RU2814662C1 - 4-oxo-3,4-dihydroquinazolinone compounds for treatment of braf-associated diseases and disorders - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3- fluoroazetidine-1-sulfonamide of formula I, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition based on it, as well as a method of treating a BRAF-associated tumour using them.

EFFECT: obtaining of 4-oxo-3,4-dihydroquinazolinone compounds for the treatment of BRAF-associated diseases and disorders.

25 cl, 1 dwg, 140 ex

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to US Provisional Application No. 63/036, 522, filed June 9, 2020, and US Provisional Application No. 63/116,204, filed November 20, 2020, and US Provisional Application No. 63/175,655, filed April 16. 2021, the contents of each of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to novel quinazolinone compounds or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer, in a subject.

BACKGROUND OF THE ART

The present invention relates to quinazolinones for the treatment of BRAF-associated diseases and disorders, including BRAF-associated tumors, including malignant and benign BRAF-associated CNS tumors and malignant extracranial BRAF-associated tumors.

The BRAF protein, a member of the RAF series/threonine kinase family, is involved in the Ras-Raf-MEK-extracellular signal-regulated kinase (ERK) pathway or mitogen-activated protein kinase (MAPK)/ERK signaling pathway, which influences 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 cancer (Cerami, E., et al., Cancer Discov. 2012, 2, 401-404). These mutations lead to ERK activation through different functional mechanisms, and are grouped into three classes, two of which are called class I and class II mutations based on their dependence on RAS dimerization and activation for activity; these properties determine their sensitivity to RAF inhibitors (Yao, A., et al., Cancer Cell 2015, 28, 370-383).

Class I BRAF activating 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 its metastatic cancers, as well as primary brain tumors. Class I mutations, such as BRAF V600 mutants, signal as RAS-independent active monomers.

Class II BRAF mutations include non-V600 mutations that activate MEK through dimerization but without the requirement for RAS (Yao, A., et al., Cancer Cell 2015, 28, 370-383). These class II mutations undergo constitutive, RAS-independent dimerization, resulting in increased ERK activation with 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. He-V600 BRAF mutants have also been found in many cancers and are more common than V600 mutations in certain tumor types. He-V600 BRAF mutations are found in 5-16% of melanomas, as well as in a variety of other tumor types (Siroy AE, et al., J Invest Dermatol. 2015; 135:508-515; Dahlman KB, et al. Cancer Discov. 2 012;2:791-797). Approximately 50-80% of BRAF mutations in non-small cell lung cancer, and 22-30% 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 other tumors, such as breast cancer, small cell lung cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendix cancer, small bowel cancer, squamous cell carcinoma of the head and neck and angiosarcoma (Sullivan, R.J., Cancer Discov February 1 2018 ( 8) (2) 184-195). Class II BRAF mutations have also been identified in metastatic cancer (Dagogo-Jack, I., Clin Cancer Res. Sept. 2018; Schirripa, M., Clin Cancer Res., May 2019; Menzer, C., J. Clin Oncol 2019, 37 (33): 3142-3151).

Additionally, in-frame BRAF deletions can function as class II mutations. For example, acquired resistance has been observed in patients treated with BRAF V600 inhibitors. Mechanisms of acquired resistance include alternative splicing. BRAF splice variants encode an active kinase but lack an intact RAS binding domain. Vemurafenib-resistant cells were found to express variant forms of BRAF V600E that lack exons spanning the RAS-binding domain, specifically lacking exons 4-10, exons 4-8, exons 2-8, or exons 2-10 (Poulikakos, P.I., et al., Nature, 480(7377):387-390.

There is currently no effective targeted treatment for patients who have non-V600 BRAF alterations or BRAF inhibitor resistance mutations.

Although some inhibitors of BRAF V600 mutations produce excellent extracranial responses, cancer metastases to the brain can still develop during or after BRAF inhibitor therapy (Oliva I.C.G, et al., Annals of Oncology, 29: 1509–1520 (2018)). An estimated 20% of all subjects with cancer develop brain metastases, with the majority of brain metastases occurring in individuals with melanoma, colorectal cancer, lung cancer, and renal cell cancer (Achrol A.S., et al., Nature Reviews ( 2019), 5:5, pp. 1-26). Although these are the most likely types of cancer, any type of cancer can spread to the brain. The development of brain metastases remains a significant factor in overall cancer mortality in patients with advanced cancer, as the prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include combinations of surgery, radiation therapy, chemotherapy, immunotherapy and/or targeted therapies.

BRAF has also been identified as a potential target for the treatment of primary brain tumors. The prevalence of the BRAF-V600E mutation in primary brain tumors was described by Schindler et al. (Acta Neuropathol 121(3):397–405, 2011) based on an analysis of 1320 central nervous system (CNS) tumors, and Behling et al. (Diagn Pathol 11(1):55, 2016), which analyzed 969 CNS tumors in children and adults. These studies, in combination with others, report the presence of BRAF-V600E mutations in a variety of cancers, including papillary craniopharyngiomas, pleomorphic xanthoastrocytomas (PXAs), gangliogliomas, astroblastomas, and others. (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).

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

Blood-brain interfaces include the cerebral microvascular endothelium, which forms the blood-brain barrier (BBB), and the choroid plexus epithelium, which forms the blood-CSF barrier (BCSFB). The blood-brain barrier (BBB) is a highly selective physical, transport and metabolic barrier separating the central nervous system from the blood. VBB can interfere with the penetration of some drugs into brain tissue and is a limiting factor in the delivery of many peripherally administered agents to the CNS. Many drugs commonly used to treat cancer are unable to penetrate the VVV. This means that the drugs are unable to enter the brain and therefore cannot effectively kill cancer cells in the brain. Current treatments for subjects with brain tumors include surgical resection, radiation therapy, and/or chemotherapy with agents such as temozolomide and/or bevacizumab. However, surgical treatment of brain cancer is not always possible or desirable; for example, the tumor may be inaccessible or the subject may be unable to withstand neurosurgical trauma. In addition, radiation therapy and treatment with cytotoxic agents are known to have unwanted side effects. For example, there is growing evidence that temozolomide alone may induce mutations and worsen prognosis in a significant proportion of subjects (B.E. Johnson et al., Science 343: 189-193 (2014)), and bevacizumab labeling contains warnings o perforation of the gastrointestinal tract, surgical and wound complications, bleeding. Kinase inhibitors are useful in the treatment of many peripheral cancers. However, due to their structural characteristics, many kinase inhibitors, such as BRAF inhibitors (eg, vemurafenib and dabrafenib), are substrates of active transporters such as P-glycoproteins (P-gp) or breast cancer resistance protein (BCRP). For example, dabrafenib has been reported to have an MDR ¹ efflux ratio of 11.4, a BCRP efflux ratio of 21.0, and a total brain-to-plasma ratio of 0.023; free brain-to-plasma ratio has not been reported (Mittapalli, RK, et al., J Pharmacol. Exp Ther 344:655-664, March 2013), and vemurafenib is reported to have an MDR ¹ efflux ratio of 83 and a BCRP efflux ratio 4 95 and total brain to plasma ratio 0.004; free brain to plasma ratio has not been reported (Mittapalli, RK. et al., J Pharmacol. Exp Ther 342:33-40 (March 2012).

Given that both P-gp and BCRP are expressed in endothelial cells lining brain capillaries, the activity of both P-gp and BCRP in the BBV plays a critical role in preventing the spread of most kinase inhibitors into the brain parenchyma. Therefore, kinase inhibitors are generally not suitable for treating tumors or cancers in the brain, which are protected by VBB.

Thus, there remains a need to treat tumors harboring BRAF mutations, including class I and class II mutations, including resistance mutations. Additionally, the need for treatment of CNS tumors, including CNS tumors harboring BRAF mutations, including resistance mutations, remains unmet.

SUMMARY OF THE INVENTION

Accordingly, provided herein is a compound of formula I:

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, AR ¹ , AR ¹ CH ₂ -, hetAR ¹ or hetCyc ¹ ;

AR ¹ is phenyl which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ , and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridging ring, and (iv) a 6-8 membered spirocyclic ring; And

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

provided that the connection does not constitute:

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

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

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

Also provided herein is a compound of Formula I-A

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, AR ¹ , AR ¹ CH ₂ -, hetAR ¹ or hetCyc ¹ ;

AR ¹ is phenyl which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCF ₂ H, -OCD ₃ , -CH ₃ and -CH ₂ CH ₃ , (ii) a 6-7 membered fused bicyclic ring, optionally substituted 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridge ring, and (iv) a 7 membered spirocyclic ring; And

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

provided that the connection does not constitute:

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

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

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

Also provided herein is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl or C1-C6 fluoroalkyl;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring; And

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

provided that the connection does not constitute:

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

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

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

Also provided herein is a compound of formula III

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, AR ¹ , AR ¹ CH ₂ -, hetAR ¹ or hetCyc ¹ ;

AR ¹ is phenyl which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ is C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring; And

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

Also provided herein is a compound of formula IV

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, AR ¹ , AR ¹ CH ₂ -, hetAR ¹ or hetCyc ¹ ;

AR ¹ is phenyl which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring; And

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

where if 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 represents -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN.

Also provided herein is a compound of formula V

or a pharmaceutically acceptable salt thereof, where:

L represents NH;

R ¹ represents C1-C6 alkyl;

R ² represents F or Cl;

R ³ represents Cl;

R ⁴ represents F;

R ⁵ represents H;

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 said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, and (iii) a 6-7 membered bridging ring.

Also provided herein is 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.

Also provided herein is a method of treating a BRAF-associated tumor in a subject in need of such treatment, 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. The compounds of the invention may be administered as single agents, or they may be administered in combination with other anticancer therapies, such as one or more additional anticancer therapies independently selected from one or more anticancer agents and/or surgery and/or radiation therapy.

Also provided herein is a method of inhibiting metastases associated with a BRAF-associated tumor in a subject in need of such treatment, wherein the method comprises 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.

Also provided herein is a method of inhibiting BRAF kinase activity in vitro or in vivo, 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, or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting the cell 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.

Also provided herein is 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.

Also provided herein is 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 the treatment of tumors.

Also provided herein is 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 inhibiting metastases associated with a BRAF-associated tumor.

Also provided herein is 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 inhibiting BRAF kinase activity.

Also provided herein is 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 the treatment of a BRAF-associated disease or disorder (eg, a BRAF-associated tumor).

Also provided herein 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, as defined herein, in the manufacture of a medicament for the treatment of a BRAF-associated tumor (e.g., BRAF -associated malignant tumor or BRAF-associated benign tumor).

Also provided herein 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, as defined herein, in the manufacture of a medicament for the inhibition of metastases associated with a BRAF-associated tumor .

Also provided herein 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 as defined herein, in the manufacture of a medicament for inhibiting BRAF kinase activity.

Also provided herein 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, as defined herein, in the manufacture of a medicament for the treatment of a BRAF-associated disease or disorder.

Also provided herein is a method of treating a BRAF-associated tumor in a subject in need thereof, 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.

Also provided herein is a pharmaceutical combination for treating a BRAF-associated tumor in a subject 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 anticancer 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 anticancer agent are formulated in separate compositions or dosages for separate or sequential use for treating a BRAF-associated tumor, wherein amounts of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof and an additional anticancer agent are together effective in treating the BRAF-associated tumor. Also provided herein is the use of such a combination for the treatment of a BRAF-associated tumor. Also provided herein is a commercial package or product containing such combination as a combination formulation for separate or sequential use in the treatment of a BRAF-associated tumor in a subject in need thereof.

Also provided herein are methods of treating a subject with a BRAF-associated tumor that comprise 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 administration of other anticancer therapy. (eg, surgery, radiation therapy and/or other anti-cancer drug).

Also provided herein is 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.

Also provided herein is a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof prepared by a process for preparing the compound as defined herein.

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention relates. Methods and materials are described herein for use in the present invention; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only 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 the event of a conflict, this specification, including definitions, will control.

Other features and advantages of the invention will be apparent from the following detailed description and drawings, as well as from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

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

DETAILED DESCRIPTION OF THE INVENTION

Provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, AR ¹ , AR ¹ CH ₂ -, hetAR ¹ or hetCyc ¹ ;

AR ¹ is phenyl which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCF ₂ H, -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, - CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridging ring, and (iv) a 6-8 membered spirocyclic ring; And

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

provided that the connection does not constitute:

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

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

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

In one embodiment, provided herein is a compound of formula I-A

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, AR ¹ , AR ¹ CH ₂ -, hetAR ¹ or hetCyc ¹ ;

AR ¹ is phenyl which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ is C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCF ₂ H, -OCD ₃ , -CH ₃ and -CH ₂ CH ₃ , (ii) a 6-7 membered fused bicyclic ring, optionally substituted 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridge ring, and (iv) a 7 membered spirocyclic ring; And

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

provided that the connection does not constitute:

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

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

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

For complex chemical names used herein, the substituent group is usually indicated before the group to which it is attached. For example, methoxyethyl includes an ethyl chain with a methoxy substituent.

The term “halogen” means -F (sometimes referred to herein as “fluorine” or “fluorine”), -Cl, -Br and -I.

The terms “C1-C3 alkyl” and “C1-C6 alkyl” as used herein refer to saturated monovalent straight-chain or branched-chain hydrocarbon radicals containing one to three or one to six carbon atoms, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, t-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl.

The term “C1-C6 fluoroalkyl” as used herein refers to a C1-C6 alkyl radical as defined herein, where one to three hydrogen atoms are replaced by one to three fluorine atoms, respectively. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

The term “C1-C6 deuteroalkyl” as used herein refers to a C1-C6 alkyl radical, as defined herein, that is substituted with one to six deuterium atoms. An example includes, but is not limited to, -CD ₃ .

The term "C3-C6 cycloalkyl" means a saturated carbocyclic ring having from 3 to 6 carbon atoms in the ring, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term “C1-C6 alkoxy” as used herein refers to saturated monovalent straight or branched chain alkoxy radicals containing from one to six carbon atoms, where the radical is on an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, propoxy and isopropoxy.

The term “(C1-C6 alkoxy)C1-C6 alkyl” as used herein refers to a C1-C6 alkyl radical as defined herein, wherein one of the carbon atoms is replaced by a C1-C6 alkoxy group. Examples of (C1-C6 alkoxy)C1-C6 alkyl groups include methoxymethyl (CH ₃ OCH ₂ -) and methoxyethyl (CH ₃ OCH ₂ CH ₂ -).

The term “heteroaryl” as used herein refers to an aromatic molecule containing at least one heteroatom as part of an aromatic ring.

The term “heterocycle” as used herein refers to a saturated cycloalkyl group in which one or more ring methylene groups (-CH2-) are replaced by a heteroatom. For example, as used herein, the term "hetCyc ¹ " refers to a saturated 4-6 membered monocyclic cycloalkyl ring in which one of the methylene groups is substituted with -O-, and the term "hetCyc ² " as used herein refers to a 5-6- a member of a saturated monocyclic cycloalkyl ring in which one or two methylene groups are replaced by a group independently selected from -O- and -N-, provided that the ring does not contain two adjacent ring heteroatoms.

Throughout the description, it should be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense.

The term “compound” as used herein is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds identified herein by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise indicated.

In one embodiment of Formula I, L is NH.

In one embodiment of Formula I, L is O.

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.

In one embodiment of Formula I, R ¹ is C1-C6 deuteroalkyl. A non-limiting example includes -CD ₃ .

In one embodiment of Formula I, R ¹ is C1-C6 fluoroalkyl. In one embodiment of Formula I, R ¹ is fluoromethyl.

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

In one embodiment of Formula I, R ¹ is (C3-C6 cycloalkyl)CH ₂ -. A non-limiting example includes cyclopropylmethyl.

In one embodiment of Formula I, R ¹ is (C1-C6 alkoxy)C1-C6 alkyl-. A non-limiting example includes methoxyethyl.

