 1 is (C3-C6 cycloalkyl)CH2-. Non-limiting examples include cyclopropylmethyl.

[0201] In one embodiment of formula I, R 1 is (C1-C6 alkoxy)C1-C6 alkyl-. Non-limiting examples include methoxyethyl.

[0202] In one embodiment of formula I, R 1 is Ar 1 . In one embodiment, Ar 1 is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen and C1-C3 alkyl. Non-limiting examples of Ar 1 are phenyl.

[0203] In one embodiment of formula I, R 1 is Ar 1 CH2-. In one embodiment, the Ar 1 moiety is optionally substituted with 1 or 2 substituents independently selected from halogen and C1-C3 alkyl. Non-limiting examples of Ar 1 CH2- are benzyl (-CH2C6H5).

[0204] In one embodiment of formula I, R 1 is hetAr 1 . In one embodiment, hetAr 1 is a 5-6 membered heteroaryl ring having 1 or 2 ring nitrogen atoms and is optionally substituted with 1 or 2 substituents independently selected from halogen and C1-C3 alkyl. In one embodiment, hetAr 1 is unsubstituted. Non-limiting examples are pyridyl.

[0205] In one embodiment of formula I, R 1 is hetCyc 1 . Non-limiting examples include tetrahydrofuranyl.

[0206] In one embodiment of formula I, R 2 is -CH3.

[0207] In one embodiment of formula I, R 2 is -CH2CH3.

[0208] In one embodiment of formula I, R 2 is -CH=CH2.

[0209] In one embodiment of formula I, R 2 is F.

[0210] In one embodiment of formula I, R 2 is Cl.

[0211] In one embodiment of formula I, R 2 is Br.

[0212] In one embodiment of formula I, R 2 is CN.

[0213] In one embodiment of formula I, R 2 is -CH3, F or Cl.

[0214] In one embodiment of formula I, R 2 is F or Cl.

[0215] In one embodiment of formula I, R 3 is F.

[0216] In one embodiment of formula I, R 3 is Cl.

[0217] In one embodiment of formula I, R 4 is H.

[0218] In one embodiment of formula I, R 4 is F.

[0219] In one embodiment of formula I, R 5 is H.

[0220] In one embodiment of formula I, R 5 is F.

[0221] In one embodiment of formula I, R 5 is Cl.

[0222] In one embodiment of formula I, R 6 is C1-C6 alkyl and R 7 is C1-C6 alkyl, hetCyc 2 or C3-C6 cycloalkyl.

[0223] In one embodiment of formula I, R 6 is methyl or ethyl.

[0224] In one embodiment of formula I, R 7 is a C1-C6 alkyl group. In one embodiment, R 7 is methyl.

[0225] In one embodiment of formula I, R 7 is hetCyc 2 . In one embodiment, R 7 is tetrahydrofuranyl.

[0226] In one embodiment of formula It, R 7 is a C3-C6 cycloalkyl group. In one embodiment, R 7 is cyclopropyl or cyclobutyl.

[0227] In one embodiment of formula I, R 6 is methyl or ethyl and R 7 is methyl, tetrahydrofuranyl, cyclopropyl or cyclobutyl.

[0228] In one embodiment of formula I, R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3 and -CH2CH3, (ii) a 6-7 membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spiro ring.

[0229] In one embodiment of formula I, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCF2H, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN. Non-limiting examples include the following structures:

[0230]

[0231] In one embodiment of Formula I, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic ring, wherein said ring is substituted with substituents selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3, and CN.

[0232] In one embodiment of Formula I, R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated 4- to 6-membered monocyclic ring substituted with F. Examples include the following structures:

[0233]

[0234] In one embodiment of Formula I, R 6 and R 7 together with the nitrogen atom to which they are attached form a 6- to 7-membered fused bicyclic ring, which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3. Non-limiting examples include the following structures:

[0235]

[0236] In one embodiment of Formula I, R 6 and R 7 together with the nitrogen atom to which they are attached form a 6- to 7-membered bridged ring. Non-limiting examples include the following structures:

[0237]

[0238] In one embodiment of Formula I, R 6 and R 7 together with the nitrogen atom to which they are attached form a 6- to 8-membered spiro ring. Non-limiting examples include the following structures:

[0239]

[0240] Any of the foregoing embodiments of Formula I can be combined with each other.

[0241] In one embodiment, provided herein is a compound of Formula II or a pharmaceutically acceptable salt thereof

[0242]

[0243] wherein:

[0244] L is NH or O;

[0245] R 1 is a C1-C6 alkyl or a C1-C6 fluoroalkyl;

[0246] R 2 is -CH3, -CH2CH3, -CH=CH2, F, Cl, Br or CN;

[0247] R 3 is F or Cl;

[0248] R 4 is H or F;

[0249] R 5 is H, F or Cl;

[0250] R 6 is a C1-C6 alkyl, and

[0251] R 7 is a C1-C6 alkyl, hetCyc 2 or a C3-C6 cycloalkyl,

[0252] or R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, (ii) a 6-7 membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spiro ring; and

[0253] hetCyc 2 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0254] provided that the compound is not: N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide,

[0255] (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide, or

[0256] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-N-ethyl-N-methylamino-1-sulfonamide.

[0257] In one embodiment of Formula II, L is NH.

[0258] In one embodiment of Formula II, L is O.

[0259] In one embodiment of Formula II, R 1 is C1-C6 alkyl. Non-limiting examples include methyl, ethyl, and isopropyl. In one embodiment of Formula II, R 1 is methyl.

[0260] In one embodiment of Formula II, R 1 is C1-C6 fluoroalkyl. In one embodiment of Formula II, R 1 is fluoromethyl.

[0261] In one embodiment of Formula II, R 2 is -CH3.

[0262] In one embodiment of Formula II, R 2 is -CH2CH3.

[0263] In one embodiment of Formula II, R 2 is -CH=CH2.

[0264] In one embodiment of Formula II, R 2 is F.

[0265] In one embodiment of Formula II, R 2 is Cl.

[0266] In one embodiment of Formula II, R 2 is Br.

[0267] In one embodiment of Formula II, R 2 is CN.

[0268] In one embodiment of Formula II, R 2 is -CH3, F, or Cl.

[0269] In one embodiment of Formula II, R 2 is F or Cl.

[0270] In one embodiment of Formula II, R 3 is F.

[0271] In one embodiment of Formula II, R 3is Cl.

[0272] In one embodiment of Formula II, R 4 is H.

[0273] In one embodiment of Formula II, R 4 is F.

[0274] In one embodiment of Formula II, R 5 is H.

[0275] In one embodiment of Formula II, R 5 is F.

[0276] In one embodiment of Formula II, R 5 is Cl.

[0277] In one embodiment of Formula II, R 6 is C1-C6 alkyl and R 7 is C1-C6 alkyl, hetCyc 2 or C3-C6 cycloalkyl.

[0278] In one embodiment of Formula II, R 6 is methyl or ethyl.

[0279] In one embodiment of Formula II, R 7 is C1-C6 alkyl. In one embodiment, R 7 is methyl.

[0280] In one embodiment of Formula II, R 7 is hetCyc 2 . In one embodiment, R 7 is tetrahydrofuranyl.

[0281] In one embodiment of Formula II, R 7 is C3-C6 cycloalkyl. In one embodiment, R 7 is cyclopropyl or cyclobutyl.

[0282] In one embodiment of Formula II, R 6 is methyl or ethyl and R 7 is methyl, tetrahydrofuranyl, cyclopropyl or cyclobutyl.

[0283] In one embodiment of Formula II, R 6 and R 7Together with the nitrogen atom to which they are attached, form a saturated ring system selected from the following: (i) a 4- to 6-membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3 and -CH2CH3, (ii) a 6- to 7-membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6- to 7-membered bridged ring, and (iv) a 6- to 8-membered spiro ring.

[0284] In one embodiment of Formula II, R 6 and R 7 Together with the nitrogen atom to which they are attached, form a 4- to 6-membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCF2H, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN. Non-limiting examples include the following structures:

[0285]

[0286]

[0287] In one embodiment of Formula II, R 6 and R 7 Together with the nitrogen atom to which they are attached, form a saturated 4- to 6-membered monocyclic ring which is optionally substituted with F. Examples include the following structures:

[0288]

[0289] In one embodiment of Formula II, R 6 and R 7 Together with the nitrogen atom to which they are attached, form a 6- to 7-membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3. Non-limiting examples include the following structures:

[0290]

[0291] In one embodiment of Formula II, R 6 and R 7 Together with the nitrogen atom to which they are attached, form a 6- to 7-membered bridged ring. Non-limiting examples include the following structures:

[0292]

[0293] In one embodiment of Formula II, R 6 and R 7 together with the nitrogen atom to which they are attached form a 6- to 8-membered spiro ring. Non-limiting examples include the following structures:

[0294]

[0295] Any of the foregoing embodiments of Formula II can be combined with each other.

[0296] In one embodiment, provided herein is a compound of Formula III or a pharmaceutically acceptable salt thereof:

[0297]

[0298] Wherein:

[0299] L is NH or O;

[0300] R 1 is C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C1-C6 alkoxy)C1-C6 alkyl-, Ar 1 、Ar 1 CH2-, hetAr 1 or hetCyc 1 ;

[0301] Ar 1 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

[0302] hetAr 1 is a 5- to 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms and optionally substituted with 1, 2 or 3 substituents independently selected from halogen and C1-C3 alkyl;

[0303] hetCyc 1 is a 4- to 6-membered saturated monocyclic heterocycle having one epoxy atom;

[0304] R 2 is -CH2CH3, -CH=CH2, F, Cl, Br or CN;

[0305] R 3 is F or Cl;

[0306] R 4 is H or F;

[0307] R 5 is H, F or Cl;

[0308] R6 is a C1-C6 alkyl group, and

[0309] R 7 is a C1-C6 alkyl group, hetCyc 2 or a C3-C6 cycloalkyl group,

[0310] or R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from the following: (i) a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, (ii) a 6-7 membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spiro ring; and

[0311] hetCyc 2 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O.

[0312] In one embodiment of Formula III, L is NH.

[0313] In one embodiment of Formula III, L is O.

[0314] In one embodiment of Formula III, R 1 is a C1-C6 alkyl group or a C1-C6 fluoroalkyl group.

[0315] In one embodiment of Formula III, R 1 is a C1-C6 alkyl group. Non-limiting examples include methyl, ethyl and isopropyl. In one embodiment of Formula III, R 1 is methyl.

[0316] In one embodiment of Formula III, R 1 is a C1-C6 fluoroalkyl group. In one embodiment of Formula III, R 1 is fluoromethyl.

[0317] In one embodiment of Formula III, R 2 is -CH=CH2.

[0318] In one embodiment of Formula III, R 2 is F.

[0319] In one embodiment of Formula III, R 2 is Cl.

[0320] In one embodiment of Formula III, R 2 is Br.

[0321] In one embodiment of Formula III, R 2 is CN.

[0322] In one embodiment of Formula III, R 2 is F or Cl

[0323] In one embodiment of Formula III, R 3 is F.

[0324] In one embodiment of Formula III, R 3 is Cl.

[0325] In one embodiment of Formula III, R 4 is H.

[0326] In one embodiment of Formula III, R 4 is F.

[0327] In one embodiment of Formula III, R 5 is H.

[0328] In one embodiment of Formula III, R 5 is F.

[0329] In one embodiment of Formula III, R 5 is Cl.

[0330] In one embodiment of Formula III, R 6 is C1-C6 alkyl and R 7 is C1-C6 alkyl, hetCyc 2 or C3-C6 cycloalkyl.

[0331] In one embodiment of Formula III, R 6 is methyl or ethyl.

[0332] In one embodiment of Formula III, R 7 is C1-C6 alkyl. In one embodiment, R 7 is methyl.

[0333] In one embodiment of Formula III, R 7 is hetCyc 2 . In one embodiment, R 7 is tetrahydrofuranyl.

[0334] In one embodiment of Formula III, R 7 is C3-C6 cycloalkyl. In one embodiment, R 7 is cyclopropyl or cyclobutyl.

[0335] In one embodiment of Formula III, R 6 is methyl or ethyl and R 7 is methyl, tetrahydrofuranyl, cyclopropyl or cyclobutyl.

[0336] In one embodiment of Formula III, R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3 and -CH2CH3, (ii) a 6-7 membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spiro ring.

[0337] In one embodiment of Formula III, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-6 membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCF2H, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN. Non-limiting examples include the following structures:

[0338]

[0339]

[0340] In one embodiment of Formula III, R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated 4-6 membered monocyclic ring optionally substituted with F. Examples include the following structures:

[0341]

[0342] In one embodiment of Formula III, R 6 and R 7Together with the nitrogen atom to which they are attached, form a 6-7 membered fused bicyclic ring, which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3. Non-limiting examples include the following structures:

[0343]

[0344] In one embodiment of Formula III, R 6 and R 7 Together with the nitrogen atom to which they are attached, form a 6-7 membered bridged ring. Non-limiting examples include the following structures:

[0345]

[0346] In one embodiment of Formula III, R 6 and R 7 Together with the nitrogen atom to which they are attached, form a 6-8 membered spiro ring. Non-limiting examples include the following structures:

[0347]

[0348] Any of the foregoing embodiments of Formula III can be combined with each other.

[0349] In one embodiment, provided herein are compounds of Formula IV or pharmaceutically acceptable salts thereof

[0350]

[0351] Wherein:

[0352] L is NH or O;

[0353] R 1 is C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2-, (C1-C6 alkoxy)C1-C6 alkyl-, Ar 1 Ar 1 CH2-, hetAr 1 or hetCyc 1 ;

[0354] Ar 1 is a phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

[0355] hetAr 1 is a 5-6 membered heteroaryl ring having 1 or 2 ring nitrogen atoms and is optionally substituted with 1, 2 or 3 substituents independently selected from halogen and C1-C3 alkyl;

[0356] hetCyc 1 is a 4- to 6-membered saturated monocyclic heterocycle having one epoxy atom;

[0357] R 2 is -CH3, -CH2CH3, -CH=CH2, F, Cl, Br or CN;

[0358] R 3 is F or Cl;

[0359] R 4 is H or F;

[0360] R 5 is H, F or Cl;

[0361] R 6 is a C1-C6 alkyl group, and

[0362] R 7 is a C1-C6 alkyl group, hetCyc 2 or a C3-C6 cycloalkyl group,

[0363] or R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4- to 6-membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, (ii) a 6- to 7-membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6- to 7-membered bridged ring, and (iv) a 6- to 8-membered spiro ring; and

[0364] hetCyc 2 is a 5- to 6-membered saturated monocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0365] wherein when R 1 is methyl, L is NH, R 3 is Cl, R 4 is F, R 5 is H and R 6 is methyl and R 7 is ethyl, or R 6 and R 7 together with the nitrogen atom to which they are attached form a pyrrolidinyl or 3-fluoropyrrolidinyl group, then R 2 is -CH2CH3, -CH=CH2, F, Cl, Br or CN.

[0366] In one embodiment of formula IV, L is NH.

[0367] In one embodiment of formula IV, L is O.

[0368] In one embodiment of formula IV, R 1 is C1-C6 alkyl or C1-C6 fluoroalkyl.

[0369] In one embodiment of formula IV, R 1 is C1-C6 alkyl. Non-limiting examples include methyl, ethyl, and isopropyl, provided that when R 1 is methyl, L is NH, R 3 is Cl, R 4 is F, R 5 is H and R 6 is methyl and R 7 is ethyl, or R 6 and R 7 together with the nitrogen atom to which they are attached form pyrrolidinyl or 3-fluoropyrrolidinyl, then R 2 is -CH2CH3, -CH=CH2, F, Cl, Br, or CN. In one embodiment of formula IV, R 1 is methyl.

[0370] In one embodiment of formula IV, R 1 is C1-C6 fluoroalkyl. In one embodiment of formula IV, R 1 is fluoromethyl.

[0371] In one embodiment of formula IV, R 2 is -CH3.

[0372] In one embodiment of formula IV, R 2 is -CH2CH3.

[0373] In one embodiment of formula IV, R 2 is -CH=CH2.

[0374] In one embodiment of formula IV, R 2 is F.

[0375] In one embodiment of formula IV, R 2 is Cl.

[0376] In one embodiment of formula IV, R 2 is Br.

[0377] In one embodiment of formula IV, R 2 is CN.

[0378] In one embodiment of formula IV, R 2 is -CH3, F or Cl.

[0379] In one embodiment of formula IV, R 2 is F or Cl

[0380] In one embodiment of formula IV, R 3 is F.

[0381] In one embodiment of formula IV, R 3 is Cl.

[0382] In one embodiment of formula IV, R 4 is H.

[0383] In one embodiment of formula IV, R 4 is F.

[0384] In one embodiment of formula IV, R 5 is H.

[0385] In one embodiment of formula IV, R 5 is F.

[0386] In one embodiment of formula IV, R 5 is Cl.

[0387] In one embodiment of formula IV, R 6 is C1-C6 alkyl and R 7 is C1-C6 alkyl, hetCyc 2 or C3-C6 cycloalkyl.

[0388] In one embodiment of formula IV, R 6 is methyl or ethyl.

[0389] In one embodiment of formula IV, R 7 is C1-C6 alkyl. In one embodiment, R 7 is methyl.

[0390] In one embodiment of formula IV, R 7 is hetCyc 2 . In one embodiment, R 7 is tetrahydrofuranyl.

[0391] In one embodiment of formula IV, R 7 is C3-C6 cycloalkyl. In one embodiment, R 7 is cyclopropyl or cyclobutyl.

[0392] In one embodiment of formula IV, R 6 is methyl or ethyl and R 7 is methyl, tetrahydrofuranyl, cyclopropyl or cyclobutyl.

[0393] In one embodiment of formula IV, R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4- to 6-membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, (ii) a 6- to 7-membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3, (iii) a 6- to 7-membered bridged ring, and (iv) a 6- to 8-membered spiro ring.

[0394] In one embodiment of formula IV, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCF2H, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN. Non-limiting examples include the following structures:

[0395]

[0396]

[0397] In one embodiment of formula IV, R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated 4- to 6-membered monocyclic ring which is optionally substituted with F. Examples include the following structures:

[0398]

[0399] In one embodiment of formula IV, R 6 and R 7 together with the nitrogen atom to which they are attached form a 6- to 7-membered fused bicyclic ring which is optionally substituted with 1 or 2 substituents independently selected from F and -CH3. Non-limiting examples include the following structures:

[0400]

[0401] In one embodiment of Formula IV, R 6 and R 7 together with the nitrogen atom to which they are attached form a 6- to 7-membered bridged ring. Non-limiting examples include the following structures:

[0402]

[0403] In one embodiment of Formula IV, R 6 and R 7 together with the nitrogen atom to which they are attached form a 6- to 8-membered spiro ring. Non-limiting examples include the following structures:

[0404]

[0405] Any of the foregoing embodiments of Formula IV can be combined with each other.

[0406] In one embodiment, provided herein is a compound of Formula V or a pharmaceutically acceptable salt thereof

[0407]

[0408] wherein:

[0409] L is NH;

[0410] R 1 is C1-C6 alkyl;

[0411] R 2 is F or Cl;

[0412] R 3 is Cl;

[0413] R 4 is F;

[0414] R 5 is H;

[0415] R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated ring system selected from: (i) a 4- to 6-membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN, and (iii) a 6- to 7-membered bridged ring.

[0416] In one embodiment of Formula V, R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated 4- to 6-membered monocyclic ring which optionally has a second ring heteroatom which is O, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH3, -OCHF2, -OCD3, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2F, -CH2OCHF2, -CH2OCF3, -OCF3, -OCH2CH3 and CN.

[0417] In one embodiment of Formula V, R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated 4- to 6-membered monocyclic ring, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F.

[0418] In one embodiment of Formula V, R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated 6- to 7-membered bridged ring.

[0419] In one embodiment of Formula V, R 1 is methyl.

[0420] In one embodiment of Formula V, R 3 is F.

[0421] In one embodiment of Formula V, R 3 is Cl.

[0422] In one embodiment of Formula V, R 1 is methyl, R 3 is F, and R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated 4- to 6-membered monocyclic ring, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F. In one embodiment, said ring is substituted with one F.

[0423] In one embodiment of Formula V, R 1 is methyl, R 3 is chlorine, and R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated 6- to 7-membered bridged ring.

[0424] The compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV and Formula V, including their pharmaceutically acceptable salts. Additionally, the compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts and which can be used as intermediates for the preparation and / or purification of the compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V and / or for the separation of enantiomers of the compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V.

[0425] The term "pharmaceutically acceptable salt" refers to conventional acid addition or base addition salts which retain the biological efficacy and properties of the compound of formula (I) and which can be formed with a suitable non-toxic organic or inorganic acid or organic or inorganic base. Examples of acid addition salts include salts derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and perchloric acid, and salts derived from various organic acids such as, but not limited to, acetic acid, propionic acid, benzoic acid, glycolic acid, phenylacetic acid, salicylic acid, malonic acid, maleic acid, oleic acid, pamoic acid, palmitic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid, etc. Examples of base addition salts are salts derived from ammonium hydroxide, potassium hydroxide, sodium hydroxide and quaternary ammonium hydroxides (such as tetramethylammonium hydroxide). These salts often exhibit more favorable solubility properties than the compounds used to prepare them and are thus more suitable for the preparation of various pharmaceutical formulations.