In one embodiment of Formula I, R ¹ is AR ¹ . In one embodiment, AR ¹ is phenyl, which is optionally substituted with 1, 2 or 3 substituents independently selected from halogen and C1-C3 alkyl. A non-limiting example of AR ¹ is phenyl.

In one embodiment of Formula I, R ¹ is AR ¹ CH ₂ -. In one embodiment, the AR ¹ portion is optionally substituted with 1 or 2 substituents independently selected from halogen and C1-C3 alkyl. A non-limiting example of AR ¹ CH ₂ - is benzyl (-CH ₂ C ₆ H ₅ ).

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 optionally substituted with 1 or 2 substituents independently selected from halogen and C1-C3 alkyl. In one embodiment, hetAR ¹ is unsubstituted. A non-limiting example is pyridyl.

In one embodiment of Formula I, R ¹ is hetCyc ¹ . A non-limiting example includes tetrahydrofuranyl.

In one embodiment of Formula I, R ² is -CH ₃ .

In one embodiment of Formula I, R ² is -CH ₂ CH ₃ .

In one embodiment of Formula I, R ² is -CH=CH ₂ .

In one embodiment of Formula I, R ² is F.

In one embodiment of Formula I, R ² represents Cl.

In one embodiment of Formula I, R ² is Br.

In one embodiment of Formula I, R ² represents CN.

In one embodiment of formula I, R ² represents -CH ₃ , F or Cl.

In one embodiment of Formula I, R ² is F or Cl.

In one embodiment of Formula I, R ³ is F.

In one embodiment of Formula I, R ³ is Cl.

In one embodiment of Formula I, R ⁴ is H.

In one embodiment of Formula I, R ⁴ is F.

In one embodiment of Formula I, R ⁵ is H.

In one embodiment of Formula I, R ⁵ is F.

In one embodiment of Formula I, R ⁵ is Cl.

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.

In one embodiment of Formula I, R ⁶ is methyl or ethyl.

In one embodiment of Formula I, R ⁷ is C1-C6 alkyl. In one embodiment, R ⁷ is methyl.

In one embodiment of Formula I, R ⁷ is hetCyc ² . In one embodiment, R ⁷ is tetrahydrofuranyl.

In one embodiment of Formula I, R ⁷ is C3-C6 cycloalkyl. In one embodiment, R ⁷ is cyclopropyl or cyclobutyl.

In one embodiment of Formula I, R ⁶ is methyl or ethyl, and R ⁷ is methyl, tetrahydrofuranyl, cyclopropyl or cyclobutyl.

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, 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, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ and -CH ₂ CH ₃ , (ii) a 6-7 membered fused bicyclic ring optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridge ring and (iv) a 6-8 membered spirocyclic ring.

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, 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, -OCH ₃ , -OCF ₂ H, -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN. Non-limiting examples include structures:

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, wherein said ring is substituted with a substituent selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and C.N.

In one embodiment of Formula I, ^R6 and ^R7 , together with the nitrogen atom to which they are attached, form a saturated 4-6 membered monocyclic ring substituted with F. Examples include structures:

In one embodiment of formula I, R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ . Non-limiting examples include structures:

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

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

Any of the above embodiments of Formula I can be combined with each other.

In one embodiment, provided herein is a compound of formula II

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl or C1-C6 fluoroalkyl;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ is C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring; And

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

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,

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

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

In one embodiment of Formula II, L is NH.

In one embodiment of Formula II, L is O.

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.

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

In one embodiment of Formula II, R ² is -CH ₃ .

In one embodiment of Formula II, R ² is -CH ₂ CH ₃ .

In one embodiment of Formula II, R ² is -CH=CH ₂ .

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

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

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

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

In one embodiment of formula II, R ² represents -CH ₃ , F or Cl.

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

In one embodiment of formula II, 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 where said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ and -CH ₂ CH ₃ , (ii) a 6-7 membered fused a bicyclic ring optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring.

In one embodiment of Formula II, R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 4-6 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, -OCH ₃ , -OCF ₂ H, -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN. Non-limiting examples include structures:

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

In one embodiment of formula II, R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ . Non-limiting examples include structures:

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

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

Any of the above embodiments of Formula II can be combined with each other.

In one embodiment, provided herein is a compound of formula III:

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, AR ¹ , AR ¹ CH ₂ -, hetAR ¹ or hetCyc ¹ ;

AR ¹ is phenyl which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen and C1-C3 alkyl;

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridging ring, and (iv) a 6-8 membered spirocyclic ring; And

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

In one embodiment of Formula III, L is NH.

In one embodiment of Formula III, L is O.

In one embodiment of Formula III, R ¹ is C1-C6 alkyl or C1-C6 fluoroalkyl.

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

In one embodiment of Formula III, R ¹ is C1-C6 fluoroalkyl. In one embodiment of Formula III, R ¹ is fluoromethyl.

In one embodiment of Formula III, R ² is -CH=CH ₂ .

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

In one embodiment of formula III, R ² represents Cl.

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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, optionally having a second ring heteroatom which is O where said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ and -CH ₂ CH ₃ , (ii) a 6-7 membered fused a bicyclic ring optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring.

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, 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, -OCH ₃ , -OCF ₂ H, -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN. Non-limiting examples include structures:

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 structures:

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 fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ . Non-limiting examples include structures:

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 bridging ring. Non-limiting examples include structures:

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 spirocyclic ring. Non-limiting examples include structures:

Any of the above embodiments of Formula III can be combined with each other.

In one embodiment, provided herein is a compound of formula IV

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, AR ¹ , AR ¹ CH ₂ -, hetAR ¹ or hetCyc ¹ ;

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

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring; And

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

where if 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 represents -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN.

In one embodiment of Formula IV, L is NH.

In one embodiment of Formula IV, L is O.

In one embodiment of Formula IV, R ¹ is C1-C6 alkyl or C1-C6 fluoroalkyl.

In one embodiment of Formula IV, R ¹ is C1-C6 alkyl. Non-limiting examples include methyl, ethyl and isopropyl, with the proviso that if 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 represents 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 represents -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN. In one embodiment of Formula IV, R ¹ is methyl.

In one embodiment of Formula IV, R ¹ is C1-C6 fluoroalkyl. In one embodiment of Formula IV, R ¹ is fluoromethyl.

In one embodiment of Formula IV, R ² is -CH ₃ .

In one embodiment of Formula IV, R ² is -CH ₂ CH ₃ .

In one embodiment of Formula IV, R ² is -CH=CH ₂ .

In one embodiment of Formula IV, R ² is F.

In one embodiment of Formula IV, R ² is Cl.

In one embodiment of Formula IV, R ² is Br.

In one embodiment of Formula IV, R ² is CN.

In one embodiment of Formula IV, R ² is -CH ₃ , F or Cl.

In one embodiment of Formula IV, R ² is F or Cl

In one embodiment of Formula IV, R ³ is F.

In one embodiment of Formula IV, R ³ is Cl.

In one embodiment of Formula IV, R ⁴ is H.

In one embodiment of Formula IV, R ⁴ is F.

In one embodiment of Formula IV, R ⁵ is H.

In one embodiment of Formula IV, R ⁵ is F.

In one embodiment of Formula IV, R ⁵ is Cl.

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.

In one embodiment of Formula IV, R ⁶ is methyl or ethyl.

In one embodiment of Formula IV, R ⁷ is C1-C6 alkyl. In one embodiment, R ⁷ is methyl.

In one embodiment of Formula IV, R ⁷ is hetCyc ² . In one embodiment, R ⁷ is tetrahydrofuranyl.

In one embodiment of Formula IV, R ⁷ is C3-C6 cycloalkyl. In one embodiment, R ⁷ is cyclopropyl or cyclobutyl.

In one embodiment of Formula IV, R ⁶ is methyl or ethyl and R ⁷ is methyl, tetrahydrofuranyl, cyclopropyl or cyclobutyl.

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 4-6 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, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring.

In one embodiment of formula IV, R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 4-6 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, -OCH ₃ , -OCF ₂ H, -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN. Non-limiting examples include structures:

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

In one embodiment of formula IV, R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ . Non-limiting examples include structures:

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

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

Any of the above embodiments of Formula IV may be combined with each other.

In one embodiment, provided herein is a compound of formula V

or a pharmaceutically acceptable salt thereof, where:

L represents NH;

R ¹ represents C1-C6 alkyl;

R ² represents F or Cl;

R ³ represents Cl;

R ⁴ represents F;

R ⁵ represents H;

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 said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, and (iii) a 6-7 membered bridging ring.

In one embodiment, formulas V, R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a saturated 4-6 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, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN.

In one embodiment, Formulas V, ^R6 and ^R7 , together with the nitrogen atom to which they are attached, form a saturated 4-6 membered monocyclic ring, wherein said ring is optionally substituted with 1 or 2 substituents independently selected from F.

In one embodiment, Formulas V, R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a saturated 6-7 membered bridging ring.

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

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

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

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 4-6 membered monocyclic ring, wherein said ring is optionally substituted 1 or 2 substituents independently selected from F. In one embodiment, said ring is substituted with one F.

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 6-7 membered bridging ring.

The compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV and Formula V, Formula IV and Formula V include their pharmaceutically acceptable salts. In addition, 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 separating enantiomers of compounds of formula I, formula I-A, formula II, formula III, formula IV or formula V.

The term "pharmaceutically acceptable salt" refers to a conventional acid addition or base addition salt which retains the biological effectiveness and properties of the compounds of formula (I), and which can be prepared with suitable non-toxic organic or inorganic acids or organic or inorganic bases. 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 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 acid, oxalic acid, tartaric acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid and the like. Examples of base addition salts are those derived from ammonium, potassium, sodium 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 therefore more suitable for use in the preparation of various pharmaceutical formulations.

It is further understood that the compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or salts thereof, can be isolated in the form of solvates and, accordingly, that any such solvate is included within the scope of the present invention. For example, the compounds of formula I and their salts can exist in either unsolvated or solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.

The term "solvate" refers to non-covalent stoichiometric or non-stoichiometric combinations of solvent and solute. The term "hydrate" refers to non-covalent stoichiometric or non-stoichiometric combinations 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 pharmaceutically acceptable salts or polymorphs thereof, may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as anisole, dichloromethane, toluene , 1,4-dioxane, water and the like.

The compounds provided herein may contain one or more asymmetric centers and can therefore be prepared and isolated in a mixture of isomers, such as a racemic mixture, or in enantiomerically pure form. The present invention includes all individual stereoisomers and geometric isomers of the compounds of the invention and mixtures thereof. Individual enantiomers can be obtained by chiral resolution or by using the corresponding enantiomer in synthesis. The bonds to the carbon atom in the compounds of the invention can be represented here by a solid line straight bold line straight dotted line solid wedge or dotted wedge Using a solid line to indicate bonds to asymmetric carbon atoms means that all possible stereoisomers (eg, specific enantiomers, racemic mixtures, etc.) on that carbon atom are included. The use of either a straight thick bar or a straight dotted bar is intended to indicate relative stereochemistry. Using either a solid wedge or a dotted wedge means absolute stereochemistry. For compounds described in the examples containing one or more stereocenters, unless specific stereochemistry is shown, the compound is intended to include a mixture of stereoisomers. As used herein, the term “stereocenter” refers to an atom with three or more different compounds, where substitution of two of these compounds results in a different stereoisomer. Examples include, but are not limited to, sp ³ (tetrahedral) carbon atom having four different compounds.

The compounds of formula I, formula I-A, formula II and formula III can exist in various geometric isomeric forms. In addition, some compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V may contain one or more asymmetric centers such that they exist in stereoisomeric and diastereomeric forms. The term "stereoisomer" means a compound that has the same molecular connectivity and multiplicity of bonds, but differs in the arrangement of atoms in space. All of these compounds, such as cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, substantially pure and pure enantiomers are included within the scope of the invention. In one embodiment, the substantially pure enantiomers contain up to 5% by weight. the corresponding opposite enantiomer. In one embodiment, the substantially pure enantiomers contain up to 2% by weight. the corresponding opposite enantiomer. In one embodiment, the substantially pure enantiomers contain up to 1% by weight. the corresponding opposite enantiomer.

Optical isomers can be prepared by resolving racemic mixtures by known methods, for example using an optically active acid or base to form diastereomeric salts or by forming covalent diastereomers. Suitable acids include, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into individual diastereoisomers based on their physical and/or chemical differences by methods known to those skilled in the art, such as chromatography or fractional crystallization. Optically active bases or acids are then released from the isolated diastereomeric salts. Various methods for separating optical isomers include chiral chromatography (eg, chiral HPLC columns), optionally using derivatization to maximize enantiomer separation. Suitable chiral columns for HPLC are Diacel columns, such as CHIRALPAK or CHIRALCEL columns, which can usually be selected as desired. Where applicable, enzymatic separations carried out by derivatization can also be used. Optically active compounds of formula I, formula I-A, formula II, formula III, formula IV or formula V can also be prepared using optically active starting materials using chiral synthesis without racemization reaction conditions.

Also included are acid addition salts or base addition salts in which the counterion is optically active, such as d-lactate or l-lysine, or racemic, such as dl-tartrate or dl-arginine.

When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound mentioned above (true racemate), which produces one homogeneous crystal form containing both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate, where the two crystal forms are formed in equimolar quantities, each containing one enantiomer.

The compounds of the invention may exhibit tautomerism and structural isomerism phenomena. For example, 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 the tautomeric set in solution. In solid form, one tautomer usually predominates. Although a single tautomer may be described, the present invention includes all tautomers of the compounds of the presented formulas.

Conventional methods for preparing/isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or racemate salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) or supercritical liquid chromatography (SLC).

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

The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically 2 to 20%, and 0 to 5% alkylamine, usually 0.1% diethylamine. The concentration of the eluent produces a rich mixture.

Stereoisomeric conglomerates can be separated by conventional methods known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994), the description of which is incorporated herein by reference in its entirety.

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 greater quantity than the other. A racemic mixture has 0% ee, while a single completely pure enantiomer has 100% ee. Similarly, diastereomeric purity can be described in terms of diastereomeric excess (di).

The compounds of the invention may exhibit tautomerism and structural isomerism phenomena. For example, 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 the tautomeric set in solution. In solid form, one tautomer usually predominates. Although a single tautomer may be described, the present invention includes all tautomers of the compounds of the presented formulas.

In addition, some of the compounds of the invention may form atropisomers (eg, substituted biaryls). Atropoisomers are conformational stereoisomers that occur when rotation around a single bond in a molecule is prevented or significantly slowed down by spatial interactions with other parts of the molecule, and the substituents on both ends of the single bond are asymmetrical. The interconversion of atropisomers occurs slowly enough that they can be separated and isolated under given conditions. The energy barrier to thermal racemization may be determined by the steric hindrance to the free rotation of one or more bonds forming a chiral axis.

Unless otherwise indicated, all references herein to the compounds of the invention include references to their salts, solvates, hydrates and complexes, and to solvates, hydrates and salt complexes, including polymorphs, stereoisomers and isotopically labeled variants thereof.

The compounds of the invention may exist in the form of pharmaceutically acceptable salts, such as, for example, acid addition salts and base addition salts of compounds of one of the formulas presented herein. As used herein, the term “pharmaceutically acceptable salt” refers to those salts that retain the biological effectiveness and properties of the parent compound. The phrase "pharmaceutically acceptable salt(s)" as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the formulas described herein.

For example, the compounds of the invention, which are basic in nature, are capable of forming a wide range of salts with various inorganic and organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, in practice it is often desirable to first isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt, and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and then convert the latter the free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of the invention can be prepared by treating the base compound with a substantially equivalent amount of a selected mineral or organic acid in an aqueous solvent or 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 adding a suitable mineral or organic acid to the solution.

Acids which can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds which form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions 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, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.

Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (for example, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butine-1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogen phosphate, edetate, edislate, estolate, esylate, ethyl succinate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolylarsanilate, heptanoate, hexine -1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, g-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate, methyl sulfate, monohydrogen phosphate, mucate , napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phosphate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, theoclate, tosylate and valerate.

Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary 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.

The compounds of the invention, which include a basic group such as an amino group, can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above.

Alternatively, useful compounds that are acidic in nature may be capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali or alkaline earth metal salts and, in particular, sodium and potassium salts. All these salts are obtained by conventional methods. The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of the present invention are those that form non-toxic basic salts with the acidic compounds of the present invention. 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), an alkali metal hydroxide or an alkaline earth metal hydroxide or the like. These salts can also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing lower alkanol solutions of acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as before. In any case, it is preferable to use stoichiometric amounts of reactants to ensure completeness of the reaction and maximum yield of the desired final product.

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

Hemi-salts of acids and bases can also be formed, for example, hemi-sulfate and hemi-calcium salts.

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

The salts of the present invention can be prepared by methods known to those skilled in the art. A pharmaceutically acceptable salt of the compounds of the invention can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate.

The salt may precipitate out of solution and be collected by filtration or may be isolated by evaporation of the solvent. The degree of ionization in salt can vary from completely ionized to almost non-ionized.

Those skilled in the art will appreciate that the compounds of the invention in free base form having basic functionality 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 invention can be reconverted to the corresponding free base by treatment with a stoichiometric excess of a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of an aqueous solvent and at a temperature between about 0°C and 100°C. The free base form can be isolated by conventional methods such as organic solvent extraction. In addition, the acid addition salts of the compounds of the present invention can be replaced by taking advantage of the different salt solubility, volatility or acidity properties of the acids, or by treatment with an appropriately loaded ion exchange resin. For example, the interconversion may be affected by the reaction of a salt of the compounds of the invention with a small stoichiometric excess of an acid with a lower pK than the acid component of the parent salt. This transformation is usually carried out at a temperature from about 0°C to the boiling point of the solvent used as the medium for the procedure. Similar exchanges are possible with base addition salts, usually via the free base form.

The compounds of the invention may exist in both non-solvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry that is 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 the humidity and drying conditions. In such cases, lack of stoichiometry will be the norm. The term “solvate” is used herein to describe a molecular complex comprising a compound of the invention and one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. The term "hydrate" is used when the solvent is water. Pharmaceutically acceptable solvates according to the invention include hydrates and solvates in which the crystallization solvent may be isotopically substituted, for example D ₂ O, d6-acetone, d6-DMSO.

The invention also relates to prodrugs of the compounds of the formulas proposed herein. Thus, certain derivatives of the compounds of the invention, which may have little or no pharmacological activity, when administered to a patient, can be converted into the compounds of the invention, for example, by hydrolytic cleavage. Such derivatives are called "prodrugs". Additional information on the use of prodrugs can be found in 'Prodrugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella); 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E In Roche, American Pharmaceutical Association), and Guarino, V.R; Stella, V.J.: Biotech Pharm. Aspects 2007 5 (Pt2) 133-187, the descriptions of which are incorporated herein by reference in their entirety.

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 of Examples 1-164 may be in free base form. In one embodiment, the compound of any of Examples 1-164 may be in acid salt form. In one embodiment, some of the compounds from Examples 1-164 are isolated as trifluoroacetates.

The compounds provided herein may also contain non-naturally occurring proportions of atomic isotopes on one or more of the atoms constituting such compounds. That is, an atom, particularly when referred to in relation to a compound of Formula I, Formula IA, Formula II, Formula III, Formula IV and Formula V, includes all isotopes and isotopic mixtures of that atom occurring naturally or synthetically produced, or in natural abundance, or in isotopically enriched form. For example, when hydrogen is mentioned, it is intended to refer to ¹ H, ² H, ³ H, or mixtures thereof; when carbon is mentioned it is meant to refer to ¹¹ C, ¹² C, ¹³ C, ¹⁴ C or mixtures thereof; when nitrogen is mentioned it is meant to refer to ¹³ N, ¹⁴ N, ¹⁵ N or mixtures thereof; when oxygen is mentioned it is meant to refer to ¹⁴ O, ¹⁵ O, ¹⁶ O, ¹⁷ O, ¹⁸ O or mixtures thereof; and when fluorine is mentioned, it is understood to refer to ¹⁸ F, ¹⁹ F, or mixtures thereof. As noted above, the compounds provided herein thus also include compounds with one or more isotopes of one or more atoms and mixtures thereof, including radioactive compounds in which one or more non-radioactive atoms are replaced by one of its radioactively enriched isotopes. The radiolabeled compounds can be used as therapeutic agents, such as anticancer therapeutic agents, research reagents, such as assay reagents, and diagnostic agents, such as in vivo imaging agents. All isotopic variants of the compounds presented herein, whether radioactive or not, are intended to be within the scope of the present invention. Certain isotopically labeled compounds of the invention, for example those incorporating radioactive isotopes such as ³ H and ¹⁴ C, can be used in drug and/or substrate tissue distribution assays. Tritium isotopes, i.e. ³ H, and carbon 14, i.e. ¹⁴ C are particularly preferred due to their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium, e.g. ^2H may provide certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. The isotopically labeled compounds of the invention can generally be prepared by following the procedures described in the Schemes and/or in the following Examples and Preparations by replacing the non-isotope-labeled reagent with an isotope-labeled reagent.

The invention also relates to prodrugs of the compounds of the formulas presented herein. Thus, certain derivatives of the compounds of the invention, which may or may not have little pharmacological activity, when administered to a patient, can be converted into the compounds of the invention, for example, by hydrolytic cleavage. Such derivatives are called "prodrugs". Additional information on 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 (ed. EB Roche, American Pharmaceutical Association), the description of which is incorporated herein by reference in its entirety.

Prodrugs according to the invention can be prepared, for example, by replacing the corresponding functional groups present in the compounds of the invention with certain groups known to those skilled in the art as "pro-groups", as described, for example, in "Design of Prodrugs "by H Bundgaard (Elsevier, 1985), the description of which is incorporated herein by reference in its entirety.

Some non-limiting examples of prodrugs of the invention include:

(i) if the compound contains a carboxylic acid functional group (-COOH), its ester, for example replacing hydrogen with (C1-C8)alkyl;

(ii) when the compound contains an alcohol functional group (-OH), its ester, for example, replacement of hydrogen by (C1-C6)alkanoyloxymethyl or a phosphate ester group; And

(iii) if the compound contains a primary or secondary amino group (-NH2 or -NHR, where R ¹ H), its amide, for example the replacement of one or both hydrogen atoms with a suitable metabolic labile group such as amide, carbamate, urea, phosphonate, sulfonate and etc.

Additional examples of substituent groups in accordance with the above examples and examples of other types of prodrugs can be found in the above references.

Finally, some compounds of the invention may themselves act as prodrugs of other compounds of the invention.

Also included within the scope of the invention are metabolites of the compounds of the formulas described herein, i.e. compounds formed in vivo upon administration of a drug.

For illustrative purposes, Schemes 1-10 show general methods for preparing the compounds presented herein, as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the invention. Although specific starting materials and reagents are depicted in the diagrams and discussed below, other starting materials and reagents can be easily substituted to produce different derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this description using conventional chemistry well known to those skilled in the art.

Scheme 1 describes the synthesis of intermediate 3, where X is a halogen, which is 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 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 in Formula I and X is halogen, in the presence of a base such as Cs ₂ CO ₃ . in a solvent such as DMF to give compound 3.

Scheme 2 describes the synthesis of intermediate 5, which can be used to prepare compounds of formula I, wherein R ¹ and R ² are as defined in formula I and L is NH. Compound 3 (prepared, for example, in accordance with Scheme 1) can be combined with a reagent having the formula (PG)NH ₂ 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 (eg Pd ₂ (dba) ₃ ) and a ligand (eg Xantphos) to give compound 4. Compound 4 can be deprotected under standard conditions, for example using TPA, to give compound 5.

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 defined for formula I. Compound 6 (where R ³ , R ⁴ and R ⁵ are defined for formula I) can react 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 temperatures, for example -78°C, to form 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 agent in a suitable solvent such as THF to give compound 8. Compound 8 can be removed by reacting with an acid such as HCl in in a suitable solvent to give compound 9. Compound 9 can be reacted with di-tert-butyl dicarbonate ((Boc) ₂ O) in the presence of a catalyst such as 4-dimethylaminopyridine (DMAP) in a suitable solvent such as THF to give compound 10. Compound 10 can be deprotected in the presence of a base such as K ₂ CO ₃ in a suitable solvent such as MeOH to give compound 11.

Scheme 4 describes the synthesis of compound 13, which is an intermediate useful for the preparation of compounds of formula I, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in formula I and L is NH. Compound 5 (prepared, for example, in accordance with Scheme 2) can be combined with compound 11 (prepared, for example, in accordance with Scheme 3) in the presence of a catalyst (for example, a palladium catalyst, for example, Pd ₂ (dba) ₃ ) and a ligand ( e.g. Xantphos) followed by deprotection under standard conditions (e.g. with TPA) to give compound 13.

Scheme 5 describes the synthesis of compound 16, which can be used to prepare compounds of formula I, where R ⁶ and R ⁷ are as defined for formula I. Amine 14 can be combined with sulfuryl dichloride 15 in the presence of a base such as TEA in a suitable solvent, such as DXM to give compound 16.

Scheme 6 describes the synthesis of a compound of formula 24 that can be used to prepare compounds of formula I wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in formula I and L is O. Compound 17 ( wherein R ² is as defined in formula I) may be coupled to compound 18, wherein R ³ , R ⁴ and R ⁵ are as defined in formula I, in a suitable solvent such as DMSO in the presence of a base such as Cs ₂ CO ₃ , at elevated temperature to give compound 19. Compound 19 can be reacted with (Boc) ₂ O in the presence of a catalyst such as DMAP in a suitable solvent such as THF to give compound 20. The nitro group of compound 20 can be reduced under standard nitro reduction conditions such as treatment with Fe and NH ₄ Cl to give compound 21. Compound 21 can be cyclized with formamidine acetate in an organic solvent such as EtOH at elevated temperature to give compound 22. Compound 22 can be alkylated a reagent having the formula R ¹ X, where R ¹ is as defined for formulas I, and X is halogen, in the presence of a base such as Cs ₂ CO ₃ in a solvent such as DMF, to obtain compound 23. Compound C 23 can be deprotected under standard conditions (for example, using TPA) to obtain compound 24.

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 for formula I, and L is NH (for example, obtained in accordance with scheme 4) or O (for example, obtained in accordance with scheme 6). Compound 25 can be combined with compound 16 in the presence of a suitable base such as pyridine, or in the presence of calcium triflimide in an organic solvent such as toluene at elevated temperatures to give compound 26.

Scheme 8 describes the synthesis of compound 27, which can be used to prepare compounds of formula I, where R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the meanings defined for formula I. Amine 11, where R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in Formula I, may be coupled with sulfonamide chloride 16, wherein R ⁶ and R ⁷ are as defined in Formula I, in the presence of a base such as NaH in a suitable solvent, such as THF to give compound 27.

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 are as defined in formula I. Compound 5 (prepared for example, in accordance with scheme 2), where R ¹ and R ² have the meanings defined for formula I, can be combined with compound 27 (obtained, for example, in accordance with scheme 8), where R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in Formula I, and PG is an amine protecting group (such as p-methoxybenzyl (PMB) or tert-butoxycarbonyl (Boc)), in the presence of a catalyst (for example, a palladium catalyst, e.g. Pd ₂ (dba) ₃ ) and a ligand (e.g. Xantphos) followed by deprotection under standard conditions (e.g. with TPA) to give compound 29.

Scheme 10 describes the synthesis of compound 33, which is a compound of formula I, where R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in formula I, and L is O. The amino group of compound 24 (where R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meaning defined for formula I), can be di-protected with a suitable amine protecting group (for example, p-methoxybenzyl (PMB) or tert-butoxycarbonyl (Boc)) by reaction with a suitable reagent (e.g., by reacting with (Boc) _2O in the presence of a catalyst such as DMAP in a suitable solvent such as THF) to produce compound 30, wherein PG is an amine protecting group (e.g., p-methoxybenzyl ( PMB) or tert-butoxycarbonyl (Boc).Compound 30 can be deprotected under suitable conditions (eg, in the presence of K ₂ CO ₃ in an organic solvent such as MeOH at elevated temperature) to give the monoprotected compound 31. Compound 31 can be coupled with sulfamoyl chloride 16 in the presence of a base such as NaH in a suitable solvent such as THF to give compound 32. Compound 32 can be deprotected under standard conditions (eg with TFA) to give compound 33.

The methods shown in Schemes 1-10 are applicable to the preparation of compounds of formulas II, III and IV, as well as for the preparation of intermediates useful for the preparation of compounds of formulas II, III and IV.

In one embodiment, provided herein is a method for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof, which comprises:

(a) for a compound of formula I, wherein L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ have the meanings defined for formula I, binding of a compound of formula (25)

where L, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined for formula I, with a compound having formula (16)

where R ⁶ and R ⁷ are as defined for formula I, in the presence of a suitable base; or

(b) for a compound of formula I wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined for formula I and L is NH, the reaction of the compound of formula (5)

where R ¹ and R ² are as defined for formula I, with a compound having formula (27)

where R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as defined for formula I and PG represents an amine protecting group in the presence of a palladium catalyst and ligand followed by removal of the amine protecting group; or

(c) for a compound of formula I wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined for formula I and L is O, the reaction of a compound having formula (31)

where R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined for formula I and PG represents an amine protecting group with a reagent having the formula

in the presence of a base followed by removal of the amino protecting group; And

optionally to form a pharmaceutically acceptable salt thereof.

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

The term "amine protecting group" as used herein refers to derivatives of groups typically used to block or protect an amine group when reacting with 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, as well as many N-heteroatom derivatives that can be removed to regenerate the desired amino group. Non-limiting examples of amine protecting groups include tert-butyloxycarbonyl (“Boc”), 2-trimethylsilylethoxymethyl (SEM) and p-methoxybenzyl (PMB). Additional examples of these groups and other protecting groups can be found in T.W. Greene, et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2014.

The compounds of formula I, formula IA, formula II, formula III, formula IV and formula V, or pharmaceutically acceptable salts thereof, are useful for the treatment of diseases and disorders that can be treated with a BRAF kinase inhibitor, such as BRAF-associated diseases and disorders, e.g. proliferative disorders such as cancers, including solid tumors. The ability of the test compounds to act as BRAF inhibitors can be demonstrated using the enzyme assay described in Example A1, the cellular assay described in Example A2, the cellular assay described in Example A3, and the proliferation assay described in Example A4. The IC ₅₀ values are shown in Tables A1 and A2.

In some embodiments, certain compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, and Formula V, or pharmaceutically acceptable salts thereof, exhibit unexpected penetrance in the brain and/or CNS. Such compounds are capable of crossing the BBB and inhibiting BRAF kinase in the brain and/or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing BBB in a therapeutically effective amount. For example, treating a subject with cancer (eg, BRAF-associated cancer, such as BRAF-associated CNS cancer) may involve administering (eg, oral administration) a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or their pharmaceutically acceptable salt to the subject. Accordingly, in some embodiments, the compounds provided herein are useful for the treatment of CNS cancer.