[0426] It is further understood that the compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or their salts can be isolated in the form of solvates and thus any such solvates are included within the scope of the present invention. For example, the compounds of Formula I and their salts can exist in unsolvated form as well as in solvated form with a pharmaceutically acceptable solvent such as water, ethanol, etc.

[0427] The term "solvate" refers to a non-covalent stoichiometric or non-stoichiometric combination of a solvent and a solute. The term "hydrate" refers to a non-covalent stoichiometric or non-stoichiometric combination of water and a solute. For example, the compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or their pharmaceutically acceptable salts or polymorphs can exist in unsolvated form as well as in solvated form with a pharmaceutically acceptable solvent such as anisole, dichloromethane, toluene, 1,4-dioxane, water, etc.

[0428] The compounds provided herein may contain one or more asymmetric centers and can thus be prepared and isolated as mixtures of isomers, such as racemic mixtures, or in enantiomerically pure form. The present invention includes all individual stereoisomers and geometric isomers of the compounds of the present invention and mixtures thereof. The individual enantiomers can be obtained by chiral separation or by using the relevant enantiomers in the synthesis. Bonds to carbon atoms of the compounds of the present invention can be depicted herein using solid lines (——), thick straight bars thin straight bars solid wedges or dashed wedges . A bond depicted with a solid line to an asymmetric carbon atom is meant to include all possible stereoisomers at that carbon atom (e.g., a particular enantiomer, a racemic mixture, etc.). A thick straight bar or a thin straight bar means relative stereochemistry. A solid wedge or a dashed wedge means absolute stereochemistry. For compounds disclosed in the examples that contain one or more stereocenters, if no specific stereochemistry is shown, the compounds are intended to include mixtures of stereoisomers. The term "stereocenter" as used herein refers to an atom having three or more different attached atoms, where the interchange of two of these attachments results in another stereoisomer. Examples include, but are not limited to, sp 3 (tetrahedral) carbon atoms.

[0429] The compounds of Formula I, Formula I-A, Formula II, and Formula III can exist in various geometric isomeric forms. In addition, certain compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V can contain one or more asymmetric centers and thus exist in stereoisomeric and diastereoisomeric forms. The term "stereoisomers" denotes compounds having the same molecular connectivity and bond multiplicity, but differing in the spatial arrangement of their atoms. All such compounds, such as cis isomers, trans isomers, mixtures of diastereoisomers, racemates, non-racemic mixtures of enantiomers, substantially pure and pure enantiomers are within the scope of the present invention. In one embodiment, a substantially pure enantiomer contains up to 5% by weight of the corresponding opposite enantiomer. In one embodiment, a substantially pure enantiomer contains up to 2% by weight of the corresponding opposite enantiomer. In one embodiment, a substantially pure enantiomer contains up to 1% by weight of the corresponding opposite enantiomer.

[0430] Optical isomers can be prepared by resolving a racemic mixture by known methods, for example, by using an optically active acid or base to form diastereomeric salts or by forming covalent diastereomers. Suitable acids include, for example, tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, xylbenzoyl tartaric acid, and camphorsulfonic acid. The diastereomeric mixture can be separated into the respective diastereomers based on their physical and / or chemical differences by methods known to those skilled in the art, such as chromatography or fractional crystallization. Subsequently, the optically active base or acid is released from the separated diastereomeric salts. Various methods for separating optical isomers include chiral chromatography (e.g., chiral HPLC columns), which can optionally be used by derivatization to maximize the separation of enantiomers. Suitable chiral HPLC columns are Diacel columns, such as CHIRALPAK or CHIRALCEL columns, which can be routinely selected as needed. When applicable, enzymatic separation by derivatization can also be used. In the absence of racemization reaction conditions, optically active compounds of formula I, formula I-A, formula II, formula III, formula IV, or formula V can also be prepared using chiral synthesis with optically active starting materials.

[0431] Also included are acid addition salts or base addition salts, wherein the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

[0432] When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound (true racemate) described above, in which a homogeneous form of crystal is produced that contains equimolar amounts of the two enantiomers. The second type is a racemic mixture or conglomerate, in which two forms of crystals are produced in equimolar amounts, each containing a single enantiomer.

[0433] The compounds of the present invention can exhibit tautomerism and structural isomerism. For example, the compounds can exist in several tautomeric forms, including enol and imine forms as well as keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of the present invention. Tautomers exist as a mixture of tautomeric ensembles in solution. In the solid form, usually one tautomer predominates. Even though one tautomer can be described, the present invention includes all tautomers of the compounds of the provided formula.

[0434] Conventional techniques for preparing / separating the respective enantiomers include chiral synthesis from a suitable optically pure precursor, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).

[0435] Alternatively, a racemate (or a racemic precursor) can be reacted with a suitable optically active compound such as an alcohol, or, in the case where the compound contains an acidic or basic moiety, with an acid or a base such as tartaric acid or 1-phenylethylamine. The resulting mixture of diastereoisomers can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers are converted into the corresponding pure enantiomers by methods well known to those skilled in the art.

[0436] Using chromatography (usually HPLC), on an asymmetric resin with a mobile phase consisting of a hydrocarbon, usually heptane or hexane, which contains 0 - 50%, usually 2 - 20%, isopropanol and 0 - 5%, usually 0.1%, diethylamine, the chiral compounds (and their chiral precursors) of the invention can be obtained in enantiomerically enriched form. Concentration of the eluate provides an enriched mixture.

[0437] The mixtures of stereoisomers can be separated by conventional techniques known to those skilled in the art; see, for example, “Stereochemistry of Organic Compounds” by E.L. Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

[0438] The enantiomeric purity of the compounds described herein can be described in terms of enantiomeric excess (ee), which indicates the extent to which a sample contains one enantiomer in a greater amount than the other enantiomer. A racemic mixture has 0% ee, while a single, completely pure enantiomer has 100% ee. Similarly, the diastereomeric purity can be described in terms of diastereomeric excess (de).

[0439] The compounds of the invention can exhibit tautomerism and structural isomerism. For example, the compounds can exist in several tautomeric forms, including enol and imine forms as well as keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of the invention. Tautomers exist as mixtures of tautomeric ensembles in solution. In the solid form, usually one tautomer predominates. Even though one tautomer can be described, the invention includes all tautomers of the compounds of the provided formula.

[0440] In addition, some compounds of the present invention can form atropisomers (e.g., substituted biaryls). Atropisomers are conformational stereoisomers that occur when rotation about a single bond in a molecule is hindered or greatly slowed due to steric interactions with other parts of the molecule and the substituents at the two ends of the single bond are asymmetric. The interconversion of atropisomers is slow enough to allow separation and isolation under predetermined conditions. The energy barrier to thermal racemization can be determined by the steric hindrance to the free rotation of one or more bonds forming a chiral axis.

[0441] Unless otherwise indicated, all references herein to the compounds of the present invention include references to their salts, solvates, hydrates, and complexes, as well as solvates, hydrates, and complexes of their salts, including their polymorphs, stereoisomers, and isotopically labeled forms.

[0442] The compounds of the present invention can exist in the form of pharmaceutically acceptable salts, such as acid addition salts and base addition salts of the compounds of one of the formulas provided herein. The term "pharmaceutically acceptable salt" as used herein refers to those salts that retain the biological effectiveness and properties of the parent compound. Unless otherwise specified, the phrase "pharmaceutically acceptable salt" as used herein includes salts of acidic or basic groups that may be present in the compounds of the formulas disclosed herein.

[0443] For example, the compounds of the present invention having basic properties are capable of forming a variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is often necessary to initially isolate the compounds of the present invention from the reaction mixture as pharmaceutically unacceptable salts and then simply convert the pharmaceutically unacceptable salts back to the free base compound by treatment with a basic reagent, and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the present invention can be prepared by treating the base compound with a stoichiometric equivalent of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by addition of a suitable inorganic or organic acid to the solution.

[0444] The acids which are pharmaceutically acceptable for the preparation of acid addition salts of such basic compounds are those which form non-toxic acid addition salts, which are salts containing a pharmacologically acceptable anion, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, mesylate, esylate, benzenesulfonate, tosylate and pamoate.

[0445] Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, camphorsulfonate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, caprate, dihydrochloride, dihydrogen phosphate, edetate, ethanedisulfonate, etoposideate, esylate, ethyl succinate, formate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, p-acetamidophenylarsonate, heptanoate, hexyne-1,6-dioate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, isothiocyanate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate, methyl sulfate, monohydrogen phosphate, mucate, naphthalenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (pamoate), palmitate, pantothenate, phenylacetate, phenylbutyrate, phenylpropionate, phthalate, phosphate / diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, basic acetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, 8-chlorotheophylline salt, tosylate and valerate.

[0446] Exemplary examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary amines, secondary amines and tertiary amines and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0447] In addition to the above acids, the compounds of the present invention including basic moieties such as amino groups can also form pharmaceutically acceptable salts with various amino acids.

[0448] Alternatively, useful compounds of acidic nature are capable of forming base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, and specifically, sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases used as reagents to prepare the pharmaceutically acceptable base salts of the compounds of the present invention are those that form non-toxic base salts with the acidic compounds herein. These salts can be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary amine), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. These salts can also be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmaceutically acceptable cation, and then preferably evaporating the resulting solution to dryness under reduced pressure. Alternatively, they can also be prepared as follows: mixing a lower alkanol solution of the acidic compound and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, preferably a stoichiometric amount of the reagent is employed to ensure the completeness of the reaction and the maximum yield of the desired final product.

[0449] The chemical bases that can be used as reagents to prepare the pharmaceutically acceptable base salts of the compounds of the present invention of acidic nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmaceutically acceptable cations as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine (meglumine), and other base salts of lower alkanolammonium and pharmaceutically acceptable organic amines.

[0450] Acid and base half-salts can also be formed, such as half-sulfates and half-calcium salts.

[0451] For a review of suitable salts, see Stahl and Wermuth's Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley VCH, 2002). Methods for preparing the pharmaceutically acceptable salts of the compounds of the present invention and for interconverting salts and free base forms are known to those skilled in the art.

[0452] The salts of the present invention can be prepared by methods known to those skilled in the art. The pharmaceutically acceptable salts of the compounds of the present invention can be readily prepared by mixing the compound and a solution of the acid or base as required, if appropriate. The salt can precipitate from the solution and can be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the salt can range from fully ionized to hardly ionized.

[0453] Those skilled in the art will understand that the compounds of the present invention in the free base form having basic functional groups can be converted into acid addition salts by treatment with a stoichiometric excess of the appropriate acid. The acid addition salts of the compounds of the present invention can be reconverted into the corresponding free bases by treatment with a stoichiometric excess of a suitable base (such as potassium carbonate or sodium hydroxide), usually in the presence of an aqueous solvent and at a temperature of about 0 °C to 100 °C. The free base form can be isolated by conventional means, such as extraction with an organic solvent. In addition, the acid addition salts of the compounds of the present invention can be interchanged by taking advantage of the differential solubility of the salts, the volatility or acidity of the acid, or by treatment with a suitably loaded ion exchange resin. For example, the interchange may be affected by factors such as the reaction of the salt of the compound of the present invention with a slightly stoichiometric excess of an acid having a pK lower than the acid component of the starting salt. This conversion is usually carried out at a temperature between about 0 °C and the boiling point of the solvent used as the medium for this procedure. Similar exchanges can be carried out with base addition salts, usually through an intermediate in the free base form.

[0454] The compounds of the present invention can exist in unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a definite stoichiometry, independent of humidity. However, when the solvent or water is weakly bound (as in channel solvates and hygroscopic compounds), the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The term "solvate" is used herein to describe a molecular complex containing a compound of the present invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is employed. The pharmaceutically acceptable solvates according to the present invention include hydrates and solvates, in which the crystallized solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO.

[0455] The present invention also relates to prodrugs of the compounds of the formulae provided herein. Accordingly, certain derivatives of the compounds of the present invention that have little or no pharmacological activity per se can be converted into the compounds of the present invention upon administration to a patient, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". For further information on the use of prodrugs, see: Prodrugs as Novel Delivery Systems, Volume 14, ACS Symposium Series (T Higuchi and W Stella); "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (edited by E B Roche, American Pharmaceutical Association), and Guarino, V.R.; Stella, V.J.: Biotech Pharm. Aspects 2007 5(Pt2) 133-187, the disclosures of which are incorporated herein by reference in their entirety.

[0456] In one embodiment, the compound of formula I, formula I-A, formula II, formula III, formula IV or formula V is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of any one of Examples 1-164 can be in free base form. In one embodiment, the compound of any one of Examples 1-164 can be in acid salt form. In one embodiment, certain compounds of Examples 1-164 are isolated as trifluoroacetates.

[0457] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more atoms that make up such compounds. That is, an atom, particularly when referring to compounds according to formulae I, I-A, II, III, IV and V, encompasses all isotopes and mixtures of isotopes of that atom, whether naturally occurring or synthetically produced, whether at natural abundance or in isotopically enriched form. For example, when hydrogen is mentioned, it should be understood to refer to 1 H, 2 H, 3 H or mixtures thereof; when carbon is mentioned, it should be understood to refer to 11 C, 12 C, 13 C, 14 C or mixtures thereof; when nitrogen is mentioned, it should be understood to refer to 13 N, 14 N, 15 N or mixtures thereof; when oxygen is mentioned, it should be understood to refer to 14 O, 15 O,16 O, 17 O, 18 O, or mixtures thereof; and when reference is made to fluorine, it should be understood to mean 18 F, 19 F, or mixtures thereof. As noted above, the compounds provided herein thus also include compounds and mixtures thereof having one or more atoms of one or more isotopes, including radioactive compounds, wherein one or more non-radioactive atoms have been replaced by one of their radioactively enriched isotopes. Radioactively labeled compounds can be used as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., detection reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variants of the compounds provided herein, whether radioactive or not, are intended to be included within the scope of the present invention. Certain isotopically labeled compounds of the present invention, e.g., those incorporating radioactive isotopes such as 3 H and 14 C, are useful in drug and / or substrate tissue distribution assays. Because of their ease of preparation and detectability, tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred. In addition, substitution with heavier isotopes (such as deuterium, i.e., 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and may thus be preferred in certain instances. Isotopically labeled compounds of the present invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent, by following the procedures disclosed in the following schemes and / or examples and preparations.

[0458] The present invention also relates to prodrugs of the compounds of the formula provided herein. Thus, certain derivatives of the compounds of the present invention that are themselves substantially or completely devoid of pharmacological activity can be converted into the compounds of the present invention upon administration to a patient, e.g., by hydrolytic cleavage. Such derivatives are referred to as “prodrugs”. Further information regarding the use of prodrugs can be found in: Prodrugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987 (E B Roche, ed., American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entirety.

[0459] For example, prodrugs according to the present invention can be prepared as follows: replace appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties", as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

[0460] Some non-limiting examples of prodrugs according to the present invention include:

[0461] (i) When the compound contains a carboxylic acid functional group (-COOH), its ester, for example, replace hydrogen with a (C1-C8) alkyl group;

[0462] (ii) When the compound contains an alcohol functional group (-OH), its ether, for example, replace hydrogen with a (C1-C6) alkanoyloxymethyl group or with a phosphoric acid ester ether group; and

[0463] (iii) When the compound contains a primary or secondary amino functional group (-NH2 or -NHR, where R≠H), its amide, for example, replace one or two hydrogens with a suitable metabolically labile group such as an amide, carbamate, urea, phosphonate, sulfonate, etc.

[0464] Other examples of alternative groups and examples of other prodrug types according to the foregoing examples can be found in the foregoing references.

[0465] Finally, certain compounds of the present invention can themselves act as prodrugs for other compounds of the present invention.

[0466] Also included within the scope of the present invention are metabolites of the compounds of the formulae described herein, i.e., compounds formed in vivo after administration of the drug.

[0467] For illustrative purposes, Schemes 1-10 show general methods for preparing the compounds provided herein and key intermediates. For a more detailed description of each reaction step, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. In addition, using conventional chemistry well known to those skilled in the art, many compounds prepared by the following methods can be further modified in accordance with the present disclosure.

[0468]

[0469] Scheme 1

[0470] Scheme 1 describes the synthesis of intermediate 3 (where X is a halogen), which can be used to prepare compounds of formula I, where R 1 and R 2 are as defined for formula I. Compound 1 can be cyclized with formamidine acetate in an organic solvent such as EtOH at an elevated temperature to give compound 2. Compound 2 can be alkylated with a reagent having the formula R 1 X (where R 1 is as defined for formula I and X is a halogen) in the presence of a base such as Cs2CO3 in a solvent such as DMF to give compound 3.

[0471]

[0472] Scheme 2

[0473] Scheme 2 describes the synthesis of intermediate 5, which can be used to prepare compounds of formula I, where R 1 and R 2 are as defined for formula I and L is NH. Compound 3 (for example, prepared according to Scheme 1) can be coupled with a reagent having the formula (PG)NH2 (where PG is an amine protecting group such as p-methoxybenzyl (PMB) or tert-butoxycarbonyl (Boc)) in the presence of a catalyst such as a palladium catalyst (e.g., Pd2(dba)3) and a ligand (e.g., Xantphos) to give compound 4. Compound 4 can be deprotected under standard conditions (e.g., using TFA) to give compound 5.

[0474]

[0475] Scheme 3

[0476] Scheme 3 describes the synthesis of intermediate 11, which can be used to prepare compounds of formula I, where R 3 , R 4 and R 5 are as defined for formula I. Compound 6 (where R 3 , R 4 and R 5As defined with respect to formula I) can be reacted with 1,2-bis(chlorodimethylsilyl)ethane in the presence of a strong base such as n-butyllithium in a suitable solvent such as THF at low temperature (e.g., -78 °C) to form the 1-aza-2,5-disilacyclopentane compound 7. Compound 7 can be reacted with iodine in the presence of, for example, n-butyllithium or a similar reagent in a suitable solvent such as THF to afford compound 8. Compound 8 can be deprotected by reaction with an acid such as HCl in a suitable solvent to provide compound 9. Compound 9 can be reacted with di-tert-butyl dicarbonate ((Boc)2O) in the presence of a catalyst such as 4-dimethylaminopyridine (DMAP) in a suitable solvent such as THF to provide compound 10. Compound 10 can be deprotected in the presence of a base such as K2CO3 in a suitable solvent such as MeOH to provide compound 11.

[0477]

[0478] Scheme 4

[0479] Scheme 4 describes the synthesis of compound 13, which is an intermediate useful for preparing compounds of formula I, wherein R 1 、R 2 、R 3 、R 4 and R 5 are as defined with respect to formula I and L is NH. Compound 5 (e.g., prepared according to Scheme 2) can be coupled with compound 11 (e.g., prepared according to Scheme 3) in the presence of a catalyst (e.g., a palladium catalyst, e.g., Pd2(dba)3) and a ligand (e.g., Xantphos), followed by deprotection under standard conditions (e.g., with TFA) to afford compound 13.

[0480]

[0481] Scheme 5

[0482] Scheme 5 describes the synthesis of compound 16, which is useful for preparing compounds of formula I, wherein R 6 and R 7 are as defined with respect to formula I. Amine 14 can be coupled with thionyl chloride 15 in the presence of a base such as TEA in a suitable solvent such as DCM to provide compound 16.

[0483]

[0484] Scheme 6

[0485] Scheme 6 describes the synthesis of the compound of formula 24, which is useful for preparing compounds of formula I, wherein R 1 、R 2, R 3 , R 4 and R 5 as defined with respect to formula I and L is O. Compound 17 (wherein R 2 as defined with respect to formula I) can be coupled with compound 18 (wherein R 3 , R 4 and R 5 as defined with respect to formula I) in a suitable solvent such as DMSO in the presence of a base such as Cs2CO3 at an elevated temperature to afford compound 19. Compound 19 can be reacted with (Boc)2O in a suitable solvent such as THF in the presence of a catalyst such as DMAP to afford compound 20. Under standard nitro reduction conditions, such as treatment with Fe and NH4Cl, the nitro group of compound 20 can be reduced to afford compound 21. Compound 21 can be cyclized with formamidine acetate in an organic solvent such as EtOH at an elevated temperature to afford compound 22. Compound 22 can be alkylated with a reagent of formula R 1 X (wherein R 1 as defined with respect to formula I and X is a halogen) in a solvent such as DMF in the presence of a base such as Cs2CO3 to afford compound 23. Compound 23 can be deprotected under standard conditions (e.g., with TFA) to afford compound 24.

[0486]

[0487] Scheme 7

[0488] Scheme 7 describes the synthesis of a compound of formula 26, which is a compound of formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined with respect to formula I and L is NH (e.g., prepared according to Scheme 4) or O (e.g., prepared according to Scheme 6). Compound 25 can be coupled with compound 16 in a suitable base such as pyridine or in the presence of calcium bis(trifluoromethanesulfonyl)imide in an organic solvent such as toluene at an elevated temperature to afford compound 26.

[0489]

[0490] Scheme 8

[0491] Scheme 8 describes the synthesis of compound 27, which can be used to prepare a compound of formula I wherein R 3 , R 4 , R 5 , R6 and R 7 as defined with respect to formula I. Amine 11 (wherein R 3 、R 4 、R 5 、R 6 and R 7 as defined with respect to formula I) can be coupled with sulfamide chloride 16 (wherein R 6 and R 7 as defined with respect to formula I) in the presence of a base such as NaH in a suitable solvent such as THF to afford compound 27.