As used herein, the terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical outcomes include, but are not limited to, complete or partial relief of symptoms associated with a disease or disorder or condition, reduction in the severity of a disease, a stabilized (i.e., not worsening) disease state, delay or slowing of disease progression, improvement or temporary relief of a disease state (eg, one or more symptoms of a disease) and remission (partial or complete), determinable or indeterminate. However, “treating” or “treatment” may also include therapeutic measures (eg, inhibition of BRAF kinase in a BRAF-associated tumor) that temporarily worsen the subject's appearance and/or symptoms. As used herein, the terms “treatment” and “treatment,” when they relate, for example, to the treatment of cancer, are not intended to be absolute terms. For example, “cancer treatment” and “cancer treatment” as used in a clinical setting are intended to produce beneficial or desired clinical results and may include improving the condition of a subject suffering from cancer. Beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation (or killing) of tumor or cancer cells, inhibiting metastasis of tumor cells, reducing metastasis in a subject, shrinking or reducing the size of a tumor, changing the growth rate of one or more multiple tumors in a subject, increasing the subject's period of remission (eg, compared with one or more in a subject with a similar cancer untreated or receiving different treatment, or compared with one or more in the same subject before treatment) , reducing symptoms resulting from the disease, improving the quality of life of those suffering from the disease (eg, assessed using FACT-G or EORTC-QLQC30), reducing the dose of other medications needed to treat the disease, slowing the progression of the disease, and/or increasing the life expectancy of subjects suffering from the disease. “Treatment” may also mean an increase in life expectancy compared to the expected survival in the absence of treatment, such as 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.

As used herein, the term “subject” refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder being treated and/or prevented. In some embodiments, the subject has been identified or diagnosed with a BRAF mutated tumor (BRAF-associated tumor) (e.g., as determined using a regulatory agency approved assay or kit, e.g., FDA approved). In some embodiments, the subject has a tumor that is positive for a BRAF mutation (eg, as determined using a regulatory agency approved assay or kit). The subject may be a subject whose tumors have a BRAF mutation (eg, when the tumor is identified as such using a kit or assay approved by a regulatory agency, such as FDA approved). In some embodiments, the subject is suspected of having a BRAF-associated tumor. In some embodiments, the subject has a medical history indicating that the subject has a tumor with a BRAF mutation (and, optionally, the medical history indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a human. In some embodiments, the human subject is a pediatric subject.

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

In some embodiments, compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, are useful for the prevention of diseases and disorders as defined herein. The term "prevention" as used herein means preventing the occurrence, recurrence or spread, in whole or in part, of a disease or condition described herein.

The term "BRAF-associated" in relation to a disease or disorder as used herein refers to diseases or disorders associated with or having one or more BRAF mutations and/or BRAF fusions. Non-limiting examples of a BRAF-associated disease or disorder include, for example, BRAF-associated tumors.

The phrase "BRAF mutation" refers to a genetic mutation (e.g., a chromosomal translocation that results in one or more mutations in the BRAF gene, resulting in the expression of a BRAF protein with one or more point mutations relative to the wild-type BRAF protein), or alternatively spliced version of BRAF mRNA that produces a BRAF protein having a deletion of at least one amino acid in the BRAF protein compared to the wild-type BRAF protein (ie, a splice variant). Non-limiting examples of BRAF mutations include class I BRAF mutations (eg, BRAF V600 mutations, such as BRAF V600E and BRAF V600K), class II BRAF mutations (eg, non-V600 BRAF mutations and BRAF splice variants), and class III BRAF mutations.

The term "BRAF T class mutations" refers to BRAF V600 mutations that signal as Ras-independent active monomers. Examples include the BRAF V600E and BRAF V600K mutations.

The term "TT class BRAF mutations" includes (i) non-V600 BRAF mutations that function as RAS-independent activated dimers of BRAF and/or CRAF, and (ii) BRAF splice variants whose activity depends on dimerization in a RAS-independent fashion .

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

The term “BRAF splice variant” refers to the aberrantly spliced V600E isoforms of BRAF. BRAF splice variants are BRAF V600E resistance mutations that lack exons encoding part of the RAS binding domain and exhibit increased dimerization in cells with low levels of RAS activation (Poulikakos et al., Nature, 480(7377):387-390 Examples of BRAF V600E splice variants include the absence of exons 4-8 (also known as p61BRAF(V600E)), exons 4-10, exons 2-8, or exons 2-10. In one embodiment, the resistance mutation is p61BRAF(V600E) .

The term “resistance mutation” refers to a mutation in the BRAF V600E mutation that occurs following exposure of the BRAF V600E mutant to a BRAF inhibitor, either alone or in combination with another anticancer agent, such as a MEK inhibitor. Tumors with resistance mutations become less sensitive (eg, resistant to treatment) to a BRAF inhibitor. In one embodiment, the resistance mutation occurs following exposure to vemurafenib.

The term “class III BRAF mutations” refers to non-V600 BRAF mutations that function as RAS-dependent activated BRAF and/or CRAF dimers. Non-limiting examples of class III BRAF mutations include G466A, G466E, G466R, G466V, D594A, D594E, D594G, D594H, G594N, D287H, V549L, S467A, S467E, S467L, G469E, N581S, N5811, F595L, G 596A, G596C, G596D, G596R and K483M.

The term "BRAF fusion" refers to a translocation of the BRAF gene that results in the expression of a fusion protein. In one embodiment, a BRAF-associated tumor or BRAF-associated cancer has one or more BRAF fusions that result in constitutive activation and transformation of a kinase, 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.

The term “BRAF-associated tumor” or “BRAF-associated cancer” as used herein refers to tumors or cancers associated with or having a BRAF mutation, and includes tumors having a class I BRAF V600 mutation, such as a BRAF V600E mutation or V600K, and tumors with class II BRAF mutation. BRAF-associated tumors include both benign BRAF-associated tumors and malignant BRAF-associated tumors (ie, BRAF-associated cancers).

The term "tumor" as used herein refers to abnormal tissue growth resulting from uncontrolled, usually rapid, cell proliferation. The tumor may be a benign tumor (non-cancerous) or a malignant tumor (ie cancer). The tumor may be a solid tumor or a hematologic malignancy (ie, a hematologic tumor, also known as a blood cancer).

The term “wild type” describes a nucleic acid (eg, BRAF gene or BRAF mRNA) that is typically found in a subject who does not have a disease or disorder relative to the reference nucleic acid or protein.

The term "wild-type BRAF" describes BRAF nucleic acid (e.g., BRAF gene or BRAF mRNA) or BRAF protein found in a subject who does not have a BRAF-associated disease, e.g., BRAF-associated cancer (and optionally also does not have increased risk of developing a BRAF-associated disease and/or is not suspected of having a BRAF-associated disease), or found in a cell or tissue of a subject who does not have a BRAF-associated disease, such as a BRAF-associated cancer (and optionally also does not have an increased risk of developing BRAF-associated disease and/or is not suspected of having BRAF-associated disease).

The term "regulatory agency" refers to the agency of a country that approves the medical use of pharmaceutical agents in a country. For example, a non-limiting example of a regulatory agency is the US Food and Drug Administration (FDA).

Provided herein is a method of treating a BRAF-associated tumor in a subject in need of such treatment, 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 their pharmaceutical composition. For example, provided herein are methods of treating a BRAF-associated tumor in a subject in need of such treatment, wherein the method comprises a) detecting a BRAF mutation in a sample taken 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 some embodiments, the BRAF mutation is a class I mutation. In some embodiments, the class I BRAF mutation is BRAFV600E. In some embodiments, the BRAF mutation is a class II mutation. In some embodiments, the class II mutation is a non-V600 mutation. In some embodiments, the non-V600 mutation is G469A. In some embodiments, the class II mutation is the BRAF V600E splice variant. In some embodiments, the BRAF V600E splice variant is p61BRAF(V600E).

In some embodiments of any of the methods of use described herein, the BRAF-associated tumor is a solid tumor. In some embodiments, the tumor is intracranial. In some embodiments, the tumor is extracranial. In some embodiments of any of the methods of use described herein, the BRAF-associated tumor is a malignant BRAF-associated tumor (ie, BRAF-associated cancer). In some 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 difficult-to-treat differentiated thyroid cancer), breast cancer, bladder cancer, ovarian cancer (ovarian carcinoma), central nervous system cancer (including gliomas and LMD), bone cancer, cancer of the anus, anal canal or anorectum, angiosarcoma, adenoid cystic carcinoma, appendix cancer, eye cancer, bile duct cancer (cholangiocarcinoma), cervical cancer, ductal carcinoma in situ, endometrial cancer, gallbladder, hepatobiliary cancer, hepato-pancreato - biliary carcinoma, squamous cell carcinoma of the head and neck, oral cancer, oral cavity cancer, leukemia, lip cancer, oropharyngeal cancer, nasal, nasal or middle ear cancer, vulvar cancer, esophageal cancer, esophagogastric cancer, cervical cancer, carcinoid tumor of the gastrointestinal tract, neuroendocrine cancer of the gastrointestinal tract, cancer of the hypopharynx, kidney cancer, laryngeal cancer, liver cancer, nasopharyngeal cancer, non-Hodgkin's lymphoma, cancer of the peripheral nervous system (for example, neuroblastoma), neuroendocrine cancer, pancreatic cancer, peritoneal cancer, plasma cell neoplasm, omental and mesenteric cancer, pharyngeal cancer, prostate cancer, kidney cancer (eg, renal cell carcinoma (RCC)), colon cancer, small bowel cancer, soft tissue sarcoma, stomach cancer, testicular cancer, uterine cancer cancer, ureteral cancer or bladder cancer.

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

In some embodiments, the BRAF-associated cancer is an extracranial cancer selected from melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, and neuroblastoma. In some embodiments, the BRAF-associated cancer is melanoma. In some embodiments, the BRAF-associated cancer is colorectal cancer. In some embodiments, the BRAF-associated cancer is thyroid cancer. In some embodiments, the BRAF-associated cancer is non-small cell lung cancer. In some embodiments, the BRAF-associated cancer is ovarian cancer. In some embodiments, the BRAF-associated cancer is a neuroblastoma.

In some embodiments, the BRAF-associated cancer is an intracranial cancer (brain cancer). In some embodiments, the BRAF-associated cancer is a CNS cancer.

In some embodiments, a BRAF-associated cancer is a cancer that has a class I BRAF mutation. In some embodiments, a BRAF-associated cancer is a cancer having the BRAF V600E or BRAF V600K mutation. In some embodiments, the BRAF-associated cancer having the BRAF V600E or BRAF V600K mutation is selected from melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, renal cell carcinoma and metastatic cancers thereof, and primary brain tumors brain In some embodiments, the BRAF-associated cancer having the BRAF V600E or BRAF V600K mutation is a CNS tumor. In some embodiments, the CNS tumor is a malignant tumor (CNS cancer). In some embodiments, the cancer is a metastatic CNS cancer. In some 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 some embodiments, the CNS tumor is an intracranial LMD or extracranial LMD.

In some embodiments, a BRAF-associated cancer is a cancer that has a class II BRAF mutation. In one embodiment, the cancer having a class II BRAF mutation is selected from lung cancer (eg, non-small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, cancer appendix, small bowel cancer, neuroendocrine gastrointestinal cancer, squamous cell carcinoma of the head and neck, angiosarcoma, bladder cancer, plasma cell neoplasm, hepatobiliary cancer, hepato-pancreato-biliary carcinoma, ovarian cancer, endometrial cancer, neuroendocrine cancer, cholangiocarcinoma, esophageal cancer, soft tissue sarcoma, leukemia, non-Hodgkin's lymphoma and central nervous system cancer (eg, glioma). In one embodiment, the cancer has the BRAF G469A mutation.

In some embodiments, a BRAF-associated cancer is a cancer that has a class III BRAF mutation. In one embodiment, the cancer having a class III BRAF mutation is selected from melanoma, small bowel cancer, colorectal cancer, non-small cell lung cancer, endometrial cancer, cervical cancer, leukemia, bladder cancer, non-Hodgkin's lymphoma, glioma, ovarian cancer, prostate cancer gland, hepatobiliary cancer, esophageal and gastric cancer, soft tissue sarcoma and breast cancer. In one embodiment, the cancer has the BRAF G466V or BRAF D594G mutation. In one embodiment, the cancer has the BRAF G466V mutation. In one embodiment, the cancer has the BRAF D594G mutation.

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

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

The term "metastasis" is a term known in the art that refers to the spread of cancer cells from the site where they first formed (the primary site) to one or more other sites in the subject (one or more secondary sites). In metastasis, cancer cells break away from the original (primary) tumor, travel through the blood or lymphatic system, and form a new tumor (metastatic tumor) in other organs or tissues of the body. The new metastatic tumor contains the same or similar cancer cells as the primary tumor. At a secondary site, a tumor cell may proliferate and begin to grow or colonize a secondary tumor at that distant site.

The term "metastatic cancer" (also known as "secondary cancer") as used herein refers to a type of cancer that begins in one type of tissue but then spreads to one or more tissues beyond the (primary) origin of the cancer. Metastatic brain cancer refers to cancer of the brain, i.e. cancer that originated in tissue other than the brain and has metastasized to the brain.

In one embodiment, the BRAF-associated tumor is a malignant BRAF-associated CNS tumor (ie, BRAF-associated CNS cancer). The term "CNS cancer" or "CNS cancer" or used interchangeably herein refers to cancer (i.e., malignancy) of the central nervous system, including cancers of the brain (also known as intracranial tumors), cancers of the spinal cord, and cancers of the meninges surrounding the brain. brain and spinal cord. The term "BRAF-associated CNS cancer" refers to CNS cancer associated with or having a BRAF mutation. CNS cancers include metastatic brain cancer and malignant primary brain tumors.

In one embodiment, the BRAF-associated CNS cancer is a BRAF-associated metastatic brain cancer. BRAF-associated metastatic brain cancer can result from any cancer described herein in which the subject has developed at least one brain metastasis. In one embodiment, the BRAF-associated metastatic brain cancer is metastatic melanoma, metastatic colorectal cancer, or metastatic non-small cell lung cancer. In one embodiment, the BRAF-associated metastatic brain cancer is metastatic melanoma. In one embodiment, the BRAF-associated metastatic brain cancer is metastatic colorectal cancer. In one embodiment, the BRAF-associated metastatic brain cancer is metastatic non-small cell lung cancer. In one embodiment, the BRAF-associated metastatic brain cancer is metastatic ovarian cancer. In one embodiment, the metastatic brain cancer is metastatic thyroid cancer. In one embodiment, the BRAF-associated metastatic brain cancer is a kidney cancer. In one embodiment, the cancer is a BRAF-associated metastatic cancer with at least one brain metastasis (ie, metastatic brain cancer). In one embodiment, the cancer is a BRAF-associated metastatic melanoma with at least one brain metastasis. In one embodiment, the cancer is BRAF-associated metastatic colorectal cancer with at least one brain metastasis. In one embodiment, the cancer is a BRAF-associated metastatic non-small cell lung cancer with at least one brain metastasis. In one embodiment, the cancer is a BRAF-associated metastatic ovarian cancer with at least one brain metastasis. In one embodiment, the cancer is a BRAF-associated metastatic thyroid cancer with at least one brain metastasis. In one embodiment, the cancer is a BRAF-associated neuroblastoma with at least one brain metastasis.

Leptomeningeal metastases (leptomeningeal disease (LMD)) are a subset of CNS metastases that grow in the lining of the brain or spinal cord and/or cerebrospinal fluid (CSF), or leptomeningeal carcinomatosis. In mammals, the meninges are represented by the dura mater, the arachnoid mater and the pia mater. CSF is located in the subarachnoid space between the arachnoid and pia mater. The arachnoid and pia mater together are sometimes called the leptomeninges. When LMD occurs in the leptomeninges and/or CSF surrounding the spinal cord, it can be called "extracranial LMD." When LMD occurs in the leptomeninges and/or CSF of the brain, it can be called “intracranial LMD.” Because LMD cancer cells can reside in the CSF, they can rapidly spread throughout the CNS. As a result, LMD has a poor prognosis, with survival usually measured in months. In one embodiment, the metastatic cancer is BRAF-associated LMD. In one embodiment, the metastatic cancer is intracranial BRAF-associated LMD. In one embodiment, the metastatic cancer is extracranial BRAF-associated LMD. BRAF-associated cancers with the highest incidence of leptomeningeal metastases are lung cancer and melanoma. In one embodiment, BRAF-associated LMD is LMD originating from metastatic melanoma (ie, the LMD is metastatic melanoma). In one embodiment, BRAF-associated LMD is LMD originating from metastatic colorectal cancer (ie, LMD is metastatic colorectal cancer). In one embodiment, BRAF-associated LMD is LMD derived from metastases of non-small cell lung cancer (ie, LMD is metastatic non-small cell lung cancer).