[0492]

[0493] Scheme 9

[0494] Scheme 9 describes the synthesis of a compound of formula 29, which is a compound of formula I, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 as defined with respect to formula I. Compound 5 (e.g., prepared according to Scheme 2) (wherein R 1 and R 2 as defined with respect to formula I) can be coupled with compound 27 (e.g., prepared according to Scheme 8) (wherein R 3 、R 4 、R 5 、R 6 and R 7 as defined with respect to formula I and PG is an amine protecting group such as p-methoxybenzyl (PMB) or tert-butoxycarbonyl (Boc)), followed by deprotection under standard conditions (e.g., with TFA) to afford compound 29.

[0495]

[0496] Scheme 10

[0497] Scheme 10 describes the synthesis of compound 33, which is a compound of formula I, wherein R 1 、R 2 、R 3 、R 4 and R 5 as defined with respect to formula I and L is O. Compound 24 (wherein R 1 、R 2 、R 3, R 4 and R 5 The amine group (as defined with respect to formula I) can be bis - protected with a suitable amine - protecting group (e.g., p - methoxybenzyl (PMB) or tert - butoxycarbonyl (Boc)) by reaction with a suitable reagent (e.g., by reaction with (Boc)2O in a suitable solvent such as THF in the presence of a catalyst such as DMAP) to provide compound 30, where PG is an amine - protecting group (e.g., p - methoxybenzyl (PMB) or tert - butoxycarbonyl (Boc)). Compound 30 can be de - protected under suitable conditions (e.g., in the presence of K2CO3, in an organic solvent such as MeOH, at elevated temperature) to provide the mono - protected compound 31. Compound 31 can be coupled with sulfamoyl chloride 16 in a suitable solvent (such as THF) in the presence of a base (such as NaH) to provide compound 32. Compound 32 can be de - protected under standard conditions (e.g., with TFA) to provide compound 33.

[0498] The methods shown in Schemes 1 - 10 can be used to prepare compounds of formulae II, III, and IV and intermediates useful for preparing compounds of formulae II, III, and IV.

[0499] In one embodiment, provided herein is a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising:

[0500] (a) For a compound of formula I, where L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined with respect to formula I, in the presence of a suitable base, coupling a compound having formula (25) (where L, R 1 , R 2 , R 3 , R 4 and R 5 are as defined with respect to formula I)

[0501]

[0502] with a compound having formula (16) (where R 6 and R 7 are as defined with respect to formula I);

[0503]

[0504] or

[0505] (b) For a compound of formula I, where R 1 , R2 , R 3 , R 4 and R 5 As defined with respect to formula I and L is NH, in the presence of a palladium catalyst and a ligand, a compound of formula (5) wherein R 1 and R 2 As defined with respect to formula I

[0506]

[0507] is reacted with a compound having formula (27) wherein R 3 , R 4 , R 5 , R 6 and R 7 As defined with respect to formula I and PG is an amine protecting group

[0508]

[0509] Subsequently, the amine protecting group is removed; or

[0510] (c) For a compound of formula I, wherein R 1 , R 2 , R 3 , R 4 and R 5 As defined with respect to formula I and L is O, in the presence of a base, a compound having formula (31) wherein R 1 , R 2 , R 3 , R 4 and R 5 As defined with respect to formula I and PG is an amine protecting group

[0511]

[0512] is reacted with a reagent having the following formula

[0513]

[0514] Subsequently, the amine protecting group is removed; and

[0515] Optionally, form its pharmaceutically acceptable salt.

[0516] Compounds of formulas 3, 5, 12, 13, 19, 20, 21, 22, 23, 24, 25, 28, 21 and 32 are synthetic intermediates useful for preparing compounds of formula I and are another aspect of the present invention.

[0517] The term “amine protecting group” as used herein refers to derivatives of groups that are commonly used to block or protect amino groups while reactions are carried out on other functional groups of a compound. Examples of suitable protecting groups for use in any of the methods described herein include carbamates, amides, alkyl and aryl groups, imines, and many N-heteroatom derivatives, which can be removed to regenerate the desired amine group. Non-limiting examples of amine protecting groups are tert-butyloxycarbonyl (“Boc”), 2-trimethylsilylethoxymethyl (SEM), and p-methoxybenzyl (PMB). Other examples of these groups and other protecting groups are found in T.W. Greene et al., Greene’s Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2014.

[0518] Compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, and Formula V, or pharmaceutically acceptable salts thereof, can be used to treat diseases and disorders that can be treated with BRAF kinase inhibitors, such as BRAF-related diseases and disorders, e.g., proliferative disorders such as cancer, including solid tumors. The ability of a test compound to act as a BRAF inhibitor can be confirmed by the enzyme assay described in Example A1, the cell assay described in Example A2, the cell assay described in Example A3, and the proliferation assay described in Example A4. IC 50 values are shown in Tables A1 and A2.

[0519] In certain embodiments, certain compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, and Formula V, or pharmaceutically acceptable salts thereof, exhibit surprising brain and / or CNS penetrability. Such compounds are capable of crossing the BBB and inhibiting BRAF kinase in the brain and / or other CNS structures. In certain embodiments, the compounds provided herein are capable of crossing the BBB in a therapeutically effective amount. For example, the treatment of a subject having cancer (e.g., a BRAF-related cancer such as a BRAF-related CNS cancer) can include administering (e.g., orally administering) a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, to the subject. Thus, in certain embodiments, the compounds provided herein can be used to treat CNS cancers.

[0520] As used herein, the term "treatment" refers to therapeutic or palliative measures. Beneficial or desired clinical outcomes include, but are not limited to: complete or partial alleviation of symptoms associated with a disease, disorder or condition, reduction in the degree of the disease, stabilization (i.e., non-worsening) of the condition, delay or slowing of disease progression, improvement or alleviation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete), whether detectable or not. However, "treatment" can also include therapeutic measures that temporarily worsen the appearance and / or symptoms of the subject (e.g., inhibition of BRAF kinase in BRAF-related tumors). When referring to the treatment of, for example, cancer, the term "treatment" as used herein is not intended to be an absolute term. For example, as used in a clinical setting, "treatment of cancer" and "treating cancer" are intended to include obtaining beneficial or desired clinical outcomes and can include improvement in the condition of a subject having cancer. Beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reduction in the proliferation of tumors or cancer cells (or destruction of tumors or cancer cells), inhibition of metastasis of tumor cells, reduction of metastasis in a subject, reduction in the size of a tumor, alteration of the growth rate of one or more tumors in a subject, increase in the remission period of a subject (e.g., compared to one or more metrics in a subject having a similar cancer but not receiving treatment or receiving a different treatment, or compared to one or more metrics in the same subject prior to treatment), reduction of symptoms caused by the disease, improvement in the quality of life of a disease sufferer (e.g., as assessed using FACT-G or EORTC-QLQC30), reduction in the dosage of other medicaments required to treat the disease, delay in the progression of the disease, and / or prolongation of the survival of a subject having the disease. "Treatment" can also mean prolonged survival compared to what would be expected without treatment, e.g., an increase in overall survival (OS) compared to a subject not receiving treatment as described herein, and / or an increase in progression-free survival (PFS) compared to a subject not receiving treatment as described herein.

[0521] As used herein, the term "subject" refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In certain embodiments, the subject is a human. In certain embodiments, the subject has experienced and / or exhibited at least one symptom of a disease or disorder to be treated and / or prevented. In certain embodiments, the subject has been determined or diagnosed as having a tumor containing a BRAF mutation (BRAF-related tumor) (e.g., as determined using an assay or kit approved by a regulatory agency (e.g., FDA-approved)). In certain embodiments, the subject has a BRAF mutation-positive tumor (e.g., as determined using an assay or kit approved by a regulatory agency). The subject can be a subject whose tumor has a BRAF mutation (e.g., where the tumor is identified as having a BRAF mutation using a kit or assay approved by a regulatory agency (e.g., FDA-approved)). In certain embodiments, the subject is suspected of having a BRAF-related tumor. In certain embodiments, the subject has a clinical record indicating that the subject has a tumor containing a BRAF mutation (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein). In certain embodiments, the subject is a human. In certain embodiments, the human subject is a pediatric subject.

[0522] As used herein, the term "pediatric subject" refers to a subject who is less than 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month up to two years); children (two years up to 12 years); and adolescents (12 years to 21 years (up to, but not including, the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE, Nelson Textbook of Pediatrics, 15th Edition, Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Edition, New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Edition, Baltimore: Williams & Wilkins; 1994. In certain embodiments, the pediatric subject is from birth to the first 28 days of life, from 29 days of age to less than 2 years, from 2 years to less than 12 years, or from 12 years to 21 years (up to, but not including, the 22nd birthday). In certain embodiments, the pediatric subject is from birth to the first 28 days of life, from 29 days of age to less than 1 year, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year, from 1 year to less than 2 years, from 2 years to less than 3 years, from 2 years to less than seven years, from 3 years to less than 5 years, from 5 years to less than 10 years, from 6 years to less than 13 years, from 10 years to less than 15 years, or from 15 years to less than 22 years.

[0523] In certain embodiments, a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, can be used to prevent the diseases and disorders defined herein. As used herein, the term "prevent" refers to completely or partially blocking the onset, recurrence or spread of a disease or condition described herein.

[0524] As used herein, the term "BRAF-related" with respect to a disease or disorder refers to a disease or disorder that is associated with and / or bears one or more BRAF mutations and / or BRAF fusions. Non-limiting examples of BRAF-related diseases or disorders include, for example, BRAF-related tumors.

[0525] The phrase “BRAF mutation” refers to a gene mutation (e.g., a chromosomal translocation that results in one or more mutations in the BRAF gene, which mutations lead to the expression of a BRAF protein having one or more point mutations compared to the wild-type BRAF protein), or an alternative spliced form of BRAF mRNA that results in a BRAF protein having at least one amino acid deletion in the BRAF protein compared to the wild-type BRAF protein (i.e., a splice variant). Non-limiting examples of BRAF mutations include Class I BRAF mutations (e.g., BRAF V600 mutations, such as BRAF V600E and BRAF V600K), Class II BRAF mutations (e.g., BRAF non-V600 mutations and BRAF splice variants), and BRAF Class III mutations.

[0526] The term “Class I BRAF mutation” refers to BRAF V600 mutations that signal as Ras-independent active monomers. Examples include BRAF V600E and BRAF V600K mutations.

[0527] The term “Class II BRAF mutation” includes (i) BRAF non-V600 mutations that act as Ras-independent activated dimers of BRAF and / or CRAF, and (ii) BRAF splice variants whose activity is dimerization-dependent in a Ras-independent manner.

[0528] Examples of BRAF non-V600 (Class II) mutations include G469A, G469R, G469V, K601E, K601N, K601T, L597Q, and L597V. In one embodiment, the BRAF non-V600 mutation is G469A.

[0529] The term “BRAF splice variant” refers to an aberrantly spliced BRAF V600E isoform. BRAF splice variants are BRAF V600E-resistant mutations that lack the exon encoding part of the RAS-binding domain and exhibit enhanced dimerization in cells with low levels of RAS activation (Poulikakos et al., Nature, 480(7377):387-390). Examples of BRAFV600E splice variants include those lacking exons 4-8 (also referred to as p61BRAF(V600E)), exons 4-10, exons 2-8, or exons 2-10. In one embodiment, the resistant mutation is p61BRAF(V600E).

[0530] The term "resistance mutation" refers to a mutation in the BRAF V600E mutation that occurs after exposure of the BRAF V600E mutant to a BRAF inhibitor alone or in combination with another anti-cancer agent (such as a MEK inhibitor). Tumors with resistance mutations become less sensitive to BRAF inhibitors (e.g., tolerant to treatment with BRAF inhibitors). In one embodiment, the resistance mutation occurs after exposure to vemurafenib.

[0531] The term "class III BRAF mutation" refers to a BRAF non-V600 mutation that functions as a RAS-dependent activating dimer of BRAF and / or CRAF. Non-limiting examples of BRAF class III mutations include G466A, G466E, G466R, G466V, D594A, D594E, D594G, D594H, G594N, D287H, V549L, S467A, S467E, S467L, G469E, N581S, N581I, F595L, G596A, G596C, G596D, G596R, and K483M.

[0532] The term "BRAF fusion" refers to a BRAF gene translocation that results in the expression of a fusion protein. In one embodiment, a BRAF-related tumor or BRAF-related cancer has one or more BRAF fusions that result in constitutive kinase activation and transformation, including, but not limited to, KIAA11549-BRAF, MKRN1-BRAF, TRIM24-BRAF, AGAP3-BRAF, ZC3HAV1-BRAF, AKAP9-BRAF, CCDC6-BRAF, AGK-BRAF, EPS15-BRAF, NUP214-BRAF, ARMC10-BRAF, BTF3L4-BRAF, GHR-BRAF, ZC3HAV1-BRAF, ZNF767-BRAF, CCDC91-BRAF, DYNC112-BRAF, ZKSCAN1-BRAF, GTF2I-BRAF, MZT1-BRAF, RAD18-BRAF, CUX1-BRAF, SLC12A7-BRAF, MYRIP-BRAF, SND1-BRAF, NUB1-BRAF, KLHL7-BRAF, TANK-BRAF, RBMS3-BRAF, STRN3-BRAF, STK35-BRAF, ETFA-BRAF, SVOPL-BRAF, JHDM1D-BRAF, or BCAP29-BRAF.

[0533] As used herein, the term "BRAF-related tumor" or "BRAF-related cancer" refers to a tumor or cancer associated with or having a BRAF mutation, and includes tumors having a class I BRAF V600 mutation (e.g., BRAF V600E or V600K mutation) and tumors having a class II BRAF mutation. BRAF-related tumors include benign BRAF-related tumors and malignant BRAF-related tumors (i.e., BRAF-related cancers).

[0534] As used herein, the term "tumor" refers to an abnormal growth of tissue caused by uncontrolled, often rapid, cell proliferation. The tumor can be a benign tumor (non-cancerous) or a malignant tumor (i.e., cancer). The tumor can be a solid tumor or a liquid tumor (i.e., a hematological tumor, also referred to as a blood cancer).

[0535] The term "wild type" describes a nucleic acid (e.g., the BRAF gene or BRAF mRNA) that is typically found in a subject without a disease or disorder associated with the reference nucleic acid or protein.

[0536] The term "wild-type BRAF" describes such a BRAF nucleic acid (e.g., the BRAF gene or BRAF mRNA) or BRAF protein that is found in a subject without a BRAF-related disease (e.g., BRAF-related cancer) (and optionally also without an increased risk of developing a BRAF-related disease and / or not suspected of having a BRAF-related disease), or in cells or tissues from a subject without a BRAF-related disease (e.g., BRAF-related cancer) (and optionally also without an increased risk of developing a BRAF-related disease and / or not suspected of having a BRAF-related disease).

[0537] The term "regulatory agency" refers to the national agency that approves the medical use of pharmaceutical reagents in a country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0538] The present invention provides a method for treating BRAF-related tumors in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, the present invention provides a method for treating BRAF-related tumors in a subject in need thereof, the method comprising: a) detecting a BRAF mutation in a sample from the subject; and b) administering a therapeutically effective amount of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V, or a pharmaceutically acceptable salt thereof. In certain embodiments, the BRAF mutation is a class I mutation. In certain embodiments, the class I BRAF mutation is BRAF V600E. In certain embodiments, the BRAF mutation is a class II mutation. In certain embodiments, the class II mutation is a non-V600 mutation. In certain embodiments, the non-V600 mutation is G469A. In certain embodiments, the class II mutation is a BRAF V600E splice variant. In certain embodiments, the BRAF V600E splice variant is p61BRAF(V600E).

[0539] In certain embodiments of any of the methods of use described herein, the BRAF-related tumor is a solid tumor. In certain embodiments, the tumor is intracranial. In certain embodiments, the tumor is extracranial. In certain embodiments of any of the methods of use described herein, the BRAF-related tumor is a malignant BRAF-related tumor (i.e., BRAF-related cancer). In certain embodiments of any of the methods of use described herein, the cancer is melanoma, colon cancer, colorectal cancer, lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), breast cancer, bladder cancer, ovarian cancer (ovarian carcinoma), cancer of the CNS (including glioma and LMD), bone cancer, anal cancer, anal canal cancer, or anorectal cancer, angiosarcoma, adenoid cystic carcinoma, appendiceal cancer, eye cancer, bile duct cancer (cholangiocarcinoma), cervical cancer, ductal carcinoma in situ, endometrial cancer, gallbladder cancer, hilar cholangiocarcinoma, hepatobiliary pancreatic cancer, head and neck squamous cell carcinoma, oral cancer, oral cavity cancer, leukemia, lip cancer, oropharyngeal cancer, nasal cancer, nasal cavity cancer, or middle ear cancer, vulvar cancer, esophageal cancer, esophagogastric cancer, cervical cancer, gastrointestinal carcinoid tumor, gastrointestinal neuroendocrine cancer, hypopharyngeal cancer, kidney cancer, laryngeal cancer, liver cancer, nasopharyngeal cancer, non-Hodgkin lymphoma, cancer of the peripheral nervous system (e.g., neuroblastoma), neuroendocrine cancer, pancreatic cancer, peritoneal cancer, plasma cell neoplasm, omental and mesenteric cancer, pharyngeal cancer, prostate cancer, kidney cancer (e.g., renal cell carcinoma (RCC)), small bowel cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, uterine cancer, ureteral cancer, or bladder cancer.

[0540] In one embodiment, the BRAF-related cancer is a CNS cancer, melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, renal cell carcinoma, or primary brain tumor.

[0541] In certain embodiments, the BRAF-related cancer is an extracranial cancer selected from melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, and neuroblastoma. In certain embodiments, the BRAF-related cancer is melanoma. In certain embodiments, the BRAF-related cancer is colorectal cancer. In certain embodiments, the BRAF-related cancer is thyroid cancer. In certain embodiments, the BRAF-related cancer is non-small cell lung cancer. In certain embodiments, the BRAF-related cancer is ovarian cancer. In certain embodiments, the BRAF-related cancer is neuroblastoma.

[0542] In certain embodiments, the BRAF-related cancer is an intracranial cancer (brain cancer). In certain embodiments, the BRAF-related cancer is a CNS cancer.

[0543] In certain embodiments, the BRAF-related cancer is a cancer having a BRAF class I mutation. In certain embodiments, the BRAF-related cancer is a cancer having a BRAF V600E or BRAF V600K mutation. In certain embodiments, the BRAF-related cancer having a BRAF V600E or BRAF V600K mutation is selected from melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, renal cell cancer, and their metastatic cancers and primary brain tumors. In certain embodiments, the BRAF-related cancer having a BRAF V600E or BRAF V600K mutation is a CNS tumor. In certain embodiments, the CNS tumor is a malignant tumor (CNS cancer). In certain embodiments, the malignant tumor is a metastatic CNS cancer. In certain embodiments, the metastatic CNS cancer is selected from metastatic melanoma, metastatic colorectal cancer, metastatic non-small cell lung cancer, metastatic thyroid cancer, and metastatic ovarian cancer. In certain embodiments, the CNS tumor is intracranial LMD or extracranial LMD.

[0544] In certain embodiments, the BRAF-related cancer is a cancer having a BRAF class II mutation. In one embodiment, the cancer having a BRAF class II mutation is selected from lung cancer (e.g., non-small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendiceal cancer, small intestine cancer, gastrointestinal neuroendocrine cancer, head and neck squamous cell carcinoma, angiosarcoma, bladder cancer, plasma cell tumor, hepatobiliary duct cancer, hepatobiliary pancreatic cancer, ovarian cancer, endometrial cancer, neuroendocrine cancer, cholangiocarcinoma, esophagogastric cancer, soft tissue sarcoma, leukemia, non-Hodgkin lymphoma, and CNS cancer (e.g., glioma). In one embodiment, the cancer has a BRAF G469A mutation.

[0545] In certain embodiments, the BRAF-related cancer is a cancer having a BRAF class III mutation. In one embodiment, the cancer having a BRAF class III mutation is selected from melanoma, small intestine cancer, colorectal cancer, non-small cell lung cancer, endometrial cancer, cervical cancer, leukemia, bladder cancer, non-Hodgkin lymphoma, glioma, ovarian cancer, prostate cancer, hepatobiliary duct cancer, esophagogastric cancer, soft tissue sarcoma, and breast cancer. In one embodiment, the cancer has a BRAF G466V or BRAF D594G mutation. In one embodiment, the cancer has a BRAF G466V mutation. In one embodiment, the cancer has a BRAF D594G mutation.