In one embodiment, the cancer is a BRAF-associated cancer with a high risk of metastasis. In one embodiment, the BRAF-associated cancer having a high risk of metastasis is a cancer having the BRAF V600E or BRAF V600K mutation. In one embodiment, the BRAF-associated cancer having 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-associated cancer with a high risk of metastasis is melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, or neuroblastoma, each of which has a BRAF V600E or BRAF V600K mutation. In one embodiment, the BRAF-associated cancer with a high risk of metastasis is melanoma. In one embodiment, the BRAF-associated cancer having a high risk of metastasis is a melanoma having the BRAF V600E mutation or the BRAF V600K mutation. In one embodiment, the BRAF-associated cancer having a high risk of metastasis is colorectal cancer. In one embodiment, the BRAF-associated cancer with a high risk of metastasis is colorectal cancer with the BRAF V600E mutation or the BRAF V600K mutation. In one embodiment, the BRAF-associated cancer having a high risk of metastasis is thyroid cancer. In one embodiment, the BRAF-associated cancer having a high risk of metastasis is a thyroid cancer having the BRAF V600E mutation or the BRAF V600K mutation. In one embodiment, the BRAF-associated cancer with a high risk of metastasis is non-small cell lung cancer. In one embodiment, the BRAF-associated cancer having a high risk of metastasis is a non-small cell lung cancer having a BRAF V600E mutation or a BRAF V600K mutation. In one embodiment, the BRAF-associated cancer having a high risk of metastasis is ovarian cancer. In one embodiment, the BRAF-associated cancer having a high risk of metastasis is an ovarian cancer having the BRAF V600E mutation or the BRAF V600K mutation. In one embodiment, the BRAF-associated cancer having a high risk of metastasis is a neuroblastoma. In one embodiment, the BRAF-associated cancer having a high risk of metastasis is a neuroblastoma having the BRAF V600E mutation or the BRAF V600K mutation.

In one embodiment, the cancer is a BRAF-associated cancer having a class II mutation. In one embodiment, the class II mutation is a non-V600 mutation. In one embodiment, the He-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-associated cancers having class II mutations include lung cancer (eg, non-small cell lung cancer and small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma , appendix cancer, small bowel cancer, head and neck squamous cell carcinoma, angiosarcoma, bladder carcinoma, plasma cell neoplasm, hepato-pancreato-biliary carcinoma, ovarian cancer, neuroendocrine cancer, cholangiocarcinoma and central nervous system tumors.

In one embodiment, the BRAF-associated cancer is a BRAF-associated CNS tumor. In one embodiment, the BRAF-associated CNS tumor is a BRAF-associated 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 the G469A mutation. Primary brain tumors are tumors that start in the brain or spine and are known collectively as gliomas. The term "glioma" is used to describe tumors originating from glial cells present in the central nervous system. According to the WHO classification of brain tumors, gliomas are classified according to cell activity and aggressiveness on a scale that includes grade I (benign tumors of the central nervous system) and grades II-IV (malignant tumors of the central nervous system):

Grade I glioma (pilocytic astrocytoma): usually occurs in children in the cerebellum or brain stem, and sometimes in the cerebral hemispheres, and grows slowly. Grade I may occur in adults. Although they are benign (WHO class I), the difficulty of treating this disease makes their growth malignant in behavior with high morbidity rates (Rostami, Acta Neurochir (Wien). 2017; 159(11): 2217-2221).

Grade II glioma (low-grade gliomas): includes astrocytoma, oligodendroglioma, and mixed oligoastrocytoma. Grade II gliomas usually occur in young adults (20–50 years old) and are most often found in the cerebral hemispheres. Due to the infiltrative nature of these tumors, recurrences are possible. Some grade II gliomas recur and develop into more aggressive tumors (grade III or IV).

Grade III glioma (malignant glioma): includes anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic mixed oligoastrocytoma. Grade III tumors are aggressive, high-grade cancers that invade nearby brain tissue with tentacle-like projections that make complete surgical removal difficult.

Grade IV gliomas: include glioblastoma multiforme (GBM) and gliosarcoma; (GBM) is a malignant glioma. GBM is the most aggressive and most common primary brain tumor. Glioblastoma multiforme usually spreads quickly and invades other parts of the brain, forming tentacle-like extensions that make complete surgical removal difficult. Gliosarcoma is a malignant cancer and is defined as a glioblastoma consisting of gliomatous and sarcomatous components.

In one embodiment, the BRAF-associated primary brain tumor is a glioma. In some embodiments, the BRAF-associated primary brain tumor is a glioma having a class I mutation. In some embodiments, the BRAF-associated primary brain tumor is a glioma having a class II mutation.

Benign primary brain tumors can cause severe pain, permanent brain damage and death, and in some cases, can become cancerous. Non-limiting examples of benign primary brain tumors include grade I gliomas, papillary craniopharyngiomas, meningioma (including rhabdoid meningioma), atypical teratoid/rhabdoid tumors and dysembryoplastic neuroepithelial tumor (DNT), pilocytic astrocytoma, oligodendroglioma, mixed oligoastrocytoma, anaplastic astrocytoma, anaplast ic oligodendroglioma, anaplastic mixed oligoastrocytoma, diffuse astrocytoma, ependymoma, pleomorphic xanthoastrocytoma (PXA), ganglioglioma, gliosarcoma or anaplastic ganglioglioma. In one embodiment, the BRAF-associated tumor is a benign primary brain tumor.

In one embodiment, the BRAF-associated cancer is a cancer of the peripheral nervous system. In one embodiment, the peripheral nervous system cancer is a neuroblastoma. In one embodiment, the cancer is a BRAF-associated cancer.

Certain compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V, or pharmaceutically acceptable salts thereof, have been found to have good penetration into the brain and/or CNS and/or exhibit low efflux. Such compounds are capable of crossing the BBB and may be useful for inhibiting BRAF kinase in the brain and/or other CNS structures.

Accordingly, certain compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or pharmaceutically acceptable salts thereof, described herein may also be used to treat BRAF-associated CNS tumors. For example, treating a subject with A BRAF-associated CNS tumor may involve administering (eg, oral administration) 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. In some embodiments, the BRAF-associated CNS cancer has a BRAF V600 mutation. In some embodiments, the BRAF-associated CNS cancer has a BRAF V600E and/or V600K mutation. In some embodiments, the BRAF-associated CNS cancer has the BRAF V600E mutation. In some embodiments, the BRAF-associated CNS cancer has a BRAF V600K mutation. In some embodiments, the subject has previously been treated with one or more other anticancer therapies, such as an anticancer agent, surgery, and/or radiation therapy, for example, as described below. In some embodiments, a 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 one or more other anticancer therapies, e.g., an anticancer agent, surgery, and/or or radiation therapy, for example as described below. In some embodiments, the subject is treated with one or more anticancer therapies, such as an anticancer agent, surgery, and/or radiation therapy, following administration of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable compound thereof. salts, for example as described below.

In some embodiments of any of the methods described herein, the tumor is a BRAF-associated CNS tumor, and 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. In some embodiments, the BRAF-associated tumor is a CNS tumor. In some embodiments, the BRAF-associated CNS tumor is a malignant CNS tumor (CNS cancer). In some embodiments, the CNS cancer is a metastatic CNS cancer. In some embodiments, the metastatic CNS cancer is metastatic melanoma. In some embodiments, the metastatic CNS cancer is colorectal cancer. In some embodiments, the metastatic CNS cancer is metastatic non-small cell lung cancer. In some embodiments, the metastatic CNS cancer is metastatic thyroid cancer. In some embodiments, the metastatic CNS cancer is metastatic ovarian cancer. In some embodiments, the BRAF-associated CNS tumor is an LMD. In some embodiments, the LMD is intracranial. In some embodiments, the LMD is extracranial. In some embodiments, the LMD is metastatic melanoma. In some embodiments, the LMD is metastatic colorectal cancer. In some embodiments, LMD is metastatic non-small cell lung cancer. In some embodiments, the BRAF-associated CNS cancer is a primary brain tumor. In some embodiments, the primary brain tumor is a grade 2 glioma. In some embodiments, the primary brain tumor is a grade 3 glioma. In some embodiments, the primary brain tumor is a grade 4 glioma. In some embodiments, the BRAF-associated CNS tumor is a benign tumor. In some embodiments, the benign CNS tumor is a papillary craniopharyngioma, meningioma (including rhabdoid meningioma), atypical teratoid/rhabdoid tumor, or dysembryoplastic neuroepithelial tumor (DNT). In some embodiments, the compound is selected from Examples 1-164 or a pharmaceutically acceptable salt thereof.

The ability to determine whether a compound may be suitable for the treatment of CNS cancer can be determined, for example, by identifying whether the compound is an efflux transporter substrate and/or measuring cell permeability and/or measuring the ratio of free brain to free plasma, as described in this document.

In some embodiments, compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or pharmaceutically acceptable salts thereof, are highly cellular permeable. Methods for determining the permeability of a compound can be determined in accordance with the analysis described in Example B, and the permeability coefficients for compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V are presented in Table B1.

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. Methods for assessing in vitro whether compounds are substrates of the efflux transporters P-glycoprotein (P-gp or multidrug resistance protein 1 (MDR1)) and breast cancer resistance protein (BCRP) are described in Example B, and the efflux ratios of the compounds formula I, formula I-A, formula II, formula III, formula IV or formula V are presented 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 coefficient of ≤3.5 when tested in cells that express P-gp. In one embodiment, compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or pharmaceutically acceptable salts thereof, have an efflux ratio of ≤3.5 when tested in cells that express P-gp and an efflux ratio of ≤5 ,5 when testing cells expressing BCRP.

In some embodiments, certain compounds of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or pharmaceutically acceptable salts thereof, exhibit moderate to high brain (unbound)/plasma (unbound) ratios (i.e., ratio free brain/plasma medium to high). The ability of a compound to penetrate the BBB of a subject (eg, a human) can be determined in a suitable animal model (eg, 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 cross the BBB in mice was determined by assessing the concentration ratio of unbound brain to unbound plasma (free B/P) in mice, e.g., as described in Example C, and the ratios of free brain to free plasma are given in Table C. A ratio of free brain to free plasma equal to or greater than 0.3 indicates a significant degree of free penetration into the CNS.

Accordingly, in some embodiments, the methods of the present invention include methods for treating BRAF-associated CNS cancer in a subject in need thereof. In one embodiment, the method includes administering a compound of Formula I, Formula IA, 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 IA, Formula II, formula III, formula IV or formula V penetrates the BBB as shown in a suitable animal model. In some embodiments, the brain/plasma ratio of the total drug is at least about 0.3 after administration (eg, oral or intravenous administration) to a subject. It should be noted that the proportion of a compound that penetrates the BBB is calculated based on the area under the concentration-time curve for a given time period (AUC _0-t ) in the brain compared to plasma. Accordingly, the fractions represent the ratio of concentrations. That is, if the ( _0-24h AUC) for a compound is 30 ng/mL in the brain and 70 ng/mL in plasma, then the proportion of the compound that penetrates the BBB is 30% (30 ng/mL in the brain divided by total concentration (30 ng/ml + 70 ng/ml)) (i.e. brain to plasma ratio 0.30). In some embodiments, the fractions are calculated based on the area under the concentration-time curve for the time period from t=0 (dose time) to the last quantifiable concentration point, i.e. (AUC _0-last ).

Mutations in the BRAF gene have been identified in malignant melanomas, papillary thyroid carcinomas, colorectal carcinomas, non-small cell lung carcinoma (NSCLC), ovarian carcinomas and their metastatic tumors, and 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), colorectal cancer brain metastases, and non-small cell cancer metastases. lung cancer to the brain (Berghoff, AS, Preusser M, Curr Opin Nenrol (2014) 27(6):689-696), papillary thyroid cancer (Kim, WW et al., J Otolaryngol Head Neck Surg. 2018 47 : 4) and ovarian cancer (Grisham RN., et al., Cancer. 2013;119:548-554).

BRAF mutations have also been observed in malignant primary brain tumors, including grade IV gliomas such as glioblastomas and gliosarcomas, 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. (Diagnon Pathol 11(1):55, 2016)), in children and adults.

BRAF mutations were also observed in benign primary brain tumors, for example, in astrocytomas of the II degree in WHO, pleomorphic xanthoastocytomas (RHA) of the II degree according to WHO, pleomorphic xanthoastocytomas with anapaplasia, pilocytic astrocytoma (RA), papillary craniopharyngiomas, gangliogliomams, astrogliomams, astroglystoms , 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)), in children and adults .

BRAF mutations have also been found in recurrent neuroblastomas (Eleveld, TF, et al., Nat Genet 47(8): 864-871, 2015). Neuroblastoma is a childhood tumor of the peripheral nervous system. In most subjects with neuroblastoma, tumors initially respond to chemotherapy, but a significant proportion of subjects experience treatment-resistant relapses.

Accordingly, also provided herein is a method of treating a subject who has been diagnosed or identified with a BRAF-associated tumor, for example, any of the exemplary BRAF-associated tumors described herein, 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, as defined herein. In some embodiments, a subject who has been identified or diagnosed with a BRAF-associated tumor by using a regulatory agency-approved, e.g., FDA-approved, test or assay to detect a BRAF mutation in the subject or a biopsy sample from the subject, or by performing any of the non-limiting examples assays described in this document. In some embodiments, the test or assay is offered as a kit. In one embodiment, a BRAF-associated tumor may be a cancer that has one or more class I BRAF mutations (eg, V600E and/or V600K). In one embodiment, the BRAF-associated tumor may be a cancer having one or more class II mutations (eg, G4 69A). In some 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 some embodiments, the BRAF-associated tumor is a malignant BRAF-associated tumor (ie, BRAF-associated cancer). In some embodiments, the BRAF-associated cancer is a BRAF-associated CNS cancer. In some embodiments, the BRAF-associated CNS cancer is a BRAF-associated metastatic cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic melanoma. In some embodiments, the BRAF-associated metastatic cancer is metastatic colorectal cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic non-small cell lung cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic thyroid cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic ovarian cancer. In some embodiments, the BRAF-associated metastatic cancer is an intracranial or extracranial LMD. In some embodiments, the BRAF-associated CNS cancer is a primary brain tumor. In some embodiments, the BRAF-associated tumor is a benign CNS tumor. In some 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, appendix cancer, cancer small intestine, squamous cell carcinoma of the head and neck, angiosarcoma and central nervous system tumors. In some embodiments, the compound is selected from Examples 1-164 or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is an adult subject. In some embodiments, the subject is a pediatric subject.

Also provided are methods of treating a tumor in a subject in need thereof, comprising: (a) detecting a BRAF-associated 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 some embodiments of these methods, the tumor is a benign BRAF-associated tumor. In some embodiments of these methods, the tumor is a BRAF-associated malignancy. In some embodiments of these methods, the tumor is a BRAF-associated malignant tumor (e.g., any of the BRAF-associated malignant tumors described herein), and the method further includes administering to the subject one or more additional antineoplastic therapies, such as surgery ( for example, at least partial tumor resection) and/or radiation therapy and/or an anticancer agent. In some embodiments of these methods, the tumor is a benign BRAF-associated tumor, e.g., a benign BRAF-associated CNS tumor, and the method further includes administering to the subject one or more additional antineoplastic therapies, e.g., surgery (e.g., at least partial tumor resection) and/or radiation therapy and/or an anticancer agent. In some embodiments, the presence of a BRAF-associated tumor is determined in a subject by using a regulatory agency-approved, e.g., FDA-approved, test or assay to detect a BRAF mutation in the subject or in a biopsy specimen from the subject (e.g., a tissue or fluid biopsy), or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is offered as a kit. In some embodiments, the BRAF-associated tumor is a malignant BRAF-associated tumor (ie, BRAF-associated cancer). In some embodiments, the BRAF-associated cancer is a BRAF-associated CNS cancer. In some embodiments, the BRAF-associated CNS cancer is a BRAF-associated metastatic cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic melanoma. In some embodiments, the BRAF-associated metastatic cancer is metastatic colorectal cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic non-small cell lung cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic thyroid cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic ovarian cancer. In some embodiments, the BRAF-associated metastatic cancer is an intracranial or extracranial LMD. In some embodiments, the BRAF-associated CNS cancer is a primary brain tumor. In some embodiments, the BRAF-associated tumor is a benign CNS tumor. In some 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, appendix cancer, cancer small intestine, squamous cell carcinoma of the head and neck, angiosarcoma and central nervous system tumors. In some embodiments, the compound is selected from Examples 1-164 or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is an adult subject. In some embodiments, the subject is a pediatric subject.

Also provided are methods of treating a subject having a BRAF-associated tumor, which include analyzing a sample obtained from the subject to determine whether the subject has a tumor having a BRAF mutation, and 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, or a pharmaceutical composition thereof to a subject who has been determined to have a BRAF mutation. In some embodiments of these methods, the BRAF-associated tumor is a malignant BRAF-associated tumor (i.e., BRAF-associated cancer), and the method further includes administering to the subject one or more other anticancer therapies, such as surgery (e.g., at least partial tumor resection) and/or radiation therapy and/or treatment with an anticancer agent. In some embodiments of these methods, the subject has previously undergone other anticancer therapy, such as surgery (eg, at least partial tumor resection) and/or radiation therapy, and/or treatment with an anticancer agent. In some embodiments, the subject is a subject suspected of having a BRAF-associated tumor, a subject who exhibits one or more symptoms of a BRAF-associated tumor, or a subject who has an increased risk of developing a BRAF-associated tumor. In some embodiments, the analysis uses next generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is a regulatory approved assay, such as an FDA approved kit. In some embodiments, the analysis is a liquid biopsy. In some embodiments, the biopsy is a tissue biopsy. In some embodiments, the cancer is a CNS cancer and the biopsy is a liquid biopsy (eg, CSF). In some embodiments, the cancer is a CNS cancer and the biopsy is a tissue biopsy (eg, a tumor sample obtained during conventional surgery, or a stereotactic needle biopsy, such as a CT- or MRI-guided stereotactic core biopsy). Described herein are additional non-limiting assays that may be used in these methods. Additional assays are also known in the art. In some embodiments, the BRAF-associated tumor is a malignant BRAF-associated tumor (ie, BRAF-associated cancer). In some embodiments, the BRAF-associated cancer is a BRAF-associated CNS cancer. In some embodiments, the BRAF-associated CNS cancer is a BRAF-associated metastatic cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic melanoma. In some embodiments, the BRAF-associated metastatic cancer is metastatic colorectal cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic non-small cell lung cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic thyroid cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic ovarian cancer. In some embodiments, the BRAF-associated metastatic cancer is an intracranial or extracranial LMD. In some embodiments, the BRAF-associated CNS cancer is a primary brain tumor. In some embodiments, the BRAF-associated tumor is a benign CNS tumor. In some 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, appendix cancer, cancer small intestine, squamous cell carcinoma of the head and neck, angiosarcoma and central nervous system tumors. In some embodiments, the subject is an adult subject. In some embodiments, the subject is a pediatric subject.

Also provided is 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 the treatment of a BRAF-associated tumor in a subject who has been identified or diagnosed with a BRAF-associated tumor by the assay step. (eg, an in vitro assay) on a sample obtained from a subject to determine that the subject has a BRAF mutation, where the presence of a BRAF mutation indicates that the subject has a BRAF-associated 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 manufacture of a medicament for the treatment of a BRAF-associated tumor in a subject who has been identified or diagnosed with a BRAF-associated tumor on the step of analyzing a sample obtained from the subject to determine whether the subject has a BRAF mutation, identifying whether the subject has a BRAF-associated tumor. Some embodiments of any of the methods or uses described herein further include recording in the subject's medical record (e.g., on a computer-readable medium) that the subject determined to have a BRAF mutation by assay is to be administered a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof. In some embodiments, the analysis uses next generation sequencing, pyrosequencing, immunohistochemistry, or separation FISH analysis. In some embodiments, the assay is a regulatory approved assay, such as an FDA approved kit. In some embodiments, the analysis is a liquid biopsy. In some embodiments, the BRAF-associated tumor is a malignant BRAF-associated tumor (ie, BRAF-associated cancer). In some embodiments, the BRAF-associated cancer is a BRAF-associated CNS cancer. In some embodiments, the BRAF-associated CNS cancer is a BRAF-associated metastatic cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic melanoma. In some embodiments, the BRAF-associated metastatic cancer is metastatic colorectal cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic non-small cell lung cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic thyroid cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic ovarian cancer. In some embodiments, the BRAF-associated metastatic cancer is an intracranial or extracranial LMD. In some embodiments, the BRAF-associated CNS cancer is a primary brain tumor. In some embodiments, the BRAF-associated tumor is a benign CNS tumor. In some 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, appendix cancer, cancer small intestine, squamous cell carcinoma of the head and neck, angiosarcoma and central nervous system tumors. In some embodiments, the subject is an adult subject. In some embodiments, the subject is a pediatric subject.

Also provided is 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 the treatment of a BRAF-associated tumor in a subject in need thereof, or a subject in whom BRAF-associated tumors are identified or diagnosed. associated 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 manufacture of a medicament for the treatment of a BRAF-associated tumor in a subject identified or diagnosed as having a BRAF-associated tumor. In some embodiments, a BRAF-associated tumor is identified or diagnosed in a subject using a regulatory agency approved, e.g. FDA approved, kit to detect a BRAF mutation in the subject or a biopsy sample from the subject. In some embodiments, the BRAF-associated tumor is a malignant BRAF-associated tumor (ie, BRAF-associated cancer). In some embodiments, the BRAF-associated cancer is a BRAF-associated CNS cancer. In some embodiments, the BRAF-associated CNS cancer is a BRAF-associated metastatic cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic melanoma. In some embodiments, the BRAF-associated metastatic cancer is metastatic colorectal cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic non-small cell lung cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic thyroid cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic ovarian cancer. In some embodiments, the BRAF-associated metastatic cancer is an intracranial or extracranial LMD. In some embodiments, the BRAF-associated CNS cancer is a primary brain tumor. In some embodiments, the BRAF-associated tumor is a benign CNS tumor. In some 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, appendix cancer, cancer small intestine, squamous cell carcinoma of the head and neck, angiosarcoma and central nervous system tumors. In some embodiments, the subject is an adult subject. In some embodiments, the subject is a pediatric subject.

In some embodiments of any of the methods or applications described herein, the assay used to determine whether a subject has a BRAF mutation using a sample from the subject may include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, Southern separation FISH analysis -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, assays are typically performed, for example, using at least one labeled nucleic acid probe or at least one labeled antibody or antigen binding fragment thereof. The assays may use other detection methods known in the art to detect BRAF mutation. In some embodiments, the sample is a biological sample or a biopsy sample (eg, a paraffin-embedded biopsy sample) of the subject. In some embodiments, the subject is a subject suspected of having a BRAF-associated tumor, a subject having one or more symptoms of a BRAF-associated tumor, and/or a subject having an increased risk of developing a BRAF-associated tumor).

In some embodiments, the biopsy is a tumor biopsy (eg, a tumor sample obtained during conventional surgery or a stereotactic needle biopsy, such as a CT- or MRI-guided stereotactic core biopsy). Tissue biopsy techniques can be used to detect total tumor burden and/or BRAF mutation.

In some embodiments, the BRAF mutation can be identified using a liquid biopsy (variously called liquid biopsy or liquid phase biopsy). See, for example, Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment,” Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy techniques can be used to determine total tumor burden and/or BRAF mutation. Liquid biopsies can be performed on biological samples that are relatively easily obtained from the subject (eg, through a simple blood draw) and are generally less invasive than traditional methods used to detect tumor mass and/or BRAF mutation. In some embodiments, liquid biopsy can be used to detect the presence of a BRAF mutation at an earlier stage than traditional methods. In some embodiments, the biological sample used for the liquid biopsy may include CSF, blood, plasma, urine, saliva, sputum, bronchoalveolar lavage, bile, lymph fluid, cystic fluid, feces, ascites, and combinations thereof. In some embodiments, liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected by liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. ctDNA analysis (eg, using sensitive detection methods such as, but not limited to, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify the BRAF mutation.

In some embodiments, the BRAF mutation identified by the liquid biopsy is also present in a cancer cell that is present in the subject (eg, a tumor). In some embodiments, any of the types of BRAF mutations can be detected using liquid biopsy. In some embodiments, a genetic mutation identified through 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 may indicate that the subject will respond to treatment that includes 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.

"Tumor burden", also called "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(s) throughout the body, including the lymph nodes and bone marrow. Tumor burden can be determined by various methods known in the art, such as, for example, by measuring the size of the tumor(s) after removal from a subject, for example, using a caliper, or while in the body using imaging techniques, for example, magnetically -resonance tomography (MRI), computed tomography (CT), multi-detector CT (MDCT), positron emission tomography (PET), x-ray, ultrasound or bone scan.

The term "tumor size" or "tumor size" refers to the overall size of the tumor, which can be measured as the length and width of the tumor. The size of a tumor can be determined by various methods known in the art, such as, for example, measuring the size of the tumor(s) when removed from the subject, for example, using a caliper, or while in the body using imaging techniques, for example, MRI, bone scan, ultrasound or CT scan.

Liquid biopsies may be performed multiple times during a diagnostic course, monitoring course, and/or treatment course to determine one or more clinically relevant parameters, including, but not limited to, disease progression or treatment response, after treatment has been administered to a subject. For example, a first liquid biopsy may be performed at a first time point, and a second liquid biopsy may be performed at a second time point during the course of diagnosis, follow-up, and/or treatment. In some embodiments, the first time point may be a point in time before the subject is diagnosed with a disease (e.g., when the subject is healthy), and the second time point may be a point in time after the subject has developed a disease (e.g., the second time point may be used to diagnose a disease in a subject). In some embodiments, the first time point may be a time point before the subject is diagnosed with a disease (eg, when the subject is healthy) after which the subject is under observation, and the second time point may be a time point after the subject is observed. In some embodiments, the first time point may be a point in time after the subject is diagnosed with a disease and the subject is subsequently treated, and the second time point can be a time after treatment has been administered; in such cases, the second time point can be used to assess the effectiveness of treatment (eg, if the genetic mutation(s) detected at the first time point are reduced or undetected). In some embodiments, the treatment to be administered to the subject may include 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, 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 with a cancer. For example, a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, may also be used in combination with one or more additional anticancer therapies, e.g., surgery, radiation therapy, and/or an anticancer agent that works by the same or a different mechanism of action. In one embodiment, treating a subject having a BRAF-associated malignancy 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 one or more additional therapies, such as surgery , radiation therapy and/or an anticancer agent, may have increased therapeutic efficacy compared to treatment of the same subject or a similar subject with a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof as monotherapy .

Accordingly, in one embodiment, provided herein are methods of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), which comprise: 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 formula V or a pharmaceutically acceptable salt thereof as monotherapy, or (ii) 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 combination with one or more additional anticancer therapies. In one embodiment, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered a second anti-cancer therapy for said period of time. In one embodiment, the second anticancer therapy is a second anticancer agent.

Also provided herein is 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 combination with adjunctive anticancer therapy. Also provided herein is an additional anticancer therapy for use 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.

Also provided herein is 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 the treatment of a BRAF-associated tumor by coadministration with additional anticancer therapy. Also provided herein is an adjunctive anticancer therapy for use in the treatment of a BRAF-associated tumor by co-administration 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 some embodiments, the subject is administered one or more anticancer 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, prior to 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. In some embodiments, the one or more anticancer therapies are selected from surgery and/or radiation therapy and/or an anticancer agent that works by the same or a different mechanism of action. For example, in some embodiments, a subject in need thereof may undergo at least partial tumor resection prior to 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. In some embodiments, treatment with at least partial tumor resection reduces the size of the tumor (e.g., tumor mass) prior to administration of one or more doses of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutical thereof acceptable salt. In some embodiments, a subject in need thereof may undergo radiation therapy prior to 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. In some embodiments, a subject in need thereof may be treated with one or more antineoplastic 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, prior to 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. In some embodiments, the subject has a cancer that is resistant to or intolerant to previous therapy.

Accordingly, in some embodiments, provided herein are methods of treating a subject having a BRAF-associated tumor, comprising (i) administering one or more anticancer therapies to said subject over a period of time, and (ii) following (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 monotherapy, 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 additional anticancer therapies.

In some 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 prior to administration of one or more anticancer therapies (e.g., surgery, radiation therapy, and/or an anticancer agent , which works by the same or a different mechanism of action) to treat a subject with a tumor. For example, in some embodiments, a subject in need thereof may undergo at least partial tumor resection following 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. In some embodiments, a subject in need thereof may undergo radiation therapy following 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. In some embodiments, a subject in need thereof may be 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, prior to administration of one or more anticancer 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 one embodiment, the compound of Formula I is a compound selected from Examples 1-164, or a pharmaceutically acceptable salt thereof.

Accordingly, in some embodiments, provided herein are methods of treating a subject having a BRAF-associated tumor, comprising (i) administering Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, for a specified period of time, and (ii) after a specified period of time, the introduction of one or more anticancer therapies. For example, a subject in need thereof may 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, over a period of time, and then undergo at least partial resection of the tumor. In some 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 tumor size (e.g., tumor burden) to at least partial resection tumors. In one embodiment, the compound of Formula I is a compound selected from Examples 1-164, or a pharmaceutically acceptable salt thereof.

In some embodiments of any of the methods described above, the additional anticancer therapy is surgery, radiation therapy, and/or an anticancer agent that works through the same or a different mechanism of action.

Non-limiting examples of additional anticancer agents that can be used in combination with a compound of formula I, II or III or a pharmaceutically acceptable salt thereof in accordance with any of the methods described above include, but are not limited to, MEK inhibitors, BRAF inhibitors (e.g., BRAF inhibitors, other than a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V), EGFR inhibitors, HER2 and/or HER3 inhibitors, Ax1 inhibitors, PI3K inhibitors and S0S1 inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors , apoptosis pathway modulators, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapies and immune-targeted agents including immunotherapy.

In one embodiment, an 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 accordance with any of the methods described above is a targeted therapeutic agent. As used herein, the term "targeted therapeutic agent" refers to a molecule that blocks the growth of cancer cells by interfering with specific target molecules required for carcinogenesis and tumor growth, rather than simply interfering with all rapidly dividing cells (e.g., traditional cytotoxic chemotherapy) and includes, but is not limited to, therapeutic agents targeting receptor tyrosine kinase, signal transduction pathway inhibitors (e.g., Ras-Raf-MEK-ERK pathway inhibitors, PI3K-Akt-mTOR-S6K pathway inhibitors (“P13K inhibitors”)), and modulators of the apoptosis pathway.