[0546] In one embodiment, the BRAF-related tumor has a BRAF-fusion protein, wherein the tumor is breast cancer (e.g., breast invasive ductal carcinoma), colorectal cancer (e.g., colon adenocarcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), glioma (e.g., desmoplastic infantile ganglioglioma of the brain, pilocytic astrocytoma of the brain, pleomorphic xanthoastrocytoma of the brain, low-grade glioma of the spinal cord (NOS), anaplastic oligodendroglioma, anaplastic ganglioglioma), head and neck cancer (e.g., head and neck neuroendocrine carcinoma), lung cancer (e.g., lung adenocarcinoma, lung non-small cell lung cancer (NOS)), melanoma (e.g., Spitzoid cutaneous melanoma, non-Spitzoid mucosal melanoma, Spitzoid cutaneous melanoma, melanoma of unknown primary, non-Spitzoid cutaneous melanoma), pancreatic cancer (e.g., adenocarcinoma, pancreatic acinar cell carcinoma), prostate cancer (e.g., prostatic acinar adenocarcinoma), sarcoma (malignant solid fibroma), thyroid cancer (papillary carcinoma of the thyroid), carcinoma of unknown primary (e.g., adenocarcinoma of unknown primary), pleural mesothelioma, rectal adenocarcinoma, endometrial cancer (e.g., endometrial adenocarcinoma (NOS)), or ovarian serous carcinoma.

[0547] In one embodiment, the BRAF-related cancer is selected from the cancers having a BRAF-fusion protein described in Table 1 (J.S. Ross et al., Int. J. Cancer: 138, 881-890 (2016)).

[0548] Table 1. Exemplary BRAF fusion partners and cancers

[0549]

[0550]

[0551]

[0552] The term "metastasis" is a term known in the art and refers to the spread of cancer cells from their initial site of formation (primary location) to one or more other locations in a subject (one or more secondary locations). In metastasis, cancer cells break away from the original (primary) tumor, travel through the bloodstream or lymphatic system, and form new tumors (metastatic tumors) in other organs or tissues of the body. The new metastatic tumors contain cancer cells that are the same or similar to those of the primary tumor. At the secondary location, the tumor cells can proliferate and initiate the growth or colonization of a secondary tumor at that distant location.

[0553] As used herein, the term "metastatic cancer" (also referred to as "secondary cancer") refers to a type of cancer that originates in one tissue type but then spreads to one or more tissues outside the origin of the (primary) cancer. Metastatic brain cancer refers to cancer in the brain, i.e., cancer that originated in a tissue other than the brain and has metastasized to the brain.

[0554] In one embodiment, the BRAF-related tumor is a malignant BRAF-related CNS tumor (i.e., BRAF-related CNS cancer). The term "CNS cancer" or "cancer of the CNS" or as used interchangeably herein, refers to cancer of the CNS (i.e., malignant tumors), including cancer of the brain (also referred to as intracranial tumors), cancer of the spinal cord, and cancer of the meninges that surround the brain and spinal cord. The term "BRAF-related CNS cancer" refers to a CNS cancer that is associated with or has a BRAF mutation. Cancers of the CNS include metastatic brain cancer and malignant primary brain tumors.

[0555] In one embodiment, the BRAF-related CNS cancer is BRAF-related metastatic brain cancer. The BRAF-related metastatic brain cancer can be the result of any of the cancers described herein, wherein the subject has developed at least one brain metastasis. In one embodiment, the BRAF-related metastatic brain cancer is metastatic melanoma, metastatic colorectal cancer, or metastatic non-small cell lung cancer. In one embodiment, the BRAF-related metastatic brain cancer is metastatic melanoma. In one embodiment, the BRAF-related metastatic brain cancer is metastatic colorectal cancer. In one embodiment, the BRAF-related metastatic brain cancer is metastatic non-small cell lung cancer. In one embodiment, the BRAF-related metastatic brain cancer is metastatic ovarian cancer. In one embodiment, the metastatic brain cancer is metastatic thyroid cancer. In one embodiment, the BRAF-related metastatic brain cancer is renal cancer. In one embodiment, the cancer is a BRAF-related metastatic cancer with at least one brain metastasis (i.e., metastatic brain cancer). In one embodiment, the cancer is a BRAF-related metastatic melanoma with at least one brain metastasis. In one embodiment, the cancer is a BRAF-related metastatic colorectal cancer with at least one brain metastasis. In one embodiment, the cancer is a BRAF-related metastatic non-small cell lung cancer with at least one brain metastasis. In one embodiment, the cancer is a BRAF-related metastatic ovarian cancer with at least one brain metastasis. In one embodiment, the cancer is a BRAF-related metastatic thyroid cancer with at least one brain metastasis. In one embodiment, the cancer is a BRAF-related neuroblastoma with at least one brain metastasis.

[0556] Leptomeningeal metastases (leptomeningeal disease (LMD)) represent a subset of CNS metastases that grow in the inner membranes of the brain or spine and / or in the cerebrospinal fluid (CSF), or leptomeningeal carcinomatosis. In mammals, the meninges are the dura mater, arachnoid mater, and pia mater. The CSF is located in the subarachnoid space between the arachnoid mater and the pia mater. The arachnoid mater and pia mater together are sometimes also referred to as the leptomeninges. When LMD occurs in the leptomeninges and / or CSF surrounding the spinal cord, it can be referred to as "extracranial LMD". When LMD occurs in the leptomeninges and / or CSF of the brain, it can be referred to as "intracranial LMD". Since LMD cancer cells can be suspended in the CSF, they can rapidly spread throughout the CNS. As a result, LMD has a poor prognosis, and survival is typically measured in months. In one embodiment, the metastatic cancer is BRAF-related LMD. In one embodiment, the metastatic cancer is intracranial BRAF-related LMD. In one embodiment, the metastatic cancer is extracranial BRAF-related LMD. The BRAF-related cancers with the highest incidence of leptomeningeal metastases are lung cancer and melanoma. In one embodiment, the BRAF-related LMD is LMD derived from melanoma metastases (i.e., LMD is metastatic melanoma). In one embodiment, the BRAF-related LMD is LMD derived from colorectal cancer metastases (i.e., LMD is metastatic colorectal cancer). In one embodiment, the BRAF-related LMD is LMD derived from non-small cell lung cancer metastases (i.e., LMD is metastatic non-small cell lung cancer).

[0557] In one embodiment, the cancer is a BRAF-related cancer with a high risk of metastasis. In one embodiment, the BRAF-related cancer with a high risk of metastasis is a cancer having a BRAF V600E or BRAF V600K mutation. In one embodiment, the BRAF-related cancer with a high risk of metastasis is melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, or neuroblastoma. In one embodiment, the BRAF-related cancer with a high risk of metastasis is melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, or neuroblastoma, each having a BRAF V600E or BRAF V600K mutation. In one embodiment, the BRAF-related cancer with a high risk of metastasis is melanoma. In one embodiment, the BRAF-related cancer with a high risk of metastasis is melanoma having a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the BRAF-related cancer with a high risk of metastasis is colorectal cancer. In one embodiment, the BRAF-related cancer with a high risk of metastasis is colorectal cancer having a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the BRAF-related cancer with a high risk of metastasis is thyroid cancer. In one embodiment, the BRAF-related cancer with a high risk of metastasis is thyroid cancer having a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the BRAF-related cancer with a high risk of metastasis is non-small cell lung cancer. In one embodiment, the BRAF-related cancer with a high risk of metastasis is non-small cell lung cancer having a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the BRAF-related cancer with a high risk of metastasis is ovarian cancer. In one embodiment, the BRAF-related cancer with a high risk of metastasis is ovarian cancer having a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the BRAF-related cancer with a high risk of metastasis is neuroblastoma. In one embodiment, the BRAF-related cancer with a high risk of metastasis is neuroblastoma having a BRAF V600E mutation or a BRAF V600K mutation.

[0558] In one embodiment, the cancer is a BRAF - related cancer with a class II mutation. In one embodiment, the class II mutation is a non - V600 mutation. In one embodiment, the non - V600 mutation is G469A, G469R, G469V, K601E, K601N, K601T, L597Q, or L597V. In one embodiment, the non - V600 mutation is G469A. In one embodiment, the class II mutation is a BRAF splice variant. In one embodiment, the BRAF splice variant lacks exons 4 - 8 (also known as p61BRAF(V600E)), exons 4 - 10, exons 2 - 8, or exons 2 - 10. In one embodiment, the BRAF splice variant is p61BRAF(V600E). Non - limiting examples of BRAF - related cancers with a class II mutation include lung cancer (e.g., non - small cell lung cancer and small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendiceal cancer, small intestine cancer, head and neck squamous cell carcinoma, angiosarcoma, bladder cancer, plasma cell tumors, hepatobiliary pancreatic cancer, ovarian cancer, neuroendocrine cancer, cholangiocarcinoma, and CNS tumors.

[0559] In one embodiment, the BRAF - related cancer is a BRAF - related CNS tumor. In one embodiment, the BRAF - related CNS tumor is a BRAF - related primary brain tumor. In one embodiment, the primary brain tumor is a malignant primary brain tumor. In one embodiment, the primary brain tumor is a benign primary brain tumor. In one embodiment, the primary brain tumor has a class I mutation. In one embodiment, the primary brain tumor has a BRAF V600 mutation. In one embodiment, the primary brain tumor has a BRAF V600E or BRAF V600K mutation. In one embodiment, the primary brain tumor has a class II mutation. In one embodiment, the primary brain tumor has a class II mutation selected from G469A, G469R, G469V, K601E, K601N, K601T, L597Q, and L597V. In one embodiment, the primary brain tumor has a G469A mutation. A primary brain tumor is a tumor that begins in the brain or spine and is collectively referred to as a glioma. The term "glioma" is used to describe tumors that originate from glial cells present in the CNS. According to the WHO classification of brain tumors, gliomas are graded according to cell activity and invasiveness, and the grades include grade I (benign CNS tumors) and grades II to IV (malignant CNS tumors):

[0560] Grade I gliomas (pilocytic astrocytomas): Usually occur in the cerebellum or brainstem of children and occasionally in the cerebral hemispheres, and grow slowly. Grade I can occur in adults. Although they are benign (WHO grade I), the difficulty in curing this disease makes their growth behavior malignant, with a high incidence (Rostami, Acta Neurochir (Wien). 2017;159(11):2217 - 2221).

[0561] Grade II gliomas (low - grade gliomas): Include astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. Grade II gliomas usually occur in young adults (in their 20s to 50s) and are most common in the cerebral hemispheres. Due to the infiltrative nature of these tumors, recurrence may occur. Some grade II gliomas recur and evolve into more aggressive tumors (grade III or IV).

[0562] Grade III gliomas (anaplastic gliomas): Include anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic mixed oligoastrocytomas. Grade III tumors are invasive, high - grade cancers that invade nearby brain tissue with finger - like projections, making complete surgical removal more difficult.

[0563] Grade IV gliomas: Include glioblastoma multiforme (GBM) and gliosarcoma; (GBM) is an anaplastic glioma. GBM is the most aggressive and most common primary brain tumor. Glioblastoma multiforme often spreads rapidly with finger - like projections and invades other parts of the brain, making complete surgical removal more difficult. Gliosarcoma is a malignant cancer and is defined as a glioblastoma composed of glial and sarcomatous components.

[0564] In one embodiment, the BRAF - related primary brain tumor is a glioma. In certain embodiments, the BRAF - related primary brain tumor is a glioma with class I mutations. In certain embodiments, the BRAF - related primary brain tumor is a glioma with class II mutations.

[0565] Benign primary brain tumors can cause severe pain, permanent brain damage, and death, and in some cases, become malignant. Non-limiting examples of benign primary brain tumors include grade I gliomas, papillary craniopharyngiomas, meningiomas (including rhabdoid meningiomas), atypical teratoid / rhabdoid tumors, and dysembryoplastic neuroepithelial tumors (DNTs), pilocytic astrocytomas, oligodendrogliomas, oligoastrocytomas, anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic oligoastrocytomas, diffuse astrocytomas, ependymomas, pleomorphic xanthoastrocytomas (PXAs), gangliogliomas, gliosarcomas, or anaplastic gangliogliomas. In one embodiment, the BRAF-related tumor is a benign primary brain tumor.

[0566] In one embodiment, the BRAF-related cancer is a peripheral nervous system cancer. In one embodiment, the peripheral nervous system cancer is neuroblastoma. In one embodiment, the cancer is a BRAF-related cancer.

[0567] Certain compounds of formula I, formula I-A, formula II, formula III, formula IV, or formula V, or pharmaceutically acceptable salts thereof, exhibit good brain and / or CNS penetration and / or exhibit low efflux. Such compounds are able to cross the BBB and can be used to inhibit BRAF kinase in the brain and / or other CNS structures.

[0568] Accordingly, certain compounds of Formula I, I-A, II, III, IV or V described herein or pharmaceutically acceptable salts thereof can also be used to treat BRAF-related CNS tumors. For example, treatment of a subject having a BRAF-related CNS tumor can include administering (e.g., orally) a compound of Formula I, I-A, II, III, IV or V or a pharmaceutically acceptable salt thereof to the subject. In certain embodiments, the BRAF-related CNS cancer has a BRAF V600 mutation. In certain embodiments, the BRAF-related CNS cancer has a BRAF V600E and / or V600K mutation. In certain embodiments, the BRAF-related CNS cancer has a BRAF V600E mutation. In certain embodiments, the BRAF-related CNS cancer has a BRAF V600K mutation. In certain embodiments, the subject has been previously treated with one or more other anti-cancer therapies (e.g., anti-cancer agents, surgery and / or radiation therapy, e.g., as described below). In certain embodiments, the subject is treated with a compound of Formula I, I-A, II, III, IV or V or a pharmaceutically acceptable salt thereof in combination with one or more other anti-cancer therapies (e.g., anti-cancer agents, surgery and / or radiation therapy, e.g., as described below). In certain embodiments, the subject is treated with one or more anti-cancer therapies (e.g., anti-cancer agents, surgery and / or radiation therapy) after administration of a compound of Formula I, I-A, II, III, IV or V or a pharmaceutically acceptable salt thereof (e.g., as described below).

[0569] In certain embodiments of any of the methods described herein, the tumor is a BRAF-related CNS tumor, and the method comprises administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In certain embodiments, the BRAF-related tumor is a CNS tumor. In certain embodiments, the BRAF-related CNS tumor is a malignant CNS tumor (CNS cancer). In certain embodiments, the malignant CNS tumor is metastatic CNS cancer. In certain embodiments, the metastatic CNS cancer is metastatic melanoma. In certain embodiments, the metastatic CNS cancer is colorectal cancer. In certain embodiments, the metastatic CNS cancer is metastatic non-small cell lung cancer. In certain embodiments, the metastatic CNS cancer is metastatic thyroid cancer. In certain embodiments, the metastatic CNS cancer is metastatic ovarian cancer. In certain embodiments, the BRAF-related CNS tumor is LMD. In certain embodiments, the LMD is intracranial. In certain embodiments, the LMD is extracranial. In certain embodiments, the LMD is metastatic melanoma. In certain embodiments, the LMD is metastatic colorectal cancer. In certain embodiments, the LMD is metastatic non-small cell lung cancer. In certain embodiments, the BRAF-related CNS cancer is a primary brain tumor. In certain embodiments, the primary brain tumor is a grade 2 glioma. In certain embodiments, the primary brain tumor is a grade 3 glioma. In certain embodiments, the primary brain tumor is a grade 4 glioma. In certain embodiments, the BRAF-related CNS tumor is a benign tumor. In certain embodiments, the benign CNS tumor is a papillary craniopharyngioma, meningioma (including rhabdoid meningioma), atypical teratoid / rhabdoid tumor or dysembryoplastic neuroepithelial tumor. In certain embodiments, the compound is selected from the compounds of Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0570] The ability of a compound to be suitable for treating CNS cancer can be determined, for example, by identifying whether the compound is a substrate of an efflux transporter and / or measuring cell permeability and / or measuring the free brain / free plasma ratio, as described herein.

[0571] In certain embodiments, a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof exhibits high cell permeability. The method for determining the permeability of a compound can be determined according to the assay described in Example B, and the permeability coefficients of the compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V are provided in Table B1.

[0572] Certain compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or pharmaceutically acceptable salts thereof, exhibit low efflux. An in vitro method for evaluating whether the compounds are substrates of the efflux transporters P-glycoprotein (P-gp or multidrug resistance 1 (MDR1) protein) and breast cancer resistance protein (BCRP) is described in Example B, and the efflux rates of the compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V are provided in Table B2. In one embodiment, the compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or pharmaceutically acceptable salts thereof, have an efflux rate of ≤3.5 when tested in cells expressing P-gp. In one embodiment, the compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or pharmaceutically acceptable salts thereof, have an efflux rate of ≤3.5 when tested in cells expressing P-gp and an efflux rate of ≤5.5 when tested in cells expressing BCRP.

[0573] In certain embodiments, certain compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or pharmaceutically acceptable salts thereof, exhibit a moderate to high brain (unbound) / plasma (unbound) ratio (i.e., a moderate to high free brain / plasma ratio). The ability of a compound to penetrate the BBB of a subject (e.g., a human) can be determined in a suitable animal model (e.g., a rodent, such as a mouse). For example, the ability of certain compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V to penetrate the BBB of a mouse is determined by evaluating the unbound brain / unbound plasma concentration (free B / P) ratio in the mouse (e.g., as described in Example C), and the free brain / free plasma ratios are provided in Table C. A free brain / free plasma ratio equal to or greater than 0.3 is evidence of a significant degree of free CNS penetration.

[0574] Accordingly, in certain embodiments, the methods of the invention include methods of treating BRAF-related CNS cancers in a subject in need thereof. In one embodiment, the method includes administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, such that at least a portion of the compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V penetrates the BBB, as demonstrated in a suitable animal model. In certain embodiments, after administration to a subject (e.g., orally or intravenously), the brain / plasma ratio of the total drug is at least about 0.3. It should be noted that the percentage of compound penetration through the BBB is calculated based on the area under the concentration-time curve (AUC 0-t ) of the brain relative to plasma over a given time period. Thus, the percentage represents a ratio of concentrations. That is, if the (AUC 0-24h)If it is 30 ng / mL in the brain and 70 ng / mL in the plasma, the percentage of the compound penetrating the BBB is 30% (30 ng / mL in the brain divided by the total concentration (30 ng / mL + 70 ng / mL)) (i.e., a brain-to-plasma ratio of 0.30). In certain embodiments, the percentage is calculated based on the area under the concentration-time curve over the period from t = 0 (the administration time point) to the last quantifiable concentration point, i.e., (AUC 0-最后 ).

[0575] Mutations in the BRAF gene have been identified in malignant melanoma, papillary thyroid cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and ovarian cancer and their metastatic tumors, as well as in primary brain tumors (Davies et al., 2002). For example, BRAF mutations have been observed in numerous metastatic CNS tumors, including melanoma brain metastases (Flaherty KT et al., Nat Rev Cancer (2012) 12(5):349 - 61), brain metastases of colorectal cancer, and non-small cell lung cancer (Berghoff, AS, Preusser M., Curr Opin Neurol (2014) 27(6):689 - 696), papillary thyroid cancer (Kim, WW et al., J Otolaryngol Head Neck Surg. 2018;47:4), and brain metastases of ovarian cancer (Grisham RN. et al., Cancer. 2013;119:548 - 554).

[0576] In pediatric and adult populations, BRAF mutations have also been observed in malignant primary brain tumors, including grade IV gliomas, such as glioblastoma and glioneuronal sarcoma, anaplastic astrocytomas (high-grade tumors), and WHO grade III anaplastic gangliogliomas (Berghoff, AS, Preusser M., Curr Opin Neurol (2014) 27(6):689 - 696); Schindler et al. (Acta Neuropathol 121(3):397 - 405, 2011); Behling et al. (Diagn Pathol 11(1):55, 2016)).

[0577] BRAF mutations have also been observed in benign primary brain tumors in pediatric and adult populations, such as in WHO grade II astrocytomas, WHO grade II pleomorphic xanthoastrocytomas (PXA), anaplastic pleomorphic xanthoastrocytomas, pilocytic astrocytomas (PA), papillary craniopharyngiomas, gangliogliomas, astroblastomas, pilocytic astrocytomas, atypical teratoid / rhabdoid tumors, rhabdoid meningiomas (Berghoff, AS, Preusser M., Curr Opin Neurol (2014) 27(6):689-696; Schindler et al. (Acta Neuropathol 121(3):397-405, 2011); Behling et al. (Diagn Pathol 11(1):55, 2016); (Behling et al., Diagn Pathol 11(1):55, 2016; Brastianos et al., Nat Genet 46(2):161-165, 2014; Dougherty et al., Neuro Oncol 12(7):621-630, 2010; Lehman et al., Neuro Oncol 19(1):31-42, 2017; Mordechai et al., Pediatr Hematol Oncol 32(3):207-211, 2015; Myung et al., Transl Oncol 5(6):430-436, 2012; Schindler et al., Acta Neuropathol 121(3):397-405, 2011)).

[0578] BRAF mutations have also been detected in recurrent neuroblastomas (Eleveld, TF et al., Nat Genet 47(8):864-871, 2015). Neuroblastoma is a pediatric tumor of the peripheral nervous system. Most neuroblastoma subjects have tumors that are initially responsive to chemotherapy, but a large proportion of subjects will experience a recurrence of therapy resistance.