In some 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 accordance with any of the methods described above is a MEK inhibitor. In one embodiment, the MEK inhibitor is binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (CT-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. Additional examples of MEK inhibitors include those described in WO 03/077 914, WO 2005/023759, WO 2005/051301, US 7,517,994, US 7,732,616, WO 2005/051906, WO 2005/051302, WO 2005/051300 and WO 2007/044084 . In some embodiments, the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof.

In some 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 accordance with any of the methods described above is another BRAF inhibitor, other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula 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 their pharmaceutically acceptable salts and compounds described in International Application No. PCT/ IB2020/055992, published on December 30, 2020 as PCT publication No. WO 2020/261156 A1, including, for example, a connection selected from:

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

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

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

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

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

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

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

N-(3-chloro-4-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-5-fluoropyridin-2-yl)propan-1-sulfonamide; And

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

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. Additional examples of BRAF inhibitors are known in the art.

In some 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 accordance with any of the methods described above is an EGFR inhibitor. Non-limiting examples of EGFR inhibitors include cetuximab (Erbitux®), panitumumab (Vectibix®), osimertinib (merelectinib, Tagrisso®), erlotinib (Tarceva®), gefitinib (Iressa®), necitumumab (Portrazza™), neratinib (Nerlynx®), lapatinib (Tykerb®), vandetanib (Caprelsa®), brigatinib (Alunbrig®) and the EGFR inhibitors described in PCT Publication No. WO 2019/071351 and WO 2017/117 680, 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.

In some 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 accordance with any of the methods described above is a HER2 inhibitor and/or or HER3. 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)quinazoline-6 -yl)allyl)acetamide (CP-724714), sapitinib, 7-[[4-[(3-ethynylphenyl)amino]-7-methoxy-6-quinazolinyl]oxy]-N-hydroxyheptanamide (CUDC-101), mubritinib , 6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AEE788 ), irbinitinib (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 (KTN001-30), dasatinib and bosutinib.

In some 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 accordance with any of the methods described above 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]-benzenacetonitrile (SGI-7079), gilteritinib, bosutinib, cabozantinib, sunitinib, foretinib, amuvatinib, glesatinib, N-(4-((2-amino-3- chlorpyridin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-3-carboxamide (BMS777607), merestinib, (Z)-3 -((3-((4-(morpholinomethyl)-1H-pyrrol-2-yl)methylene)-2-oxoindolin-5-yl)methyl)thiazolidin-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.

In some 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 for any of the above methods is an SOS1 inhibitor.

Non-limiting examples of SOS1 inhibitors include those described in PCT publication No. WO 2018/115380, which is incorporated herein by reference in its entirety.

In some 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 for any of the above methods is a PI3K inhibitor.

Non-limiting examples include buparlisib (BKM120), alpelisib (BYL719), samotolisib (LY3023414), 8-[(1R)-1-[(3,5-difluorophenyl)amino]ethyl]-N, N-dimethyl-2-(morpholine -4-yl)-4-oxo-4H-chromene-6-carboxamide (AZD8186), tenalisib (RP6530), voctalisib hydrochloride (SAR-245409), gedatolisib (PF-05212384), panulisib (P-7170), tazelisib ( 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), duvelisib (ABBV-954), N2-[4-oxo-4-[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholin- 4-ium-4-ylmethoxy]butyryl]-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 (BAY 84-1236), 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.

In some embodiments, an 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 for any of the above methods is an immunotherapy. The term "immunotherapy" refers to an agent that modulates the immune system. In some embodiments, immunotherapy may increase the expression and/or activity of an immune system regulator. In some embodiments, immunotherapy may reduce the expression and/or activity of an immune system regulator. In some embodiments, immunotherapy can recruit and/or enhance immune cell activity.

In some 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 therapy (eg , monoclonal antibody, conjugated antibody). In some embodiments, the antibody therapy is bevacizumab (Mvasti™, Avastin®), trastuzumab (Herceptin®), avelumab (Bavencio®), rituximab (MabThera™, Rituxan®), edrecolomab (Panorex), daratumumab (Darzalex®), olaratumab (Lartruvo™), ofatumumab (Arzerra®), alemtuzumab (Campath®), cetuximab (Erbitux®), oregovomab, pembrolizumab (Keytruda®), dinutiximab (Unituxin®), obinutuzumab (Gazyva®), tremelimumab (CP-675, 20b), ramicurimab (Cyramza®), ublituximab (TG-1101), panitumumab (Vectibix®), elotuzumab (Empliciti™), necitumumab (Portrazza™), cirmtuzumab (UC-961), ibritumomab (Zevalin®), isatuximab (SAR650984 ), nimotuzumab, fresolimumab (GC1008), lirilumab (INN), mogamulizumab (Poteligeo®), ficlatuzumab (AV-299), denosumab (Xgeva®), ganitumab, urelumab, pidilizumab, amatuximab, blinatumomab (AMG103; Blincyto®) or midostaurin (Rydapt).

In some embodiments, the immunotherapy, which 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 means. In some embodiments, the antibody-drug conjugate is gemtuzumab ozogamicin (Mylotarg™), inotuzumab ozogamicin (Besponsa®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (TDM-1; Kadcyla®), mirvetuximab soravtansine (IMGN853 ) or anetumab ravtansine.

In some embodiments, the immunotherapy, which 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 some embodiments, the immunotherapy is denileukin diftitox (Ontak®).

In some 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 a cytokine therapy. In some 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), interleukin 7 (IL-7) therapy or erythropoietin-alpha (EPO) therapy. In some embodiments, the IL-2 therapy is aldesleukin (Proleukin®). In some embodiments, the IFNα therapy is IntronA® (Roferon-A®). In some embodiments, the G-CSF therapy is filgrastim (Neupogen®).

In some embodiments, the immunotherapy, which 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 some embodiments, the immunotherapy includes one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab (Yervoy®) or tremelimumab (CP-675,206). In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the PD-L1 inhibitor is atezolizumab (Tecentriq®), avelumab (Bavencio®), or durvalumab (Imfinzi™). In some embodiments, the PD-1 inhibitor is RN888 (sasanlimab).

In some embodiments, the immunotherapy, which 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 mRNA-based immunotherapy . In some embodiments, the mRNA immunotherapy is CV9104 (see, for example, Rausch et al. (2014) Human Vaccine Immunother 10(11): 3146-52; and Kubler et al. (2015) J. Immunother Cancer 3 :26).

In some 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 oncolytic viral therapy. In some embodiments, the oncolytic viral therapy is talimogene alherparepvec (T-VEC; Imlygic®).

In some embodiments, the immunotherapy, which 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 cancer vaccine. In some embodiments, the cancer vaccine is a human papillomavirus (HPV) vaccine. In some embodiments, the HPV vaccine is Gardasil®, Gardasil9®, or Cervarix®. In some embodiments, the cancer vaccine is a hepatitis B virus (HBV) vaccine. In some embodiments, the HBV vaccine is Engerix-B®, Recombivax HB®, or GI-13020 (Tarmogen®). In some embodiments, the cancer vaccine is Twinrix® or Pediarix®. In some embodiments, the cancer vaccine is BiovaxID®, Oncophage®, GVAX, ADXS11-001, ALVAC-CEA, PROSTVAC®, Rindopepimut®, CimaVax-EGF, lapuleucel-T (APC8024; Neuvenge™), GRNVAC1, GRNVAC2, GRN -1201, Hepcortespenlisimuth-L (Hepko-V5), DCVAX®, SCIB1, BMT CTN 1401, PrCa VBIR, PANVAC, ProstAtak®, DPX-Survivac or Viagenpumatucel-L (HS-110).

In some embodiments, the immunotherapy, which 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 peptide vaccine. In some embodiments, the peptide vaccine is nelipepimut-S (E75) (NeuVax™), IMA901, or SurVaxM (SVN53-67). In some 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 some embodiments, the cancer vaccine is RGSH4K or NEO-PV-01. In some embodiments, the cancer vaccine is a DNA-based vaccine. In some embodiments, the DNA vaccine is a mammaglobin-A DNA vaccine (see, e.g., Kim et al. (2016) OncoImmunology 5(2): e1069940).

In some 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 a cellular immunotherapy (eg , adoptive T-cell therapy, dendritic cell therapy, natural killer cell therapy). In some embodiments, the cellular immunotherapy is sipuleucel-T (APC8015; Provenge™; Plosker (2011) Drugs 71(1): 101-108). In some embodiments, the cellular immunotherapy includes cells expressing a chimeric antigen receptor (CAR). In some embodiments, the cellular immunotherapy is a CAR-T cell therapy. In some embodiments, the CAR-T cell therapy is tisagenlecleucel (Kymriah™).

In some 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, folinic acid, gemcitabine, irinotecan, lomustine, methotrex t, mitomycin C , oxaliplatin, paclitaxel, pemetrexed, temozolomide and vincristine and combinations thereof, such as Nordic FLOX (fluorouracil, folinic acid and oxaliplatin), FOLFOXIRI (oxaliplatin, irinotecan and fluorouracil), FOLFIRI (folinic acid, fluorouracil and irinotecan) or CAPEX (capecitabine and oxaliplatin).

In some embodiments, an 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 accordance with any of the methods described above is an angiogenesis- targeted therapy. Non-limiting examples of angiogenesis-targeted therapy include aflibercept and bevacizumab.

In some embodiments, an 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 accordance with any of the methods described above, includes apoptosis pathway modulators (eg obataclax).

In some 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 radiation therapy. Non-limiting examples of radiation therapy include external beam radiation therapy (eg, external beam therapy using kilovolt X-rays or megavoltage X-rays) or internal radiation therapy. Internal radiation therapy (also called brachytherapy) may involve the use of, for example, low-dose internal radiation therapy or high-dose internal radiation therapy. Low-dose internal radiation therapy involves, for example, injecting small radioactive beads (also called seeds) into or proximally the subject's cancerous tissue. High-dose internal radiation therapy involves, for example, inserting a thin tube (eg, a catheter) or implant into or proximally the cancerous tissue of a subject, and delivering a high dose of radiation to the thin tube or implant using a radiation machine. Methods for administering radiation therapy to a subject having cancer are known in the art. In embodiments in which the tumor is a CNS tumor, radiation therapy may include whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS), such as Cyberknife®, XKnife®, Gamma knife®, or ExacTrac®.

In some 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 surgery.

Non-limiting examples of surgery include, for example, open surgery or minimally invasive surgery. Surgery may 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 is causing pain or pressure in the subject. Methods are known in the art for performing open surgery and minimally invasive surgery on a subject having cancer.

In some embodiments, the adjunctive therapy includes any of the above-listed therapies or anticancer agents that are standard of care for cancer treatment where the cancer has a BRAF mutation.

In one embodiment, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered a MEK inhibitor (eg, any of the MEK inhibitors described herein) for a specified 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.

In one embodiment, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 where the subject is administered a BRAF inhibitor (e.g., any of the BRAF inhibitors described herein, including a second compound of Formula I, Formula I-A, Formula II, Formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof) for a specified 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, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered an EGFR inhibitor (eg, any of the EGFR inhibitors described herein) for a specified 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.

In one embodiment, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered an inhibitor of HER2 and/or HER3 for a specified 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, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered an Axl inhibitor (eg, any of the Axl inhibitors described herein) for a specified 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, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered an SOS1 inhibitor (eg, any of the SOS1 inhibitors described herein) for a specified period of time. In one embodiment, Compound I is a compound selected from Examples 1-164, or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered a signal transduction inhibitor (eg, any of the signal transduction inhibitors described herein) for a specified 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, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered a checkpoint inhibitor (eg, any of the checkpoint inhibitors described herein) for a specified 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, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered an apoptosis pathway modulator (eg, any of the apoptosis pathway modulators described herein) for a specified 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, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered a cytotoxic chemotherapeutic agent (eg, any of the cytotoxic chemotherapeutic agents described herein) for a specified 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, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered an angiogenesis-targeted therapy (eg, any of the angiogenesis-targeted therapies described herein) for a specified period of time. In one embodiment, the compound of Formula I is a compound selected from Examples 1-164, or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method of treating a subject having a BRAF-associated tumor (e.g., any of the BRAF-associated tumors described herein), 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 the subject is administered an immunotargeting agent (eg, any of the immunotargeting agents described herein) for a specified period of time. In one embodiment, the compound of Formula I is a compound selected from Examples 1-164, or a pharmaceutically acceptable salt thereof.

Also provided herein is a pharmaceutical combination for treating a BRAF-associated tumor in a subject 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) at least one additional anticancer agent (for example, any of the exemplary additional anticancer 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 at least one additional anticancer agent are separately formulated for simultaneous, separate or sequential use for the treatment of a tumor, wherein the amounts of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof and an additional anticancer agent are together effective in treating a tumor; (ii) use of such combination for the preparation of a medicament for the treatment of a tumor; and (iii) a commercial package or product containing such combination as a combination product for simultaneous, separate or sequential use; and a method of treating a tumor in a subject in need thereof.

As used herein, the term “pharmaceutical 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 anticancer agent are formulated in separate compositions or dosages, those that can be administered to a subject in need thereof simultaneously, concurrently, or sequentially, with various intervening time frames, where such administration provides effective levels of two or more compounds in the subject's body. They are also applicable to cocktail therapy, such as the administration of three or more active ingredients.

Accordingly, also provided herein is a method of treating a BRAF-associated tumor, comprising administering to a subject in need thereof a pharmaceutical combination for treating said tumor, which includes (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 anticancer agent for simultaneous, separate or sequential use for the treatment of a tumor, wherein the 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 salts and an additional anticancer agent together are effective in treating the tumor. In one embodiment, the BRAF-associated tumor is a malignant tumor, and the additional anticancer agent is an anticancer agent, for example, any of the anticancer agents described herein. In some embodiments, a 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 anticancer agent are administered simultaneously in separate doses. In some embodiments, a 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 anticancer agent are administered in separate doses sequentially, in any order, for example, daily or in periodic doses, in co-therapeutically effective amounts. Additional anticancer agents may be administered 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, or a pharmaceutical composition thereof, as part of the same or separate dosage units. forms, by the same or different routes of administration and/or by the same or different schedules of administration in accordance with standard pharmaceutical practice known to one skilled in the art. In some embodiments, the BRAF-associated tumor is a malignant BRAF-associated tumor (ie, BRAF-associated cancer). In some embodiments, the BRAF-associated cancer is a BRAF-associated CNS cancer. In some embodiments, the BRAF-associated CNS cancer is a BRAF-associated metastatic cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic melanoma. In some embodiments, the BRAF-associated metastatic cancer is metastatic colorectal cancer. In some embodiments, the BRAF associated metastatic cancer is metastatic non-small cell lung cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic thyroid cancer. In some embodiments, the BRAF-associated metastatic cancer is metastatic ovarian cancer. In some embodiments, the BRAF-associated metastatic cancer is an intracranial or extracranial LMD. In some embodiments, the BRAF-associated CNS cancer is a primary brain tumor. In some embodiments, the BRAF-associated tumor is a benign CNS tumor. In some 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, appendix cancer, cancer small intestine, squamous cell carcinoma of the head and neck, angiosarcoma and central nervous system tumors.

In some embodiments of any of the methods described herein, the subject has a BRAF-associated tumor (e.g., benign, malignant, or metastatic tumor) where the subject has previously received treatment or standard therapy (e.g., treatment with one or more anticancer agents other than from a compound of formula I, formula I-A, formula II, formula III, formula IV or formula V or a pharmaceutically acceptable salt thereof, and/or radiation therapy and/or surgery), wherein said BRAF-associated tumor has become resistant to or does not tolerate said precursor therapy. In some embodiments, the subject has a BRAF-associated tumor (eg, locally advanced or metastatic tumor) that is refractory to standard therapy. In one embodiment, the method includes administering a compound of Formula I selected from Examples 1-164, or a pharmaceutically acceptable salt thereof.