[0579] Accordingly, the present invention also provides a method for treating a subject diagnosed with or identified as having a BRAF-related tumor (e.g., any of the exemplary BRAF-related tumors disclosed herein), the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the subject has been identified or diagnosed as having a BRAF-related tumor by using an assay or determination approved by a regulatory agency (e.g., FDA-approved) for identifying BRAF mutations in a subject or a biopsy sample from a subject, or by performing any non-limiting example of the assays described herein. In certain embodiments, the assay or determination is provided as a kit. In one embodiment, the BRAF-related tumor can be a cancer having one or more Class I BRAF mutations (e.g., V600E and / or V600K). In one embodiment, the BRAF-related tumor can be a cancer having one or more Class II mutations (e.g., G469A). In certain embodiments, the compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof. In certain embodiments, the BRAF-related tumor is a malignant BRAF-related tumor (i.e., BRAF-related cancer). In certain embodiments, the BRAF-related cancer is a BRAF-related CNS cancer. In certain embodiments, the BRAF-related CNS cancer is a BRAF-related metastatic cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic melanoma. In certain embodiments, the BRAF-related metastatic cancer is metastatic colorectal cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic non-small cell lung cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic thyroid cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic ovarian cancer. In certain embodiments, the BRAF-related metastatic cancer is intracranial LMD or extracranial LMD. In certain embodiments, the BRAF-related CNS cancer is a primary brain tumor. In certain embodiments, the BRAF-related tumor is a benign CNS tumor. In certain embodiments, the cancer is selected from lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendiceal cancer, small intestine cancer, head and neck squamous cell carcinoma, angiosarcoma, and CNS tumors. In certain embodiments, the compound is selected from the compounds of Examples 1-164 or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject is an adult subject. In certain embodiments, the subject is a pediatric subject.

[0580] Also provided are methods of treating tumors in a subject in need thereof, the methods comprising: (a) detecting a BRAF-related tumor in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments of these methods, the tumor is a benign BRAF-related tumor. In certain embodiments of these methods, the tumor is a malignant BRAF-related tumor. In certain embodiments of these methods, the tumor is a malignant BRAF-related tumor (e.g., any of the malignant BRAF-related tumors described herein), and the method further comprises administering to the subject one or more additional anti-cancer therapies, e.g., surgery (e.g., at least partial resection of the tumor) and / or radiation therapy and / or anti-cancer agents. In certain embodiments of these methods, the tumor is a benign BRAF-related tumor, e.g., a benign BRAF-related CNS tumor, and the method further comprises administering to the subject one or more additional anti-cancer therapies, e.g., surgery (e.g., at least partial resection of the tumor) and / or radiation therapy and / or anti-cancer agents. In certain embodiments, it is determined that the subject has a BRAF-related tumor by using an assay or determination approved by a regulatory agency (e.g., FDA-approved) for identifying BRAF mutations in a subject or a biopsy sample from a subject (e.g., a tissue or liquid biopsy), or by performing any non-limiting example of the assays described herein. In certain embodiments, the assay or determination is provided as a kit. In certain embodiments, the BRAF-related tumor is a malignant BRAF-related tumor (i.e., BRAF-related cancer). In certain embodiments, the BRAF-related cancer is a BRAF-related CNS cancer. In certain embodiments, the BRAF-related CNS cancer is a BRAF-related metastatic cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic melanoma. In certain embodiments, the BRAF-related metastatic cancer is metastatic colorectal cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic non-small cell lung cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic thyroid cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic ovarian cancer. In certain embodiments, the BRAF-related metastatic cancer is intracranial LMD or extracranial LMD. In certain embodiments, the BRAF-related CNS cancer is a primary brain tumor. In certain embodiments, the BRAF-related tumor is a benign CNS tumor.In certain embodiments, the cancer is selected from lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendiceal cancer, small intestine cancer, head and neck squamous cell carcinoma, angiosarcoma, and CNS tumors. In certain embodiments, the compound is selected from the compounds of Examples 1-164 or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject is an adult subject. In certain embodiments, the subject is a pediatric subject.

[0581] Also provided are methods of treating a subject having a BRAF-related tumor, the methods comprising performing an assay on a sample obtained from the subject to determine that the subject has a tumor containing a BRAF mutation, and administering to the subject determined to have the BRAF mutation a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments of these methods, the BRAF-related tumor is a malignant BRAF-related tumor (i.e., a BRAF-related cancer), and the method further comprises administering to the subject one or more other anti-cancer therapies, such as surgery (e.g., at least partial resection of the tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In certain embodiments of these methods, the subject has been previously treated with another anti-cancer treatment such as surgery (e.g., at least partial resection of the tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In certain embodiments, the subject is a subject suspected of having a BRAF-related tumor, a subject presenting one or more symptoms of a BRAF-related tumor, or a subject having an elevated risk of developing a BRAF-related tumor. In certain embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry, or disassociation FISH analysis. In certain embodiments, the assay is an assay approved by a regulatory agency, such as an FDA-approved kit. In certain embodiments, the assay is a liquid biopsy. In certain embodiments, the biopsy is a tissue biopsy. In certain embodiments, the cancer is a CNS cancer and the biopsy is a liquid biopsy (e.g., CSF). In certain embodiments, the cancer is a CNS cancer and the biopsy is a tissue biopsy (e.g., a tumor sample obtained during conventional surgery or stereotactic needle biopsy (e.g., stereotactic needle biopsy guided by CT or MRI scan)). Additional non-limiting assays that can be used in these methods are described herein. Additional assays are also known in the art. In certain embodiments, the BRAF-related tumor is a malignant BRAF-related tumor (i.e., a BRAF-related cancer). In certain embodiments, the BRAF-related cancer is a BRAF-related CNS cancer. In certain embodiments, the BRAF-related CNS cancer is a BRAF-related metastatic cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic melanoma. In certain embodiments, the BRAF-related metastatic cancer is metastatic colorectal cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic non-small cell lung cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic thyroid cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic ovarian cancer.In certain embodiments, the BRAF-related metastatic cancer is intracranial LMD or extracranial LMD. In certain embodiments, the BRAF-related CNS cancer is a primary brain tumor. In certain embodiments, the BRAF-related tumor is a benign CNS tumor. In certain embodiments, the cancer is selected from lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendiceal cancer, small intestine cancer, head and neck squamous cell carcinoma, angiosarcoma, and CNS tumors. In certain embodiments, the subject is an adult subject. In certain embodiments, the subject is a pediatric subject.

[0582] Also provided are compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or pharmaceutically acceptable salts thereof for treating BRAF-related tumors in a subject identified or diagnosed as having a BRAF-related tumor, said identification or diagnosis being achieved by performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine that the subject has a BRAF mutation, wherein the presence of the BRAF mutation identifies the subject as having a BRAF-related tumor. Also provided is the use of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating BRAF-related tumors in a subject identified or diagnosed as having a BRAF-related tumor, said identification or diagnosis being achieved by performing an assay on a sample obtained from the subject to determine whether the subject has a BRAF mutation, thereby identifying the subject as having a BRAF-related tumor. Certain embodiments of any of the methods or uses described herein further comprise recording in the clinical record (e.g., a computer-readable medium) of the subject that the subject has been determined to have a BRAF mutation by performing the assay and that a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof should be administered. In certain embodiments, the assay utilizes next-generation sequencing, pyrosequencing, immunohistochemistry or break-apart FISH analysis. In certain embodiments, the assay is an assay approved by a regulatory agency, e.g., an FDA-approved kit. In certain embodiments, the assay is a liquid biopsy. In certain embodiments, the BRAF-related tumor is a malignant BRAF-related tumor (i.e., a BRAF-related cancer). In certain embodiments, the BRAF-related cancer is a BRAF-related CNS cancer. In certain embodiments, the BRAF-related CNS cancer is a BRAF-related metastatic cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic melanoma. In certain embodiments, the BRAF-related metastatic cancer is metastatic colorectal cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic non-small cell lung cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic thyroid cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic ovarian cancer. In certain embodiments, the BRAF-related metastatic cancer is intracranial LMD or extracranial LMD. In certain embodiments, the BRAF-related CNS cancer is a primary brain tumor. In certain embodiments, the BRAF-related tumor is a benign CNS tumor.In certain embodiments, the cancer is selected from lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendiceal cancer, small intestine cancer, head and neck squamous cell carcinoma, angiosarcoma, and CNS tumors. In certain embodiments, the subject is an adult subject. In certain embodiments, the subject is a pediatric subject.

[0583] Also provided are compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V or pharmaceutically acceptable salts thereof for treating BRAF-related tumors in a subject in need thereof or a subject identified or diagnosed as having a BRAF-related tumor. Also provided is the use of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V or pharmaceutically acceptable salts thereof for the preparation of a medicament for treating BRAF-related tumors in a subject identified or diagnosed as having a BRAF-related tumor. In certain embodiments, a kit approved by a regulatory agency (e.g., FDA-approved) for identifying BRAF mutations in a subject or a biopsy sample from a subject is used to identify or diagnose a subject as having a BRAF-related tumor. In certain embodiments, the BRAF-related tumor is a malignant BRAF-related tumor (i.e., BRAF-related cancer). In certain embodiments, the BRAF-related cancer is BRAF-related CNS cancer. In certain embodiments, the BRAF-related CNS cancer is BRAF-related metastatic cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic melanoma. In certain embodiments, the BRAF-related metastatic cancer is metastatic colorectal cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic non-small cell lung cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic thyroid cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic ovarian cancer. In certain embodiments, the BRAF-related metastatic cancer is intracranial LMD or extracranial LMD. In certain embodiments, the BRAF-related CNS cancer is a primary brain tumor. In certain embodiments, the BRAF-related tumor is a benign CNS tumor. In certain embodiments, the cancer is selected from lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendiceal cancer, small intestine cancer, head and neck squamous cell carcinoma, angiosarcoma, and CNS tumors. In certain embodiments, the subject is an adult subject. In certain embodiments, the subject is a pediatric subject.

[0584] In certain embodiments of any of the methods or uses described herein, an assay for using a sample from an object to determine whether the object has a BRAF mutation can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, the assay is typically performed, for example, with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assay can utilize other detection methods known in the art for detecting BRAF mutations. In certain embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the object. In certain embodiments, the object is an object suspected of having a BRAF-related tumor, an object having one or more symptoms of a BRAF-related tumor, and / or an object having an increased risk of developing a BRAF-related tumor).

[0585] In certain embodiments, the biopsy is a tumor biopsy (e.g., a tumor sample obtained during traditional surgery or stereotactic needle biopsy (e.g., stereotactic needle biopsy guided by CT or MRI scan)). Tissue biopsy methods can be used to detect total tumor burden and / or BRAF mutations.

[0586] In certain embodiments, a liquid biopsy (also referred to as a fluid biopsy or fluid-phase biopsy) can be used to identify BRAF mutations. See, e.g., Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and / or BRAF mutations. Liquid biopsies can be performed on biological samples obtained from a subject relatively easily (e.g., via a simple blood draw) and are generally less invasive compared to conventional methods for detecting tumor burden and / or BRAF mutations. In certain embodiments, liquid biopsies can be used to detect the presence of BRAF mutations at an earlier stage than conventional methods. In certain embodiments, the biological samples to be used for liquid biopsies can include CSF, blood, plasma, urine, saliva, sputum, bronchoalveolar lavage fluid, bile, lymph fluid, cyst fluid, feces, ascites, and combinations thereof. In certain embodiments, liquid biopsies can be used to detect circulating tumor cells (CTCs). In certain embodiments, liquid biopsies can be used to detect cell-free DNA. In certain embodiments, the cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify BRAF mutations.

[0587] In certain embodiments, the BRAF mutations identified using a liquid biopsy are also present in the cancer cells present in a subject (e.g., in a tumor). In certain embodiments, a liquid biopsy can be used to detect any of the BRAF mutation types. In certain embodiments, the gene mutations identified via a liquid biopsy can be used to identify a subject as a candidate for a particular treatment. For example, detection of a BRAF mutation in a subject can indicate that the subject will respond to a treatment comprising administration of a compound of formula I, formula I-A, formula II, formula III, formula IV, or formula V, or a pharmaceutically acceptable salt thereof.

[0588] "Tumor burden", also referred to as "tumor load", refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor throughout the body (including lymph nodes and bone marrow). Tumor burden can be determined by a variety of methods known in the art, for example, by measuring the size of the tumor (e.g., using calipers) after removal from the subject, or by using imaging techniques when the tumor is in the body, such as magnetic resonance imaging (MRI) scans, computed tomography (CT), multi-detector CT (MDCT), positron emission tomography (PET), X-rays, ultrasound, or bone scans.

[0589] The term "tumor size" or "size of the tumor" refers to the total size of the tumor that can be measured as the length and width of the tumor. Tumor size can be determined by a variety of methods known in the art, for example, by measuring the size of the tumor (e.g., using calipers) after removal from the subject, or by using imaging techniques when the tumor is in the body, such as MRI scans, bone scans, ultrasound, or CT.

[0590] Liquid biopsies can be performed multiple times during the diagnostic process, the monitoring process, and / or the treatment process to determine one or more clinically relevant parameters, including but not limited to the progression of the disease or the efficacy of the treatment after administration of the treatment to the subject. For example, during the diagnostic process, the monitoring process, and / or the treatment process, a first liquid biopsy can be performed at a first time point, and a second liquid biopsy can be performed at a second time point. In certain embodiments, the first time point can be a time point before diagnosing the subject with the disease (e.g., when the subject is healthy), and the second time point can be a time point after the subject has developed the disease (e.g., the second time point can be used to diagnose the subject with the disease). In certain embodiments, the first time point can be a time point before diagnosing the subject with the disease (e.g., when the subject is healthy), and then the subject is monitored, and the second time point can be a time point after monitoring the subject. In certain embodiments, the first time point can be a time point after diagnosing the subject with the disease, and then a treatment is administered to the subject, and the second time point can be a time point after administering the treatment; in such a case, the second time point can be used to evaluate the efficacy of the treatment (e.g., if a gene mutation detected at the first time point decreases in abundance or is undetectable). In certain embodiments, the treatment to be administered to the subject can include a compound of formula I, formula I-A, formula II, formula III, formula IV, or formula V or a pharmaceutically acceptable salt thereof.

[0591] In one embodiment, a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof can be used alone or in combination with one or more different forms of therapy to treat a subject having a malignancy. For example, a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof can also be used in combination with one or more additional anti-cancer therapies (e.g., surgery, radiation therapy and / or anti-cancer agents that act via the same or different mechanisms of action). In one embodiment, compared to treating the same or similar subjects with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof as a single therapy, treating a subject having a BRAF-related malignancy with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof in combination with one or more additional therapies (e.g., surgery, radiation therapy and / or anti-cancer agents) can have enhanced therapeutic efficacy.

[0592] Accordingly, in one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising: administering to the subject (i) a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof as a single therapy, or (ii) a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof in combination with one or more additional anti-cancer therapies. In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof for a period of time, wherein a second anti-cancer therapy is administered to the subject during the period of time. In one embodiment, the second anti-cancer therapy is a second anti-cancer agent.

[0593] Also provided herein are a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof for use in combination with an additional anti-cancer therapy. Also provided herein is an additional anti-cancer therapy for use in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof.

[0594] The present invention also provides a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof for treating BRAF-related tumors by co-administering with another anti-cancer therapy. The present invention also provides another anti-cancer therapy for treating BRAF-related tumors by co-administering with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof.

[0595] In certain embodiments, prior to administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, one or more anti-cancer therapies other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof are administered to the subject. In certain embodiments, the one or more anti-cancer therapies are selected from surgery and / or radiotherapy and / or anti-cancer agents that act via the same or different mechanisms of action. For example, in certain embodiments, prior to administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, a subject in need thereof may undergo at least partial resection of the tumor. In certain embodiments, treatment by at least partial resection of the tumor reduces the size (e.g., tumor burden) of the tumor that exists prior to administering one or more doses of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof. In certain embodiments, prior to administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, a subject in need thereof may undergo radiotherapy. In certain embodiments, prior to administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, a subject in need thereof may undergo treatment with one or more anti-cancer agents other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof. In certain embodiments, the subject has cancer that is resistant or intolerant to a prior therapy.

[0596] Accordingly, in certain embodiments, the present invention provides a method of treating a subject having a BRAF-related tumor, the method comprising: (i) administering to the subject one or more anti-cancer therapies over a period of time, and (ii) after (i), administering (a) a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof as a single therapy, or (b) a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof in combination with one or more other anti-cancer therapies.

[0597] In certain embodiments, a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof can be administered before administering one or more anti-cancer therapies (e.g., surgery, radiation therapy, and / or anti-cancer agents that act via the same or different mechanisms of action) to a subject having a tumor. For example, in certain embodiments, after administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, a subject in need thereof can undergo at least partial resection of the tumor. In certain embodiments, after administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, a subject in need thereof can undergo radiation therapy. In certain embodiments, before administering one or more anti-cancer agents other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, a subject in need thereof can undergo treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula I is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0598] Accordingly, in certain embodiments, provided herein are methods of treating a subject having a BRAF-related tumor, the method comprising: (i) administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof for a period of time, and (ii) after the period of time, administering one or more anti-cancer therapies. For example, a subject in need thereof can be administered one or more doses of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor. In certain embodiments, treatment with one or more doses of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof reduces the tumor size (e.g., tumor burden) prior to at least partial resection of the tumor. In one embodiment, the compound of Formula I is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0599] In certain embodiments of any of the above methods, the additional anti-cancer therapy is surgery, radiation therapy, and / or anti-cancer agents that act via the same or different mechanisms of action.

[0600] Non-limiting examples of additional anti-cancer agents that can be used in combination with a compound of formula I, II or III or a pharmaceutically acceptable salt thereof according to any of the above methods include, but are not limited to, MEK inhibitors, BRAF inhibitors (e.g., BRAF inhibitors other than compounds of formula I, I-A, II, III, IV or V), EGFR inhibitors, inhibitors of HER2 and / or HER3, Axl inhibitors, PI3K inhibitors and SOS1 inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapies and immune-targeted agents (including immunotherapies).

[0601] In one embodiment, the anti-cancer agent that can be used in combination with a compound of formula I, I-A, II, III, IV or V or a pharmaceutically acceptable salt thereof according to any of the above methods is a targeted therapeutic agent. As used herein, "targeted therapeutic agent" includes, denotes a molecule that blocks cancer cell growth by interfering with specific targeted molecules required for carcinogenesis and tumor growth rather than simply interfering with all rapidly dividing cells (e.g., using traditional cytotoxic chemotherapy), and includes, but is not limited to, receptor tyrosine kinase targeted therapeutic agents, signal transduction pathway inhibitors (e.g., Ras-Raf-MEK-ERK pathway inhibitors, PI3K-Akt-mTOR-S6K pathway inhibitors ("PI3K inhibitors")) and modulators of the apoptosis pathway.

[0602] In certain embodiments, the anticancer agent that can be used in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof according to any of the above methods is a MEK inhibitor. In one embodiment, the MEK inhibitor is binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733) or a pharmaceutically acceptable salt thereof. Further examples of MEK inhibitors include the compounds disclosed in WO 03 / 077914, WO 2005 / 023759, WO 2005 / 051301, US 7,517,994, US7,732,616, WO 2005 / 051906, WO 2005 / 051302, WO 2005 / 051300 and WO 2007 / 044084. In certain embodiments, the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof.

[0603] In certain embodiments, the anticancer agent that can be used in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof according to any of the above methods is another BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V. Non-limiting examples of other BRAF inhibitors include encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) and pharmaceutically acceptable salts thereof, and the compounds disclosed in International Application No. PCT / IB2020 / 055992 (published as PCT Publication No. WO2020 / 261156 A1 on December 30, 2020), including, for example, compounds selected from:

[0604] N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4-difluorophenyl)propane-1-sulfonamide;

[0605] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropropane-1-sulfonamide;

[0606] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)propane-1-sulfonamide;

[0607] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)propane-1-sulfonamide;

[0608] N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide;

[0609] N-(2-chloro-4-fluoro-3-((5-methyl-3-(methyl-d3)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropropane-1-sulfonamide;

[0610] N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-4-fluorophenyl}propane-1-sulfonamide;

[0611] N-(3-chloro-4-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-5-fluoropyridin-2-yl)propane-1-sulfonamide; and

[0612] N-{2-chloro-3-[(3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]-4-fluorophenyl}-3-fluoropropane-1-sulfonamide;

[0613] or a pharmaceutically acceptable salt thereof. In one embodiment, the BRAF inhibitor is encorafenib or a pharmaceutically acceptable salt thereof. In one embodiment, the BRAF inhibitor is N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropropane-1-sulfonamide or a pharmaceutically acceptable salt thereof. Further examples of BRAF inhibitors are known in the art.

[0614] In certain embodiments, the anti-cancer agent that can be used in combination with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof according to any of the above methods is an EGFR inhibitor. Non-limiting examples of EGFR inhibitors include cetuximab pembrolizumab osimertinib (merelectinib, ), erlotinib gefitinib necitumumab (Portrazza TM ), neratinib lapatinib vandetanib brigatinib and inhibitors of EGFR disclosed in PCT Publication Nos. WO 2019 / 071351 and WO 2017 / 117680, both of which are incorporated herein by reference in their entirety. Additional examples of EGFR inhibitors are known in the art. In one embodiment, the EGFR inhibitor is cetuximab.

[0615] In certain embodiments, the anti-cancer agent that can be used in combination with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof according to any of the above methods is a HER2 and / or HER3 inhibitor. Non-limiting examples of HER2 and / or HER3 inhibitors include lapatinib, canertinib, (E)-2-methoxy-N-(3-(4-(3-methyl-4-(6-methylpyridin-3-yloxy)phenylamino)quinazolin-6-yl)allyl)acetamide (CP-724714), sapitinib, 7-[[4-[(3-ethynylphenyl)amino]-7-methoxy-6-quinazolinyl]oxy]-N-hydroxy-heptanamide (CUDC-101), mulitinib, 6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE788), tucatinib (tucatinib), poziotinib, N-[4-[1-[4-(4-acetyl-1-piperazinyl)cyclohexyl]-4-amino-3-pyrazolo[3,4-d]pyrimidinyl]-2-methoxyphenyl]-1-methyl-2-indolecarboxamide (KIN001-111), 7-cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (KIN001-051), 6,7-dimethoxy-N-(4-phenoxyphenyl)quinazolin-4-amine (KIN001-30), dasatinib and bosutinib.

[0616] In certain embodiments, the anti-cancer agent that can be used in combination with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof in any of the above methods is an Axl inhibitor. Non-limiting examples of Axl inhibitors include bemcentinib, YW327.6S2 (monoclonal antibody), GL2I.T (decoy receptor), 2-(5-chloro-2-(4-((4-methylpiperazin-1-yl)methyl)phenylamino)pyrimidin-4-ylamino)-N,N-dimethylbenzenesulfonamide (TP-0903), 3-[2-[[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]amino]-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-benzonitrile (SGI-7079), gilteritinib, bosutinib, cabozantinib, sunitinib, fruquintinib, amuvatinib, gleciratinib, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS777607), masitinib, (Z)-3-((3-((4-(morpholinomethyl)-1H-pyrrol-2-yl)methylene)-2-oxoindolin-5-yl)methyl)thiazolidine-2,4-dione (S49076) and (R)-N-(3-fluoro-4-((3-((1-hydroxypropan-2-yl)amino)-1H-pyrazolo[3,4-b]pyridin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide.

[0617] In certain embodiments, the anti-cancer agent that can be used in combination with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof in any of the above methods is a SOS1 inhibitor. Non-limiting examples of SOS1 inhibitors include those disclosed in PCT Publication No. WO 2018 / 115380, which is incorporated herein by reference in its entirety.

[0618] In certain embodiments, the anti-cancer agent that can be used in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof for any of the above methods is a PI3K inhibitor. Non-limiting examples include buparlisib (BKM120), alpelisib (BYL719), sartanserin (LY3023414), 8-[(1R)-1-[(3,5-difluorophenyl)amino]ethyl]-N,N-dimethyl-2-(morpholin-4-yl)-4-oxo-4H-chromene-6-carboxamide (AZD8186), taselisib (RP6530), volasertib hydrochloride (SAR-245409), gedatolisib (PF-05212384), panulisib (P-7170), taselisib (GDC-0032), trans-2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PF-04691502), dactolisib (ABBV-954), N2-[4-oxo-4-[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholin-4-ium-4-ylmethoxy]butanoyl]-L-arginyl-glycyl-L-aspartyl-L-serine acetate (SF-1126), pictilisib (GDC-0941), 2-methyl-1-[2-methyl-3-(trifluoromethyl)benzyl]-6-(morpholin-4-yl)-1H-benzimidazole-4-carboxylic acid (GSK2636771), idelalisib (GS-1101), umbralisib tosylate (TGR-1202), pictilisib (GDC-0941), copanlisib hydrochloride (BAY84-1236), dactolisib (BEZ-235), 1-(4-[5-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1-ethyl-1H-1,2,4-triazol-3-yl]piperidin-1-yl)-3-hydroxypropan-1-one (AZD-8835), 5-[6,6-dimethyl-4-(morpholin-4-yl)-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl]pyrimidin-2-amine (GDC-0084), everolimus, rapamycin, perifosine, sirolimus, and temsirolimus.

[0619] In certain embodiments, an anti-cancer agent that can be used in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof in any of the above methods is immunotherapy. The term "immunotherapy" refers to an agent that modulates the immune system. In certain embodiments, immunotherapy can increase the expression and / or activity of a modulator of the immune system. In certain embodiments, immunotherapy can decrease the expression and / or activity of a modulator of the immune system. In certain embodiments, immunotherapy can recruit and / or enhance the activity of immune cells.

[0620] In certain embodiments, an immunotherapy that can be used in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof in any of the above methods is antibody therapy (e.g., monoclonal antibody, conjugated antibody). In certain embodiments, the antibody therapy is bevacizumab (Mvasti TM 、 ), trastuzumab avelumab rituximab (MabTheraT M 、 ), erlotumumab (Panorex), daratumumab olaratumab (Lartruvo TM ), ofatumumab alemtuzumab cetuximab ogivumab, pembrolizumab dinutuximab atezolizumab tremelimumab (CP-675, 206), ramucirumab umatuximab (TG-1101), pamumab elotuzumab (Empliciti TM ), necitumumab (Portrazza TM ), cirmtuzumab (UC-961), ibritumomab isatuximab (SAR650984), nimotuzumab, fusumumab (GC1008), leridumab (INN), mogamulizumab ficlatuzumab (AV-299), denosumab ganitumab, urelumab, pidilizumab, amatuximab, lintuzumab (AMG103; ), or midostaurin (Rydapt).

[0621] In certain embodiments, an immunotherapy that can be used in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V or a pharmaceutically acceptable salt thereof in any of the above methods is an antibody-drug conjugate. In certain embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg TM ), inotuzumab ozogamicin brentuximab vedotin ado-trastuzumab emtansine (TDM-1; ), cintredekin besudotox (IMGN853) or sarecycline.

[0622] In certain embodiments, an immunotherapy that can be used in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V or a pharmaceutically acceptable salt thereof in any of the above methods includes a toxin. In certain embodiments, the immunotherapy is denileukin diftitox

[0623] In certain embodiments, an immunotherapy that can be used in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V or a pharmaceutically acceptable salt thereof in any of the above methods is cytokine therapy. In certain embodiments, the cytokine therapy is interleukin-2 (IL-2) therapy, interferon-alpha (IFNα) therapy, granulocyte colony-stimulating factor (G-CSF) therapy, interleukin-12 (IL-12) therapy, interleukin-15 (IL-15) therapy, interleukin-7 (IL-7) therapy, or erythropoietin-alpha (EPO) therapy. In certain embodiments, the IL-2 therapy is aldesleukin In certain embodiments, the IFNα therapy is In certain embodiments, the G-CSF therapy is filgrastim

[0624] In certain embodiments, an immunotherapy that can be used in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V or a pharmaceutically acceptable salt thereof in any of the above methods is an immune checkpoint inhibitor. In certain embodiments, the immunotherapy includes one or more immune checkpoint inhibitors. In certain embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In certain embodiments, the CTLA-4 inhibitor is ipilimumab or tremelimumab (CP-675,206). In certain embodiments, the PD-1 inhibitor is pembrolizumab or nivolumab In certain embodiments, the PD-L1 inhibitor is atezolizumab avelumab or durvalumab (Imfinzi TM ). In certain embodiments, the PD-1 inhibitor is RN888 (sasimolimab).

[0625] In certain embodiments, an immunotherapy that can be combined with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof for any of the above methods is mRNA-based immunotherapy. In certain embodiments, the mRNA-based immunotherapy is CV9104 (see, e.g., Rausch et al. (2014) Human Vaccine Immunother 10(11): 3146-52; and Kubler et al. (2015) J. Immunother Cancer 3: 26).

[0626] In certain embodiments, an immunotherapy that can be combined with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof for any of the above methods is oncolytic virus therapy. In certain embodiments, the oncolytic virus therapy is talimogene alherparepvec (T-VEC; ).

[0627] In certain embodiments, an immunotherapy that can be combined with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof for any of the above methods is a cancer vaccine. In certain embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In certain embodiments, the HPV vaccine is or In certain embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In certain embodiments, the HBV vaccine is or GI-13020 In certain embodiments, the cancer vaccine is or In certain embodiments, the cancer vaccine is GVAX, ADXS11-001, ALVAC-CEA, CimaVax-EGF, lapuleucel-T (APC8024; Neuvenge TM)、GRNVAC1, GRNVAC2, GRN-1201, hepcortespenlisimut-L (Hepko-V5), SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, DPX-Survivac, or viagenpumatucel-L (HS-110).

[0628] In certain embodiments, the immunotherapy that can be used in any of the above methods in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof is a peptide vaccine. In certain embodiments, the peptide vaccine is nelipepimut-S (E75) (NeuVax TM ), IMA901 or SurVaxM (SVN53-67). In certain embodiments, the cancer vaccine is an immunogenic personal neoantigen vaccine (see, e.g., Ott et al. (2017) Nature 547:217-221; Sahin et al. (2017) Nature 547:222-226). In certain embodiments, the cancer vaccine is RGSH4K or NEO-PV-01. In certain embodiments, the cancer vaccine is a DNA-based vaccine. In certain embodiments, the DNA-based vaccine is a mammaglobin-A DNA vaccine (see, e.g., Kim et al. (2016) OncoImmunology 5(2):e1069940).

[0629] In certain embodiments, the immunotherapy that can be used in any of the above methods in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof is a cellular immunotherapy (e.g., adoptive T-cell therapy, dendritic cell therapy, natural killer cell therapy). In certain embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge TM ; Plosker (2011) Drugs 71(1):101-108). In certain embodiments, the cellular immunotherapy includes cells expressing a chimeric antigen receptor (CAR). In certain embodiments, the cellular immunotherapy is CAR-T cell therapy. In certain embodiments, the CAR-T cell therapy is tisagenlecleucel (Kymriah TM ).

[0630] In certain embodiments, the anticancer agent that can be used in combination with a compound of formula I, I-A, II, III, IV or V or a pharmaceutically acceptable salt thereof in any of the above methods is a cytotoxic chemotherapeutic agent. Non-limiting examples of cytotoxic chemotherapeutic agents include arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, 5-fluorouracil, leucovorin, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine and combinations thereof, for example, Nordic FLOX (fluorouracil, leucovorin, and oxaliplatin), FOLFOXIRI (oxaliplatin, irinotecan, and fluorouracil), FOLFIRI (leucovorin, fluorouracil, and irinotecan), or CAPEOX (capecitabine and oxaliplatin).

[0631] In certain embodiments, the anticancer agent that can be used in combination with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof in any of the above methods is an angiogenesis-targeted therapy. Non-limiting examples of angiogenesis-targeted therapies include aflibercept and bevacizumab.

[0632] In certain embodiments, the anticancer agent that can be used in combination with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof in any of the above methods includes a modulator of the apoptotic pathway (such as obataclax).

[0633] In certain embodiments, the anticancer therapy that can be used in combination with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof in any of the above methods is radiotherapy. Non-limiting examples of radiotherapy include external radiation beam therapy (e.g., external beam therapy using kilovolt X-rays or megavolt X-rays) or internal radiotherapy. Internal radiotherapy (also known as brachytherapy) can include the use of, for example, low-dose internal radiotherapy or high-dose internal radiotherapy. Low-dose internal radiotherapy includes, for example, inserting small radioactive pellets (also known as seeds) into or near the cancerous tissue of a subject. High-dose internal radiotherapy includes, for example, inserting a thin tube (e.g., a catheter) or an implant into or near the cancerous tissue of a subject and using a radiotherapy machine to deliver a high dose of radiation to the thin tube or implant. Methods of performing radiotherapy on a subject having cancer are known in the art. In embodiments where the tumor is a CNS tumor, the radiotherapy can include whole brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) such as Gamma or

[0634] In certain embodiments, the anti-cancer therapy that can be used in combination with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof in any of the above methods is surgery. Non-limiting examples of surgery include, for example, open surgery or minimally invasive surgery. Surgery can include, for example, at least partial resection of the tumor, removal of the entire tumor, debulking of the tumor, or removal of a tumor that causes pain or pressure in the subject. Methods of performing open surgery and minimally invasive surgery in a subject with cancer are known in the art.

[0635] In certain embodiments, the additional therapy includes any of the therapies or anti-cancer agents listed above that are the standard of care for cancer, wherein the cancer has a BRAF mutation.

[0636] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof for a period of time, wherein a MEK inhibitor (e.g., any of the MEK inhibitors disclosed herein) is administered to the subject during the period of time. In one embodiment, the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof. In one embodiment, the compound of Formula I is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0637] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof for a period of time, wherein a BRAF inhibitor (e.g., any of the BRAF inhibitors disclosed herein, including a second compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof) is administered to the subject during the period of time. In one embodiment, the compound is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0638] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, for a period of time, wherein an EGFR inhibitor (e.g., any of the EGFR inhibitors disclosed herein) is administered to the subject during the period of time. In one embodiment, the compound is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof. In one embodiment, the tumor is lung cancer.

[0639] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, for a period of time, wherein an inhibitor of HER2 and / or HER3 is administered to the subject during the period of time. In one embodiment, the compound is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0640] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, for a period of time, wherein an Axl inhibitor (e.g., any of the Axl inhibitors disclosed herein) is administered to the subject during the period of time. In one embodiment, the compound is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0641] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, for a period of time, wherein an SOS 1 inhibitor (e.g., any of the SOS 1 inhibitors disclosed herein) is administered to the subject during the period of time. In one embodiment, Compound I is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0642] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof for a period of time, wherein during the period of time a signal transduction inhibitor (e.g., any of the signal transduction inhibitors disclosed herein) is administered to the subject. In one embodiment, the compound is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0643] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof for a period of time, wherein during the period of time a checkpoint inhibitor (e.g., any of the checkpoint inhibitors disclosed herein) is administered to the subject. In one embodiment, the compound is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0644] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof for a period of time, wherein during the period of time a modulator of the apoptotic pathway (e.g., any of the modulators of the apoptotic pathway disclosed herein) is administered to the subject. In one embodiment, the compound is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0645] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof for a period of time, wherein during the period of time a cytotoxic chemotherapeutic agent (e.g., any of the cytotoxic chemotherapeutic agents disclosed herein) is administered to the subject. In one embodiment, the compound is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0646] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, for a period of time, wherein during the period, an angiogenesis-targeting therapy (e.g., any of the angiogenesis-targeting therapies disclosed herein) is administered to the subject. In one embodiment, the compound of Formula I is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0647] In one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor (e.g., any of the BRAF-related tumors described herein), the method comprising administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, for a period of time, wherein during the period, an immune-targeting agent (e.g., any of the immune-targeting agents disclosed herein) is administered to the subject. In one embodiment, the compound of Formula I is a compound selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

[0648] Also provided herein is a pharmaceutical combination for treating a BRAF-related tumor in a subject in need thereof, comprising (a) a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, and (b) at least one additional anti-cancer agent (e.g., any of the exemplary additional anti-cancer agents described herein or known in the art), wherein the compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer agent are formulated for simultaneous, separate or sequential use to treat the tumor, wherein the amount of the compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, and the amount of the additional anti-cancer agent together effectively treat the tumor; (ii) the use of such a combination for the preparation of a medicament for treating a tumor; and (iii) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and a method of treating a tumor in a subject in need thereof.

[0649] As used herein, the term "drug combination" refers to a non-fixed combination of active ingredients. The term "non-fixed combination" means that a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof and at least one additional anti-cancer agent are formulated into separate compositions or dosages such that they can be administered simultaneously, in parallel or sequentially at variable time intervals to a subject in need thereof, wherein such administration provides effective levels of two or more compounds in the subject. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0650] Accordingly, the present invention also provides a method for treating BRAF-related tumors, the method comprising administering to a subject in need thereof a pharmaceutical combination for treating said tumors, which comprises (a) a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof, and (b) an additional anti-cancer agent, which are used simultaneously, separately or sequentially to treat said tumors, wherein the amount of the compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof and the amount of the additional anti-cancer agent together effectively treat the tumors. In one embodiment, the BRAF-related tumor is a malignant tumor and the additional anti-cancer agent is an anti-cancer agent, for example, any one of the anti-cancer agents described herein. In certain embodiments, the compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof and the additional anti-cancer agent are administered simultaneously as separate doses. In certain embodiments, the compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof and the additional anti-cancer agent are administered sequentially as separate doses in any order, for example, daily or at spaced intervals, in an amount effective for combination therapy. The additional anti-cancer agent may be administered together with one or more doses of the compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, as part of the same or separate dosage forms, by the same or different routes of administration, and / or according to standard pharmaceutical practices known to those skilled in the art according to the same or different dosing regimens. In certain embodiments, the BRAF-related tumor is a malignant BRAF-related tumor (i.e., BRAF-related cancer). In certain embodiments, the BRAF-related cancer is a BRAF-related CNS cancer. In certain embodiments, the BRAF-related CNS cancer is a BRAF-related metastatic cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic melanoma. In certain embodiments, the BRAF-related metastatic cancer is metastatic colorectal cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic non-small cell lung cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic thyroid cancer. In certain embodiments, the BRAF-related metastatic cancer is metastatic ovarian cancer. In certain embodiments, the BRAF-related metastatic cancer is intracranial LMD or extracranial LMD. In certain embodiments, the BRAF-related CNS cancer is a primary brain tumor. In certain embodiments, the BRAF-related tumor is a benign CNS tumor.In certain embodiments, the cancer is selected from lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendiceal cancer, small intestine cancer, head and neck squamous cell carcinoma, angiosarcoma, and CNS tumors.

[0651] In certain embodiments of any of the methods described herein, the subject has a BRAF-related tumor (e.g., a benign, malignant, or metastatic tumor), wherein the subject has been treated with a prior therapy or a standard therapy (e.g., treated with one or more anti-cancer agents and / or radiation therapy and / or surgery other than a compound of formula I, formula I-A, formula II, formula III, formula IV, or formula V or a pharmaceutically acceptable salt thereof), and wherein the BRAF-related tumor has become resistant or intolerant to the prior therapy. In certain embodiments, the subject has a BRAF-related tumor that does not have a standard therapy (e.g., a locally advanced or metastatic tumor). In one embodiment, the method comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof selected from Examples 1-164.

[0652] Thus, in one embodiment, provided herein is a method of treating a subject having a BRAF-related tumor, wherein the subject has been previously treated with one or more anti-cancer therapies (e.g., anti-cancer agents, radiation therapy, and / or surgery), the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, formula I-A, formula II, formula III, formula IV, or formula V or a pharmaceutically acceptable salt thereof. In one embodiment, the BRAF-related tumor has become resistant to the prior therapy. In one embodiment, the cancer is a BRAF-related cancer having a class II mutation. In one embodiment, the class II mutation is a non-V600 mutation. In one embodiment, the non-V600 mutation is G469A, G469R, G469V, K601E, K601N, K601T, L597Q, or L597V. In one embodiment, the non-V600 mutation is G469A. In one embodiment, the class II mutation is a BRAF splice variant. In one embodiment, the BRAF splice variant lacks exons 4-8 (also referred to as p61BRAF(V600E)), exons 4-10, exons 2-8, or exons 2-10. In one embodiment, the BRAF splice variant is p61BRAF(V600E). Non-limiting examples of BRAF-related cancers having a class II mutation include lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendiceal cancer, small intestine cancer, head and neck squamous cell carcinoma, angiosarcoma, and CNS tumors.

[0653] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having a BRAF-related cancer has been previously treated with a BRAF inhibitor (i.e., a BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof) alone or in combination with another anti-cancer agent. In one embodiment, the subject has been previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide, (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib and vemurafenib or a pharmaceutically acceptable salt thereof. In one embodiment, the BRAF-related cancer treated with the prior BRAF inhibitor is a BRAF V600 mutant cancer (e.g., a BRAF V600E or BRAF V600K mutant cancer). In one embodiment, the BRAF-related cancer becomes resistant to the prior treatment. In one embodiment, during or after the prior treatment, the BRAF-related cancer expresses a BRAF V600 resistant mutation. In one embodiment, the subject develops brain metastases during the prior treatment.

[0654] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic melanoma has been treated with a BRAF inhibitor (i.e., a BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof). In one embodiment, the subject has been previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide, (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib and vemurafenib or a pharmaceutically acceptable salt thereof. In one embodiment, the melanoma has become resistant to the prior treatment. In one embodiment, during or after the prior treatment, the melanoma expresses a BRAF V600E resistance mutation. In one embodiment, the subject develops brain metastases during the prior treatment.

[0655] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic melanoma has been treated with a BRAF inhibitor (e.g., other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V or a pharmaceutically acceptable salt thereof) and a MEK inhibitor. In one embodiment, the subject has been previously treated with a BRAF inhibitor and a MEK inhibitor, the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide, and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, and the MEK inhibitor being selected from binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, modafenib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor and a MEK inhibitor, the BRAF inhibitor being selected from encorafenib, dabrafenib, and vemurafenib or a pharmaceutically acceptable salt thereof, and the MEK inhibitor being selected from binimetinib, trametinib, and cobimetinib or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with encorafenib or a pharmaceutically acceptable salt thereof and binimetinib or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with dabrafenib or a pharmaceutically acceptable salt thereof and trametinib or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with vemurafenib or a pharmaceutically acceptable salt thereof and cobimetinib or a pharmaceutically acceptable salt thereof. In one embodiment, the melanoma has become resistant to the prior treatment. In one embodiment, during or after the prior treatment, the melanoma expresses a BRAF V600E resistance mutation. In one embodiment, the subject develops brain metastases during the prior treatment.

[0656] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic melanoma has been treated with one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and / or a PD-L1 inhibitor). In one embodiment, the subject has been previously treated with one or more checkpoint inhibitors independently selected from ipilimumab, nivolumab, pembrolizumab, and avelumab. In one embodiment, the melanoma has become resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0657] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic melanoma has been treated with one or more PI3K inhibitors. In one embodiment, the subject has been previously treated with one or more PI3K inhibitors selected from buparlisib (BKM120), alpelisib (BYL719), satoralisib (LY3023414), 8-[(1R)-1-[(3,5-difluorophenyl)amino]ethyl]-N,N-dimethyl-2-(morpholin-4-yl)-4-oxo-4H-chromene-6-carboxamide (AZD8186), taselisib (RP6530), volasertib hydrochloride (SAR-245409), gedatolisib (PF-05212384), panulisib (P-7170), taselisib (GDC-0032), trans-2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PF-04691502), dactolisib (ABBV-954), N2-[4-oxo-4-[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholin-4-ium-4-ylmethoxy]butanoyl]-L-arginyl-glycyl-L-aspartyl-L-serine acetate (SF-1126), pictilisib (GDC-0941), 2-methyl-1-[2-methyl-3-(trifluoromethyl)benzyl]-6-(morpholin-4-yl)-1H-benzimidazole-4-carboxylic acid (GSK2636771), idelalisib (GS-1101), umbralisib tosylate (TGR-1202), pictilisib (GDC-0941), copanlisib hydrochloride (BAY84-1236), dactolisib (BEZ-235), 1-(4-[5-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1-ethyl-1H-1,2,4-triazol-3-yl]piperidin-1-yl)-3-hydroxypropan-1-one (AZD-8835), 5-[6,6-dimethyl-4-(morpholin-4-yl)-8,9-dihydro-6H-[1,4]oxazino[4,3-e]purin-2-yl]pyrimidin-2-amine (GDC-0084), everolimus, sirolimus, perifosine, sirolimus and temsirolimus. In one embodiment, the subject has been previously treated with buparlisib or alpelisib alone or in combination. In one embodiment, the melanoma has become resistant to the previous treatment. In one embodiment, the subject developed brain metastases during the previous treatment. In one embodiment, the subject developed brain metastases during the previous treatment.

[0658] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic melanoma has been treated with a BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor and / or a PD-L1 inhibitor). In one embodiment, the subject has been previously treated with a BRAF inhibitor and one or more checkpoint inhibitors, the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, and the checkpoint inhibitor being independently selected from ipilimumab, nivolumab and pembrolizumab. In one embodiment, the melanoma becomes resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0659] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic melanoma has been treated with a BRAF inhibitor (e.g., other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof), a MEK inhibitor, and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and / or a PD-L1 inhibitor). In one embodiment, the subject has been previously treated with a BRAF inhibitor, a MEK inhibitor, and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and / or a PD-L1 inhibitor), the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, the MEK inhibitor being selected from binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, modafinilmetinib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor, a MEK inhibitor, and one or more checkpoint inhibitors, the BRAF inhibitor being selected from encorafenib, dabrafenib, and vemurafenib or a pharmaceutically acceptable salt thereof, the MEK inhibitor being selected from binimetinib, trametinib, and cobimetinib, and the checkpoint inhibitor being independently selected from ipilimumab, nivolumab, pembrolizumab, and avelumab. In one embodiment, the melanoma becomes resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0660] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic melanoma has been treated with one or more alkylating agents. In one embodiment, the subject has been previously treated with one or more alkylating agents selected from temozolomide, fotemustine, lomustine and carmustine. In one embodiment, the subject has been previously treated with temozolomide. In one embodiment, the melanoma has become resistant to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0661] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic colorectal cancer has been treated with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor, the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, the MEK inhibitor being selected from binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, modafenib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733) or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor being selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib. In one embodiment, the subject has been previously treated with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor, the BRAF inhibitor being selected from encorafenib, dabrafenib, and vemurafenib or a pharmaceutically acceptable salt thereof, the MEK inhibitor being selected from binimetinib, trametinib, and cobimetinib or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor being selected from cetuximab and pembrolizumab. In one embodiment, the subject has been previously treated with encorafenib or a pharmaceutically acceptable salt thereof, binimetinib or a pharmaceutically acceptable salt thereof, and cetuximab. In one embodiment, the subject has been previously treated with dabrafenib or a pharmaceutically acceptable salt thereof, trametinib or a pharmaceutically acceptable salt thereof, and pembrolizumab. In one embodiment, the colorectal cancer has become resistant to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0662] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic colorectal cancer has been treated with an EGFR inhibitor. In certain embodiments, a subject having BRAF-related metastatic colorectal cancer (e.g., BRAF-mutated metastatic colorectal cancer) has been treated with an EGFR inhibitor and a BRAF inhibitor, the EGFR inhibitor being selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib and brigatinib, and the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof. In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic colorectal cancer has been treated with cetuximab or pembrolizumab. In one embodiment, the colorectal cancer becomes resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0663] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject with BRAF-related metastatic colorectal cancer has been treated with an EGFR inhibitor and one or more cytotoxic chemotherapeutic agents. In certain embodiments, a subject with BRAF-related metastatic colorectal cancer has been treated with an EGFR inhibitor and one or more cytotoxic chemotherapeutic agents, and the EGFR inhibitor is selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib and brigatinib. In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject with BRAF-related metastatic colorectal cancer (e.g., BRAF-mutated metastatic colorectal cancer) has been treated with an EGFR inhibitor and one or more cytotoxic chemotherapeutic agents such as Nordic FLOX (fluorouracil, leucovorin and oxaliplatin), and the EGFR inhibitor is selected from cetuximab or pembrolizumab. In one embodiment, the colorectal cancer becomes resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0664] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic colorectal cancer has been treated with an EGFR inhibitor and a BRAF inhibitor. In certain embodiments, a subject having BRAF-related metastatic colorectal cancer has been treated with an EGFR inhibitor and a BRAF inhibitor, the EGFR inhibitor being selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib and brigatinib, and the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with an EGFR inhibitor and a BRAF inhibitor, the EGFR inhibitor being selected from cetuximab and pembrolizumab, and the BRAF inhibitor being selected from encorafenib, dabrafenib and vemurafenib or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with encorafenib or a pharmaceutically acceptable salt thereof and cetuximab. In one embodiment, the subject has been previously treated with vemurafenib or a pharmaceutically acceptable salt thereof and pembrolizumab. In one embodiment, the subject has been previously treated with dabrafenib or a pharmaceutically acceptable salt thereof and pembrolizumab. In one embodiment, the colorectal cancer has become resistant to the prior treatment. In one embodiment, the subject has developed brain metastases during the prior treatment.

[0665] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V, or a pharmaceutically acceptable salt thereof, a subject having metastatic colorectal cancer has been treated with a MEK inhibitor and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and / or a PD-L1 inhibitor). In one embodiment, the subject has been previously treated with a MEK inhibitor and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and / or a PD-L1 inhibitor), and the MEK inhibitor is selected from binimetinib, trametinib, cobimetinib, selumetinib, pemigatinib, refametinib, modafenib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733). In one embodiment, the subject has been previously treated with a MEK inhibitor and one or more checkpoint inhibitors, the MEK inhibitor is selected from binimetinib, trametinib, and cobimetinib, and the checkpoint inhibitor is independently selected from ipilimumab, nivolumab, pembrolizumab, and avelumab. In one embodiment, the subject has been previously treated with a MEK inhibitor and a checkpoint inhibitor, the MEK inhibitor is binimetinib, and the checkpoint inhibitors are nivolumab and ipilimumab. In one embodiment, the subject has been previously treated with the MEK inhibitor binimetinib and the checkpoint inhibitor pembrolizumab. In one embodiment, the subject has been previously treated with the MEK inhibitor binimetinib and the checkpoint inhibitor avelumab. In one embodiment, the subject has been previously treated with the MEK inhibitor trametinib and the checkpoint inhibitors nivolumab and ipilimumab. In one embodiment, the colorectal cancer has become resistant to the previous treatment. In one embodiment, the subject developed brain metastases during the previous treatment.

[0666] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic colorectal cancer has been treated with one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and / or a PD-L1 inhibitor). In one embodiment, the subject has been previously treated with one or more checkpoint inhibitors independently selected from ipilimumab, nivolumab, pembrolizumab, and avelumab. In one embodiment, the subject has been previously treated with nivolumab. In one embodiment, the colorectal cancer has become resistant to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0667] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic colorectal cancer (e.g., BRAF-mutated metastatic colorectal cancer) has been treated with one or more cytotoxic chemotherapeutic agents. In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic colorectal cancer has been treated with oxaliplatin, irinotecan, FOLFOXIRI (oxaliplatin, irinotecan, and fluorouracil), FOLFIRI (leucovorin, fluorouracil, and irinotecan), or CAPEOX (capecitabine and oxaliplatin). In one embodiment, the colorectal cancer has become resistant to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0668] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject with BRAF-related metastatic colorectal cancer has been treated with an antibody therapy and one or more cytotoxic chemotherapeutic agents. In certain embodiments, a subject with BRAF-related metastatic colorectal cancer (e.g., BRAF-mutated metastatic colorectal cancer) has been treated with an antibody therapy and one or more cytotoxic chemotherapeutic agents, and the antibody therapy is bevacizumab. In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject with BRAF-related metastatic colorectal cancer (e.g., BRAF-mutated metastatic colorectal cancer) has been treated with bevacizumab and irinotecan, bevacizumab and FOLFOXIRI (oxaliplatin, irinotecan, and fluorouracil), or bevacizumab and FOLFIRI (leucovorin, fluorouracil, and irinotecan). In one embodiment, the colorectal cancer becomes resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0669] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject with BRAF-related metastatic colorectal cancer has been treated with an EGFR inhibitor, a BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V, and one or more cytotoxic chemotherapeutic agents. In certain embodiments, a subject with BRAF-related metastatic colorectal cancer has been treated with an EGFR inhibitor, a BRAF inhibitor, and one or more cytotoxic chemotherapeutic agents, wherein the EGFR inhibitor is selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib, and the BRAF inhibitor is selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof. In certain embodiments, a subject with BRAF-related metastatic colorectal cancer has been treated with an EGFR inhibitor, a BRAF inhibitor, and a cytotoxic chemotherapeutic agent, wherein the EGFR inhibitor is selected from cetuximab and pembrolizumab, the BRAF inhibitor is vemurafenib or a pharmaceutically acceptable salt thereof, and the cytotoxic chemotherapeutic agent is irinotecan. In one embodiment, the colorectal cancer becomes resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0670] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject with BRAF-related metastatic colorectal cancer (e.g., BRAF-mutated metastatic colorectal cancer) has received treatment with an EGFR inhibitor and one or more cytotoxic chemotherapeutic agents. In certain embodiments, a subject with BRAF-related metastatic colorectal cancer (e.g., BRAF-mutated metastatic colorectal cancer) has received treatment with an EGFR inhibitor and one or more cytotoxic chemotherapeutic agents, where the EGFR inhibitor is selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib. In certain embodiments, a subject with BRAF-related metastatic colorectal cancer (e.g., BRAF-mutated metastatic colorectal cancer) has received treatment with an EGFR inhibitor and a cytotoxic chemotherapeutic agent, where the EGFR inhibitor is selected from cetuximab and pembrolizumab, and the cytotoxic chemotherapeutic agent is irinotecan or FOLFIRI (leucovorin, fluorouracil, and irinotecan). In one embodiment, the colorectal cancer becomes resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0671] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject with BRAF-related metastatic colorectal cancer has received treatment with surgery. In one embodiment, the subject becomes refractory to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0672] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject with BRAF-related metastatic colorectal cancer has been treated with surgery, followed by treatment with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with surgery and has been previously treated with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor, the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, the MEK inhibitor being selected from binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, modafinilmetinib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733) or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor being selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib. In one embodiment, the subject has been previously treated with surgery and has been previously treated with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor, the BRAF inhibitor being selected from encorafenib, dabrafenib, and vemurafenib, the MEK inhibitor being selected from binimetinib, trametinib, and cobimetinib or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor being selected from cetuximab and pembrolizumab. In one embodiment, the colorectal cancer has become resistant to the prior treatment. In one embodiment, the subject has developed brain metastases during the prior treatment.

[0673] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic colorectal cancer has been treated with radiation therapy (e.g., whole brain radiation therapy or stereotactic radiosurgery). In one embodiment, the subject has become resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0674] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof, a subject with BRAF-related metastatic colorectal cancer has been treated with radiation therapy (e.g., whole brain radiation therapy or stereotactic radiosurgery), followed by treatment with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor. In one embodiment, the subject has been previously treated with radiation therapy and has been previously treated with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor, the BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, the MEK inhibitor selected from binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, modafenib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733) or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib. In one embodiment, the subject has been previously treated with surgery and has been previously treated with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor, the BRAF inhibitor selected from encorafenib, dabrafenib, and vemurafenib or a pharmaceutically acceptable salt thereof, the MEK inhibitor selected from binimetinib, trametinib, and cobimetinib or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor selected from cetuximab and pembrolizumab. In one embodiment, the colorectal cancer becomes resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0675] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic non-small cell lung cancer (e.g., BRAF-mutated metastatic non-small cell lung cancer) has been treated with one or more EGFR inhibitors. In one embodiment, the subject has been previously treated with one or more EGFR inhibitors, which are independently selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib and brigatinib. In one embodiment, the subject has been previously treated with erlotinib. In one embodiment, the subject has been previously treated with gefitinib. In one embodiment, the subject has been previously treated with erlotinib and gefitinib. In one embodiment, the non-small cell lung cancer has become resistant to the previous treatment. In one embodiment, the subject developed brain metastases during the previous treatment.

[0676] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof, a subject with BRAF-related metastatic non-small cell lung cancer has been treated with a BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor, the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, the MEK inhibitor being selected from binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, modafenib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733) or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor being selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib. In one embodiment, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof, the subject has been previously treated with a BRAF inhibitor and an EGFR inhibitor, the BRAF inhibitor being selected from vemurafenib, dabrafenib, and encorafenib or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor being selected from cetuximab and pembrolizumab. In one embodiment, the non-small cell lung cancer becomes resistant to the prior treatment. In one embodiment, the subject develops brain metastases during the prior treatment.

[0677] In certain embodiments, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, a subject having BRAF-related metastatic thyroid cancer (e.g., BRAF-mutated metastatic thyroid cancer) has been treated with a BRAF inhibitor (i.e., a BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof). In one embodiment, the subject has been previously treated with a BRAF inhibitor, a MEK inhibitor and an EGFR inhibitor, the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, the MEK inhibitor being selected from binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, modafenib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040) and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733) or a pharmaceutically acceptable salt thereof, and the EGFR inhibitor being selected from cetuximab, pembrolizumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib and brigatinib. In one embodiment, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, the subject has been previously treated with a BRAF inhibitor selected from vemurafenib, dabrafenib and encorafenib. In one embodiment, the thyroid cancer has become resistant to the prior treatment. In one embodiment, the subject developed brain metastases during the prior treatment.

[0678] In one embodiment, the subject has a BRAF-related LMD and has been previously treated with a BRAF inhibitor (i.e., a BRAF inhibitor other than a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof) and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor and / or a PD-L1 inhibitor) prior to treatment with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor and one or more checkpoint inhibitors, the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, and the checkpoint inhibitor being independently selected from ipilimumab, nivolumab, pembrolizumab and avelumab. In one embodiment, the LMD becomes resistant to the prior treatment.

[0679] In one embodiment, the subject has a BRAF-related LMD and, prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof, has been previously treated with a BRAF inhibitor (i.e., a BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof), a MEK inhibitor, and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and / or a PD-L1 inhibitor). In one embodiment, the subject has been previously treated with a BRAF inhibitor, a MEK inhibitor, and a checkpoint inhibitor (e.g., any of the checkpoint inhibitors disclosed herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and / or a PD-L1 inhibitor), the BRAF inhibitor being selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, the MEK inhibitor being selected from binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, modafenib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor, a MEK inhibitor, and one or more checkpoint inhibitors, the BRAF inhibitor being selected from encorafenib, dabrafenib, and vemurafenib or a pharmaceutically acceptable salt thereof, the MEK inhibitor being selected from binimetinib, trametinib, and cobimetinib or a pharmaceutically acceptable salt thereof, the checkpoint inhibitor being independently selected from ipilimumab, nivolumab, pembrolizumab, and avelumab. In one embodiment, the LMD becomes resistant to the prior treatment.

[0680] In one embodiment, the subject has BRAF-related LMD and has been previously treated with one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors disclosed herein, e.g., CTLA-4 inhibitors, PD-1 inhibitors, and / or PD-L1 inhibitors) prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with one or more checkpoint inhibitors independently selected from ipilimumab, nivolumab, pembrolizumab, avelumab, and RN888. In one embodiment, the LMD becomes resistant to the prior treatment.

[0681] In one embodiment, the subject has BRAF-related glioma and has been previously treated with surgery prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof. In one embodiment, the glioma becomes resistant to the prior treatment. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0682] In one embodiment, the subject has BRAF-related glioma and has been previously treated with radiation therapy (e.g., whole brain radiation therapy or stereotactic radiosurgery) prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof. In one embodiment, the glioma becomes resistant to the prior treatment. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0683] In one embodiment, the subject has BRAF-related glioma and has been previously treated with one or more cytotoxic chemotherapeutic agents prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with one or more cytotoxic chemotherapeutic agents independently selected from cisplatin, pemetrexed, vinorelbine, and paclitaxel. In one embodiment, the glioma becomes resistant to the prior treatment. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0684] In one embodiment, the subject has a BRAF-related glioma and has been previously treated with an ornithine decarboxylase inhibitor prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with an ornithine decarboxylase inhibitor, which is eflornithine (as a racemate or D or L enantiomer). In one embodiment, the glioma becomes resistant to the previous treatment. In one embodiment, the glioma is a grade 2, 3 or 4 glioma.

[0685] In one embodiment, the subject has a BRAF-related glioma and has been previously treated with an alkylating agent prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with an alkylating agent selected from temozolomide, lomustine and carmustine. In one embodiment, the glioma becomes resistant to the previous treatment. In one embodiment, the glioma is a grade 2, 3 or 4 glioma.

[0686] In one embodiment, the subject has a BRAF-related glioma and has been previously treated with an alkylating agent and an ornithine decarboxylase inhibitor prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with an alkylating agent and an ornithine decarboxylase inhibitor, the alkylating agent being selected from temozolomide, lomustine and carmustine, and the ornithine decarboxylase inhibitor being eflornithine (as a racemate or D or L enantiomer). In one embodiment, the glioma becomes resistant to the previous treatment. In one embodiment, the glioma is a grade 2, 3 or 4 glioma.

[0687] In one embodiment, the subject has a BRAF-related glioma and has been previously treated with radiation therapy (e.g., whole brain radiation therapy or stereotactic radiosurgery) and an alkylating agent prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with radiation therapy (e.g., whole brain radiation therapy or stereotactic radiosurgery) and an alkylating agent, the alkylating agent being selected from temozolomide, lomustine and carmustine. In one embodiment, the subject becomes resistant to the previous treatment. In one embodiment, the glioma is a grade 2, 3 or 4 glioma.

[0688] In one embodiment, the subject has a BRAF-related glioma and has been previously treated with antibody therapy prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with antibody therapy, and the antibody therapy is bevacizumab. In one embodiment, the glioma becomes resistant to the previous treatment. In one embodiment, the glioma is a grade 2, 3 or 4 glioma.

[0689] In one embodiment, the subject has a BRAF-related glioma and has been previously treated with surgery and radiation therapy prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In one embodiment, the glioma becomes resistant to the previous treatment. In one embodiment, the glioma is a grade 2, 3 or 4 glioma.

[0690] In one embodiment, the subject has a BRAF-related glioma and has been previously treated with surgery, radiation therapy and an alkylating agent prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with surgery, radiation therapy (e.g., whole brain radiotherapy or stereotactic radiosurgery) and an alkylating agent selected from temozolomide, lomustine and carmustine. In one embodiment, the glioma becomes resistant to the previous treatment. In one embodiment, the glioma is a grade 2, 3 or 4 glioma.

[0691] In one embodiment, the subject has a BRAF-related glioma and has been previously treated with a BRAF inhibitor (i.e., a BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof) prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor selected from N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), vemurafenib, dabrafenib, encorafenib, and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394). In one embodiment, the glioma has become resistant to the previous treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

[0692] In one embodiment, the subject has a BRAF-related glioma and has been previously treated with a BRAF inhibitor (i.e., a BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof) and a MEK inhibitor prior to treatment with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with a BRAF inhibitor and a MEK inhibitor, the BRAF inhibitor being selected from N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propane-1-sulfonamide (PLX4720), vemurafenib, dabrafenib, encorafenib, and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394), and the MEK inhibitor being selected from binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, modafenib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040), and 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733). In one embodiment, the subject has been previously treated with a BRAF inhibitor and a MEK inhibitor, the BRAF inhibitor being selected from encorafenib, dabrafenib, and vemurafenib or a pharmaceutically acceptable salt thereof, and the MEK inhibitor being selected from binimetinib, trametinib, and cobimetinib or a pharmaceutically acceptable salt thereof. In one embodiment, the glioma has become resistant to the previous treatment. In one embodiment, the glioma is a grade 2, 3, or 4 glioma.

[0693] In one embodiment, the subject has BRAF - related brainstem ganglioglioma and was previously treated with a BRAF inhibitor (i.e., a BRAF inhibitor other than a compound of formula I, formula I - A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof) prior to treatment with a compound of formula I, formula I - A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N - [3 - (5 - chloro - 1H - pyrrolo[2,3 - b]pyridin - 3 - ylcarbonyl)-2,4 - difluorophenyl]propane - 1 - sulfonamide (PLX4720) and (3R)-N-(3 - [[5-(2 - cyclopropylpyrimidin - 5 - yl)-1H - pyrrolo[2,3 - b]pyridin - 3 - yl]carbonyl]-2,4 - difluorophenyl)-3 - fluoropyrrolidine - 1 - sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof. In one embodiment, the subject was previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib and vemurafenib or a pharmaceutically acceptable salt thereof. In one embodiment, the ganglioglioma became resistant to the previous treatment.

[0694] Although the genetic basis of tumorigenesis may vary between different cancer types, the cellular and molecular mechanisms required for metastasis appear to be similar for all solid tumor types. During the metastatic cascade, cancer cells lose growth - inhibitory responses, undergo changes in adhesiveness, and produce enzymes that can degrade extracellular matrix components. This results in the detachment of tumor cells from the primary tumor, infiltration into the circulation through newly formed vasculature, migration and extravasation of tumor cells at favorable distant sites where they may form colonies. Many genes have been identified as promoters or inhibitors of metastasis.

[0695] Accordingly, the present invention also provides a method for treating, inhibiting, preventing, assisting in preventing or alleviating metastatic symptoms of BRAF-related cancers in subjects in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In certain embodiments, the compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof is used in combination with another anti-cancer treatment such as surgery (e.g., at least partial resection of the tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In one embodiment, the cancer is a metastatic cancer with brain metastases, and the method comprises administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is metastatic melanoma with brain metastases. In one embodiment, the cancer is metastatic colorectal cancer with brain metastases. In one embodiment, the cancer is metastatic non-small cell lung cancer with brain metastases. In one embodiment, the cancer is metastatic ovarian cancer with brain metastases. In one embodiment, the cancer is metastatic thyroid cancer with brain metastases. In one embodiment, the cancer is neuroblastoma with brain metastases, and the method comprises administering a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has been previously treated with another anti-cancer treatment such as surgery (e.g., at least partial resection of the tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In one embodiment, the subject has become resistant to the previous treatment. In one embodiment, the subject is treated with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof in combination with another anti-cancer treatment such as surgery (e.g., at least partial resection of the tumor) and / or radiotherapy and / or treatment with an anti-cancer agent.

[0696] The present invention also provides a method of inhibiting metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, is used in combination with another anti-cancer treatment such as surgery (e.g., at least partial resection of a tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In one embodiment, the cancer is metastatic cancer with brain metastases. In one embodiment, the cancer is metastatic melanoma with brain metastases. In one embodiment, the cancer is metastatic colorectal cancer with brain metastases. In one embodiment, the cancer is metastatic non-small cell lung cancer with brain metastases. In one embodiment, the cancer is metastatic ovarian cancer with brain metastases. In one embodiment, the cancer is metastatic thyroid cancer with brain metastases. In one embodiment, the cancer is neuroblastoma with brain metastases. In one embodiment, the subject has been previously treated with another anti-cancer treatment such as surgery (e.g., at least partial resection of a tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In one embodiment, the subject has become resistant to the previous treatment. In one embodiment, the subject is treated with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, in combination with another anti-cancer treatment such as surgery (e.g., at least partial resection of a tumor) and / or radiotherapy and / or treatment with an additional anti-cancer agent. In one embodiment, the additional anti-cancer therapy is an anti-cancer agent. In one embodiment, the additional anti-cancer agent is selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, inhibitors of HER2 and / or HER3, Axl inhibitors, PI3K inhibitors, SOS1 inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapies, and immune-targeting agents. In one embodiment, the additional anti-cancer agent is a MEK inhibitor. In one embodiment, the MEK inhibitor is binimetinib, trametinib, cobimetinib or a pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof.

[0697] As used herein, the term "treating metastasis" refers to reducing the size, progression, and / or further spread of one or more metastatic lesions.

[0698] The present invention also provides a method for inhibiting metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the compound of formula I, formula I-A, formula II, formula III, formula IV or formula V, or a pharmaceutically acceptable salt thereof, is used in combination with another anti-cancer treatment such as surgery (e.g., at least partial resection of the tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In one embodiment, the cancer is metastatic cancer with brain metastases. In one embodiment, the cancer is metastatic melanoma with brain metastases. In one embodiment, the cancer is metastatic colorectal cancer with brain metastases. In one embodiment, the cancer is metastatic non-small cell lung cancer with brain metastases. In one embodiment, the cancer is metastatic ovarian cancer with brain metastases. In one embodiment, the cancer is metastatic thyroid cancer with brain metastases. In one embodiment, the cancer is neuroblastoma with brain metastases. In one embodiment, the subject has been previously treated with another anti-cancer treatment such as surgery (e.g., at least partial resection of the tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In one embodiment, the subject has become resistant to the previous treatment. In one embodiment, the subject is treated with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V, or a pharmaceutically acceptable salt thereof, in combination with another anti-cancer treatment such as surgery (e.g., at least partial resection of the tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In one embodiment, the anti-cancer therapy is an anti-cancer agent. In one embodiment, the anti-cancer agent is selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, inhibitors of HER2 and / or HER3, Axl inhibitors, PI3K inhibitors, SOS 1 inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway, cytotoxic chemotherapeutic agents, angiogenesis targeting therapies, and immune targeting agents. In one embodiment, the anti-cancer agent is a MEK inhibitor. In one embodiment, the MEK inhibitor is binimetinib, trametinib, cobimetinib, or a pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof.

[0699] As used herein, the term "inhibiting metastasis" refers to reducing the occurrence (or recurrence) of one or more metastatic foci, preventing the occurrence (or recurrence) of one or more metastatic foci, or reducing the spread of one or more metastatic foci.

[0700] Also provided are methods of reducing the risk of developing one or more metastases or one or more additional metastases in a subject having a BRAF-related cancer, the methods comprising: selecting, identifying or diagnosing a subject as having a BRAF-related cancer, and administering to the subject so selected, identified or diagnosed as having a BRAF-related cancer a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof. Also provided are methods of reducing the risk of developing one or more metastases or one or more additional metastases in a subject having a BRAF-related cancer, the methods comprising administering to a subject having a BRAF-related cancer a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof. The reduction in the risk of developing one or more metastases or one or more additional metastases in a subject having a BRAF-related cancer can be relative to the risk of developing one or more metastases or one or more additional metastases in that subject prior to treatment, or relative to a subject or group of subjects having a similar or identical BRAF-related cancer who have not received treatment or have received a different treatment.

[0701] The phrase "risk of developing one or more metastases" refers to the risk that a subject having a primary tumor will develop additional tumors (e.g., solid tumors) at a site distant from the subject's primary tumor during a specified time period, wherein the additional tumors comprise cancer cells that are the same as or similar to those of the primary tumor. Methods for reducing the risk of developing one or more metastases in a subject having a cancer are described herein.

[0702] The phrase "risk of developing additional metastases" refers to the risk that a subject having a primary tumor and one or more additional tumors at a site distant from the primary tumor (wherein the one or more additional tumors comprise cancer cells that are the same as or similar to those of the primary tumor) will develop one or more additional tumors at a site distant from the primary tumor, wherein the additional tumors comprise cancer cells that are the same as or similar to those of the primary tumor. Methods for reducing the risk of developing additional metastases are described herein.

[0703] The present invention also provides a method for treating BRAF-related tumors, metastases of BRAF-related tumors, or combinations thereof, in a subject in need thereof, the method comprising administering to the subject a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V, or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has at least one metastasis or is at risk of developing at least one metastasis. In one embodiment, the subject has at least one metastasis. In one embodiment, the subject is at risk of developing at least one metastasis. In one embodiment, the subject is at risk of developing at least one metastasis, wherein the subject has a cancer selected from melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer or ovarian cancer. In one embodiment, the cancer is a cancer having a BRAF class I mutation (e.g., a BRAF V600 mutation cancer, e.g., a cancer having a BRAF V600E and / or BRAF V600K mutation). In one embodiment, the cancer is a cancer having a BRAF class II mutation (e.g., a G469A mutation or a BRAF V600E splice variant). In one embodiment, the subject has been previously treated with another anti-cancer treatment such as surgery (e.g., at least partial resection of the tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In one embodiment, the subject has become resistant to the previous treatment. In one embodiment, the subject is treated with a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V, or a pharmaceutically acceptable salt thereof, in combination with another anti-cancer treatment such as surgery (e.g., at least partial resection of the tumor) and / or radiotherapy and / or treatment with an anti-cancer agent. In one embodiment, the anti-cancer therapy is an anti-cancer agent selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, SOS 1 inhibitors, inhibitors of HER2 and / or HER3, Axl inhibitors, PI3K inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapies and immune-targeting agents. In one embodiment, the anti-cancer agent is a MEK inhibitor. In one embodiment, the MEK inhibitor is binimetinib, trametinib, cobimetinib or a pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof.

[0704] In certain embodiments, one or more agents are administered to a subject to ameliorate the side effects of a treatment (e.g., one or more of a corticosteroid, a serotonin antagonist, a dopamine antagonist, an NK-1 inhibitor, a cannabinoid, an anti-anxiety drug (e.g., lorazepam or diazepam), an antibiotic, an antifungal, a colony stimulating factor, an iron supplement, Procrit, epoetin alfa, darbepoetin alfa, an antiemetic, a diuretic, an NSAID, an analgesic, methotrexate, an antidiuretic, a probiotic, a blood pressure drug, an anti-nausea drug, a laxative, etc.).

[0705] In one embodiment, the BRAF-related tumor is a benign tumor, and a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof can be used alone or in combination with one or more different forms of treatment to treat a subject having a benign tumor.

[0706] In certain embodiments, the subject has a CNS tumor and is administered one or more agents to ameliorate one or more symptoms associated with the CNS tumor, including but not limited to seizures, nausea, headache, blurred vision, vision loss, loss of balance, changes in fine motor skills, and drowsiness. Examples of such agents for ameliorating one or more symptoms associated with a CNS tumor include corticosteroids, anti-seizure drugs (e.g., cannabidiol, gabapentin or pregabalin), pain medications (e.g., NSAIDS, acetaminophen), and anti-nausea drugs.

[0707] Also provided is a method for inhibiting BRAF kinase activity in mammalian cells, the method comprising contacting the cells with an effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof. In certain embodiments, the contacting is in vitro. In certain embodiments, the contacting is in vivo. In certain embodiments, the contacting is in vivo, wherein the method comprises administering a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof to a subject having cells with BRAF kinase activity. In certain embodiments, the cells are cancer cells. In certain embodiments, the cancer cells are any cancer as described herein. In certain embodiments, the cancer cells are BRAF-related cancer cells. In certain embodiments, the cells are brain cells (e.g., neurons or glial cells).

[0708] As used herein, the term "contacting" means bringing the indicated moieties together in an in vitro system or an in vivo system. For example, "contacting" a BRAF kinase with a compound provided herein includes contacting a cell containing the BRAF kinase with a compound provided herein, and, for example, introducing a compound provided herein into a sample containing a cell preparation or a purified preparation that contains the BRAF kinase.

[0709] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0710] A "therapeutically effective amount" of a compound, its pharmaceutical composition, or its pharmaceutical combination used herein is an amount sufficient to achieve any one or more beneficial or desired results. For prophylactic applications, beneficial or desired results include eliminating or reducing risk, alleviating severity, or delaying the onset of a disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that arise during the progression of the disease. For therapeutic applications, beneficial or desired results include providing a therapeutic effect, which can include reducing the size of a tumor, inhibiting (e.g., slowing to some extent, preferably stopping) tumor progression, inhibiting (e.g., slowing to some extent, preferably stopping) tumor growth, inhibiting (e.g., slowing to some extent, preferably stopping) tumor invasion, and / or inhibiting (e.g., slowing to some extent, preferably stopping) tumor metastasis. One of ordinary skill in the art understands that tumor progression in a human subject can be determined by a variety of methods. For example, the size of a tumor near the skin can be measured by establishing the width and depth of the tumor with calipers and then calculating the tumor volume. Tumors that are more difficult to access, such as lung and CNS cancers, can be measured by observing images obtained from magnetic resonance imaging (MRI) scans. CNS tumors, such as brain tumors, can be measured by combining MRI scans and by monitoring neurological performance. The growth of a brain tumor is typically associated with a decrease in neurological performance. Providing a therapeutic effect also includes prolonging the survival of the subject beyond the expected survival in the absence of treatment and / or alleviating (or preferably eliminating) one or more signs or symptoms associated with cancer to some extent. In one embodiment, treating a subject with a compound or combination according to the invention will prolong survival beyond the expected survival in the absence of treatment by 1 or more months, such as 3 or more months, such as 6 or more months, such as 1 year or more, such as 2 years or more, such as 3 years or more, such as 5 years or more, such as 10 years or more. Providing a therapeutic effect also includes reducing the number of cancer cells. Providing a therapeutic effect also includes eliminating cancer cells. Providing a therapeutic effect also includes reducing tumor mass. Providing a therapeutic effect also includes causing a cancer remission. A therapeutically effective amount can be administered in one or more administrations. For the purposes of the present invention, a dose therapeutically effective amount of a compound or its pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As understood in a clinical context, a dose therapeutically effective amount of a compound or its pharmaceutical composition can be achieved in combination with another therapy. Thus, a "therapeutically effective amount" can be considered in the context of administering one or more therapies (e.g., one or more anti-cancer agents), and a single agent can be considered to be administered in a therapeutically effective amount if a desired result is achieved or can be achieved when combined with one or more other agents.When referring to the treatment of cancer, the therapeutically effective amount can also refer to an amount having the following effects: (1) reducing the size of a tumor, (2) inhibiting (i.e., slowing to some extent, preferably stopping) the occurrence of tumor metastasis, (3) inhibiting (i.e., slowing to some extent, preferably stopping) tumor growth or tumor invasion to some extent, and / or (4) alleviating (or, preferably, eliminating) one or more signs or symptoms associated with cancer to some extent. The therapeutic or pharmacological effectiveness of a dosage and administration regimen can also be characterized as the ability to induce, enhance, maintain, or prolong disease control and / or overall survival (which can be measured as an extension of the time before disease progression) in subjects having these particular tumors.

[0711] In one embodiment, according to one or more standard response assessment criteria known in the art, including RECIST (Response Evaluation Criteria in Solid Tumors, e.g., RECIST version 1.0, RECIST 1.1, and modified RECIST 1.1 (mRECIST 1.1)), RANO-BM (Response Assessment in Neuro-Oncology Brain Metastases), Macdonald, RANO-LMD, and NANO (Neurological Assessment in Neuro-Oncology), a subject treated according to any method disclosed herein can be evaluated. In one embodiment of any of the said criteria, the tumor is evaluated by an imaging study (e.g., MRI, CT, MDCT, or PET). In one embodiment, treatment response is evaluated according to RECIST version 1.1, wherein: Complete Response (CR) is defined as the complete disappearance of all tumor lesions; Partial Response (PR) is defined as at least a 30% reduction in the sum of tumor measurements; Progressive Disease (PD) is defined as at least a 20% increase in the sum of tumor measurements (where the occurrence of new lesions or substantial progression of non-target lesions is also defined as PD), where an increase of at least 5 mm from baseline is evaluated as PD; and Stable Disease (SD) is defined as, with reference to the minimum total diameter at the time of treatment, neither sufficiently reduced to meet the PR criteria nor sufficiently increased to meet the PD criteria. In one embodiment, the evaluation includes intracranial response (evaluated according to modified RECIST using gadolinium-enhanced MRI), extracranial response, overall response rate, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

[0712] In one embodiment, the subject has a CNS tumor and has at least one measurable intracranial tumor. In one embodiment, the at least one measurable intracranial tumor is measured by an MRI CT scan.

[0713] A "measurable" tumor (tumor lesion) refers to a tumor that can be accurately measured in at least one dimension (the longest diameter in the measurement plane is not recorded), and its minimum size is as follows: by CT scan, 10 mm (the CT scan slice thickness is not more than 5 mm); by clinical examination, the measurement value with a 10 mm caliper; by chest X-ray, 20 mm.

[0714] When used as a medicine, the compounds of formula I, formula I-A, formula II, formula III, formula IV or formula V or their pharmaceutically acceptable salts can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well-known in the pharmaceutical field and can be administered by various routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be local (including transdermal, epidermal, ocular and to mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Oral administration can include formulating dosage forms for once-daily or twice-daily (BID) administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by continuous perfusion pump. Pharmaceutical compositions and preparations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickening agents, etc. may be necessary or required.

[0715] The present invention also provides a pharmaceutical composition, which contains a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers (excipients). For example, a pharmaceutical composition prepared using a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof. In certain embodiments, the composition is suitable for topical administration. When preparing the compositions provided herein, the active ingredient is usually admixed with an excipient, diluted with an excipient, or enclosed within a carrier such as, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Accordingly, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or in a liquid medium), ointments (which contain, for example, up to 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In certain embodiments, the composition is formulated for oral administration. In certain embodiments, the composition is a solid oral formulation. In certain embodiments, the composition is formulated as a tablet or a capsule.

[0716] The present invention further provides a pharmaceutical composition, which contains a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition containing a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by intimately mixing the compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Depending on the desired route of administration (e.g., oral, parenteral), the carrier can take a variety of forms. In certain embodiments, the composition is a solid oral composition.

[0717] Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

[0718] Methods of formulating pharmaceutical compositions have been described in a variety of publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1 - 3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1 - 2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1 - 2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

[0719] In preparing compositions in oral dosage form, any of the common pharmaceutical media may be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents, etc.; for solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, etc. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or β - lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc. Solid oral preparations may also be coated with substances such as sugar or enteric coatings to modify the site of primary absorption. For parenteral administration, the carrier will generally consist of sterile water, and other ingredients may be added thereto to increase solubility or stability. Injectable suspensions or solutions may also be prepared using aqueous carriers and appropriate additives. The pharmaceutical compositions herein will contain in each dosage unit, for example, tablets, capsules, powders, injections, teaspoonfuls, etc., the amount of the active ingredient necessary to deliver a therapeutically effective amount as described herein.

[0720] A pharmaceutical composition comprising a compound of Formula I, Formula I - A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof can be formulated into unit dosage forms, each dosage containing from about 5 to about 1,000 mg (1 g), more usually from about 100 mg to about 500 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other subjects, each unit containing a predetermined quantity of the active substance (i.e., a compound of Formula I, Formula I - A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof) calculated to produce the desired therapeutic effect, together with the appropriate pharmaceutical excipients.

[0721] In certain embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient. One of ordinary skill in the art will appreciate that this encompasses compounds or compositions containing from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, or from about 45 mg to about 50 mg of the active ingredient.

[0722] In certain embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. One of ordinary skill in the art will appreciate that this encompasses compounds or compositions containing from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 350 mg to about 400 mg, or from about 450 mg to about 500 mg of the active ingredient. In certain embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of the active ingredient.

[0723] The daily dose of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, can vary widely from 1.0 to 10,000 mg or more per adult per day, or any range therein. For oral administration, the composition is preferably provided in tablet form containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250, and 500 milligrams of the active ingredient for symptomatic adjustment of the dose for the subject to be treated. A therapeutically effective amount of the drug is typically provided at a dosage level of from about 0.1 mg / kg to about 1000 mg / kg body weight per day, or any range therein. Preferably, the range is from about 0.5 to about 500 mg / kg body weight per day or any range therein. More preferably, from about 1.0 to about 250 mg / kg body weight per day or any range therein. Even more preferably, from about 0.1 to about 100 mg / kg body weight per day or any range therein. In one embodiment, the range can be from about 0.1 to about 50.0 mg / kg body weight per day, or any amount or range therein. In another embodiment, the range can be from about 0.1 to about 15.0 mg / kg body weight per day or any range therein. In yet another embodiment, the range can be from about 0.5 to about 7.5 mg / kg body weight per day or any amount to range therein. A pharmaceutical composition containing a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, can be administered in a regimen of 1 to 4 times per day or as a single daily dose.

[0724] The active compounds can be effective in a wide dosage range and are generally administered in a therapeutically effective amount. The optimal dosage to be administered can be readily determined by those skilled in the art. Thus, it will be understood that the amount of the compound actually administered will generally be determined by a physician and will vary according to the relevant circumstances, including the mode of administration, the actual compound being administered, the strength of the formulation, the disorder to be treated, and the progression of the disease condition. Additionally, factors related to the particular subject being treated (includ...

Claims

1. A compound, which is N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide having the following structure: or a pharmaceutically acceptable salt thereof.

2. A compound, which is N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide having the following structure:

3. A pharmaceutical composition, which comprises the compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

4. Use of the compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating BRAF-related tumors in a subject in need thereof.

5. The use according to claim 4, wherein the compound or a pharmaceutically acceptable salt thereof is further co-administered with binimetinib or a pharmaceutically acceptable salt thereof or cetuximab.

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