Accordingly, in one embodiment, provided herein is a method of treating a subject having a BRAF-associated tumor, where the subject has previously been treated with one or more anticancer therapies (e.g., an anticancer agent, radiation therapy, and/or surgery), wherein the method includes 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-associated tumor has become resistant to said prior therapy. In one embodiment, the cancer is a BRAF-associated cancer having a class II mutation. In one embodiment, the class II mutation is a He-V600 mutation. In one embodiment, the non-VGOO mutation is G469A, G469R, G469V, K601E, K601N, K601T, L597Q, or L597V. In one embodiment, the He-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-associated cancers having class II mutations include lung cancer (eg, non-small cell lung cancer and small cell lung cancer), melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma , appendix cancer, small bowel cancer, squamous cell carcinoma of the head and neck, angiosarcoma and central nervous system tumors.

In some embodiments, the subject having a BRAF-associated 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 Formula V, or a pharmaceutically acceptable salt thereof ), alone or in combination with another anticancer agent, before 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 previously been 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 previously been treated with a BRAF inhibitor selected from encorafenib, dabrafenib and vemurafenib or a pharmaceutically acceptable salt thereof. In one embodiment, the BRAF-associated cancer that was treated with a prior BRAF inhibitor was a cancer with a BRAF V600 mutation (eg, a cancer with a BRAF V600E or BRAF V600K mutation). In one embodiment, the BRAF-associated cancer has become resistant to said prior treatment. In one embodiment, the BRAF-associated cancer expressed the BRAF V600 resistance mutation during or after said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic melanoma has received treatment 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 ) before 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 previously been treated with a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl)-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 previously been 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 said prior treatment. In one embodiment, the melanoma expressed the BRAF V600E resistance mutation during or after said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic melanoma has received treatment 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 prior to treatment 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 previously been 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]propan-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 a MEK inhibitor selected from binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 2-(2-chloro- 4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (ST-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 selected from encorafenib, dabrafenib and vemurafenib or a pharmaceutically acceptable salt thereof, and a MEK inhibitor selected from binimetinib, trametinib and cobinimetinib 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 previously been treated with dabrafenib or a pharmaceutically acceptable salt thereof and trametinib or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has previously been treated with vemurafenib or a pharmaceutically acceptable salt thereof and cobinimetinib or a pharmaceutically acceptable salt thereof. In one embodiment, the melanoma has become resistant to said prior treatment. In one embodiment, the melanoma expressed the BRAF V600E resistance mutation during or after said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic melanoma has received treatment with one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors described herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and/or a PD inhibitor -L1) before 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 one or more checkpoint inhibitors independently selected from ipilimumab, nivolumab, pembrolizumab and avelumab. In one embodiment, the melanoma has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic melanoma has received treatment with one or more PI3K inhibitors 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 one or more PI3K inhibitors selected from buparlisib (BKM120), alpelisib (BYL719), samotolisib (LY3023414), 8-[(1R)-1-[(3,5-difluorophenyl)amino] ethyl]-N, N-dimethyl-2-(morpholin-4-yl)-4-oxo-4H-chromene-6-carboxamide (AZD8186), tenalisib (RP6530), voctalisib 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), duvelisib (ABBV-954), N2-[4-oxo-4-[4-(4-oxo-8-phenyl -4H-1-benzopyran-2-yl)morpholin-4-ium-4-ylmethoxy]butyryl]-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 (BAY 84-1236), dactolisib (BEZ-235), 1-(4-[5-[5-amino-6-(5-tert- butyl-1,3,4-oxadiazol-2-yl)pierazin-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]purine -2-yl]pyrimidin-2-amine (GDC-0084), everolimus, rapamycin, 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 said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic melanoma has received treatment with 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 ( for example, any of the checkpoint inhibitors described herein, for example, a CTLA-4 inhibitor, a PD-1 inhibitor and/or a PD-L1 inhibitor) before 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 previously been 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 and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-3yl]carbonyl]-2, 4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof and one or more checkpoint inhibitors independently selected from ipilimumab, nivolumab and pembrolizumab. In one embodiment, the melanoma has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic melanoma has received treatment 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), a MEK inhibitor, and one or multiple checkpoint inhibitors (e.g., any of the checkpoint inhibitors described 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 previously been 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, a MEK inhibitor selected from binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 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 one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors points described herein, for example, 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 selected from encorafenib, dabrafenib and vemurafenib or a pharmaceutically acceptable salt thereof, a MEK inhibitor selected from binimetinib, trametinib and cobinimetinib, and one or more checkpoint inhibitors independently selected from ipilimumab, nivolumab, pembrolizumab and avelumab. In one embodiment, the melanoma has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic melanoma has been treated with one or more alkylating agents 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 previously been treated with one or more alkylating agents selected from temozolomide, fotemustine, lomustine and carmustine. In one embodiment, the subject has previously been treated with temozolomide. In one embodiment, the melanoma has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject having BRAF-associated metastatic colorectal cancer has received treatment with 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, a MEK inhibitor, and an inhibitor thereof. EGFR before 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 previously been 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, a MEK inhibitor selected from binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 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 an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib and brigatinib. 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, a MEK inhibitor selected from binimetinib, trametinib and cobinimetinib or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor selected from cetuximab and panitumumab. 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 previously been treated with dabrafenib or a pharmaceutically acceptable salt thereof, trametinib or a pharmaceutically acceptable salt thereof, and panitumumab. In one embodiment, the colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has received treatment with an EGFR 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 some embodiments, a subject with BRAF-associated metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF mutation) was treated with an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib , and a BRAF inhibitor selected from encorafenib, dabrafenib, vemurafenib, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbonyl)-2,4-difluorophenyl]propan-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 some embodiments, a subject with BRAF-associated metastatic colorectal cancer has received treatment with cetuximab or panitumumab 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 colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has received treatment with an EGFR inhibitor and 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 Formula V, or a pharmaceutically acceptable salt thereof. . In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has received treatment with an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib, and one or more cytotoxic chemotherapeutic agents. In some embodiments, a subject having BRAF-associated metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF mutation) has received treatment with an EGFR inhibitor selected from cetuximab or panitumumab and one or more cytotoxic chemotherapy agents, such as Nordic FLOX (fluorouracil , folinic acid and oxaliplatin) before 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 colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject having BRAF-associated metastatic colorectal cancer has received treatment with an EGFR inhibitor and a BRAF 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 some embodiments, a subject with BRAF-associated metastatic colorectal cancer has received treatment with an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib, and 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 has previously received treatment with an EGFR inhibitor selected from cetuximab and panitumumab, and a BRAF inhibitor 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 previously been treated with vemurafenib or a pharmaceutically acceptable salt thereof and panitumumab. In one embodiment, the subject has been previously treated with dabrafenib or a pharmaceutically acceptable salt thereof and panitumumab. In one embodiment, the colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with metastatic colorectal cancer has received treatment with a MEK inhibitor and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors described herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and/or PD-L1 inhibitor) before 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 previously been treated with a MEK inhibitor selected from binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 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) and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors described herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and/or a PD-1 inhibitor L1). In one embodiment, the subject has been previously treated with a MEK inhibitor selected from binimetinib, trametinib and cobinimetinib, and one or more checkpoint inhibitors independently selected from ipilimumab, nivolumab, pembrolizumab and avelumab. In one embodiment, the subject has previously been treated with a MEK inhibitor, which is binimetinib, and the checkpoint inhibitors nivolumab and ipilimumab. In one embodiment, the subject has previously been treated with the MEK inhibitor binimetinib and the checkpoint inhibitor pembrolizumab. In one embodiment, the subject has previously been 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 said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has received treatment with one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors described herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and/or PD-L1 inhibitor) before treatment with 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 one or more checkpoint inhibitors independently selected from ipilimumab, nivolumab, pembrolizumab and avelumab. In one embodiment, the subject has previously been treated with nivolumab. In one embodiment, the colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has been 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 Formula V, or a pharmaceutically acceptable salt thereof. In some embodiments, a subject with BRAF-associated metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF mutation) has received treatment with oxaliplatin, irinotecan, FOLFOXIRI (oxaliplatin, irinotecan, and fluorouracil), FOLFIRI (folinic acid, fluorouracil, and irinotecan), or CAPEX (capecitabine and oxaliplatin) before 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 colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has been treated with antibody therapy and 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 Formula V, or thereof pharmaceutically acceptable salt. In some embodiments, a subject having BRAF-associated metastatic colorectal cancer (eg, metastatic colorectal cancer with a BRAF mutation) has received treatment with an antibody therapy that is bevacizumab and one or more cytotoxic chemotherapeutic agents. In some embodiments, a subject with BRAF-associated metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF mutation) was treated with bevacizumab and irinotecan, bevacizumab and FOLFOXIRI (oxaliplatin, irinotecan, and fluorouracil), or bevacizumab and FOLFIRI (folinic acid, fluorouracil, and irinotecan ) before 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 colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has received treatment with an EGFR inhibitor, a BRAF inhibitor other than a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, and 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 formula V or a pharmaceutically acceptable salt thereof. In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has received treatment with an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib, a BRAF inhibitor selected from 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, and one or more cytotoxic chemotherapeutic agents selected from cetuximab and panitumumab, a BRAF inhibitor which is vemurafenib or a pharmaceutically acceptable salt thereof, and a cytotoxic chemotherapeutic agent which is irinotecan. In one embodiment, the colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject having BRAF-associated metastatic colorectal cancer (eg, metastatic colorectal cancer with a BRAF mutation) has received treatment with an EGFR inhibitor and 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 formula V or a pharmaceutically acceptable salt thereof. In some embodiments, a subject with BRAF-associated metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF mutation) was treated with an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib , and one or more cytotoxic chemotherapeutic agents. In some embodiments, a subject with BRAF-associated metastatic colorectal cancer (e.g., metastatic colorectal cancer with a BRAF mutation) has received treatment with an EGFR inhibitor selected from cetuximab and panitumumab, and a cytotoxic chemotherapy agent that is irinotecan or FOLFIRI (folic acid, fluorouracil and irinotecan). In one embodiment, the colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, the subject with BRAF-associated metastatic colorectal cancer has undergone surgery 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 become refractory to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has undergone surgery followed by treatment with 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, a MEK inhibitor and an EGFR inhibitor before 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 surgery and has previously been 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]propan-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, a MEK inhibitor selected from binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 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 an EGFR inhibitor selected from cetuximab, panitumumab , 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 selected from encorafenib, dabrafenib and vemurafenib, a MEK inhibitor selected from binimetinib, trametinib and cobinimetinib or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor selected from cetuximab and panitumumab. In one embodiment, the colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has undergone radiation therapy (eg, 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 Formula V, or thereof pharmaceutically acceptable salt. In one embodiment, the subject has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic colorectal cancer has undergone radiation therapy (eg, whole brain radiation therapy or stereotactic radiosurgery) followed by treatment with a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor before 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 radiation therapy and has previously been 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]propan-1-sulfonamide (PLX4720) and (3R)-N-(3-[[5-(2-cyclopropylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine -3-yl]carbonyl]-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (PLX8394) or a pharmaceutically acceptable salt thereof, a MEK inhibitor selected from binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 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 an EGFR inhibitor selected from cetuximab, panitumumab , osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib and brigatinib. In one embodiment, the subject has previously undergone surgery and has been previously treated with a BRAF inhibitor selected from encorafenib, dabrafenib and vemurafenib, or a pharmaceutically acceptable salt thereof, a MEK inhibitor selected from binimetinib, trametinib and cobinimetinib, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor , selected from cetuximab and panitumumab. In one embodiment, the colorectal cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject having BRAF-associated metastatic non-small cell lung cancer (e.g., metastatic non-small cell lung cancer with a BRAF mutation) has received treatment with one or more EGFR inhibitors 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 one or more EGFR inhibitors independently selected from cetuximab, panitumumab, 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 previously been 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 said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject with BRAF-associated metastatic non-small cell lung cancer has received treatment with 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 has previously been 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, a MEK inhibitor selected from binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 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 an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib and brigatinib. In one embodiment, the subject has been previously treated with a BRAF inhibitor selected from vemurafenib, dabrafenib and encorafenib or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor selected from cetuximab and panitumumab, 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 non-small cell lung cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In some embodiments, a subject having BRAF-associated metastatic thyroid cancer (e.g., metastatic thyroid cancer with a BRAF mutation) has received treatment 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) before 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 previously been 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, a MEK inhibitor selected from binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 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 an EGFR inhibitor selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib and brigatinib. In one embodiment, the subject has been previously treated with a BRAF inhibitor selected from vemurafenib, dabrafenib, and encorafenib, 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 thyroid cancer has become resistant to said prior treatment. In one embodiment, the subject developed brain metastases during said prior treatment.

In one embodiment, the subject has BRAF-associated LMD and has previously 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 Formula V, or a pharmaceutically acceptable salt thereof) and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors described 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 previously been 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, and one or more checkpoint inhibitors independently selected from ipilimumab, nivolumab, pembrolizumab and avelumab. In one embodiment, the LMD has become resistant to said prior treatment.

In one embodiment, the subject has BRAF-related LMD and has previously 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 Formula V, or a pharmaceutically acceptable salt thereof) , a MEK inhibitor, and one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors described 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 previously been 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, a MEK inhibitor selected from binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 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 a checkpoint inhibitor (e.g., any of the checkpoint inhibitors described herein, for example, 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 selected from encorafenib, dabrafenib and vemurafenib or a pharmaceutically acceptable salt thereof, a MEK inhibitor selected from binimetinib, trametinib and cobinimetinib or a pharmaceutically acceptable salt thereof, and one or more checkpoint inhibitors independently selected of ipilimumab, nivolumab, pembrolizumab and avelumab. In one embodiment, the LMD has become resistant to said prior treatment.

In one embodiment, the subject has BRAF-associated LMD and has been previously treated with one or more checkpoint inhibitors (e.g., any of the checkpoint inhibitors described herein, e.g., a CTLA-4 inhibitor, a PD-1 inhibitor, and/or a PD inhibitor -L1) before 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 one or more checkpoint inhibitors independently selected from ipilimumab, nivolumab, pembrolizumab, avelumab and RN888. In one embodiment, the LMD has become resistant to said prior treatment.

In one embodiment, the subject has a BRAF-associated glioma and has previously undergone surgery 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 glioma has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF associated glioma and has previously undergone radiation therapy (eg, 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 Formula V, or a pharmaceutically acceptable compound thereof salt. In one embodiment, the glioma has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated 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 Formula 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 has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated 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 Formula V, or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has previously received treatment with an ornithine decarboxylase inhibitor, which is eflornithine (as a racemate or D- or L-enantiomer). In one embodiment, the glioma has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated 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 Formula V, or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has previously been treated with an alkylating agent selected from temozolomide, lomustine and carmustine. In one embodiment, the glioma has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated 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 Formula V, or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has previously received treatment with an alkylating agent selected from temozolomide, lomustine and carmustine, and an ornithine decarboxylase inhibitor that is eflornithine (as a racemate or D- or L-enantiomer). In one embodiment, the glioma has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated glioma and has been previously treated with radiation therapy (eg, 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 Formula V or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has previously received radiation therapy (eg, whole brain radiation therapy or stereotactic radiosurgery) and an alkylating agent selected from temozolomide, lomustine, and carmustine. In one embodiment, the subject has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated glioma and has previously undergone antibody therapy 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 previously received treatment with an antibody therapy that is bevacizumab. In one embodiment, the glioma has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated glioma and has previously undergone surgery and radiation therapy 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 glioma has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated glioma and has previously undergone 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 Formula V, or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has previously undergone surgery, radiation therapy (eg, whole brain radiation therapy or stereotactic radiosurgery), and an alkylating agent selected from temozolomide, lomustine, and carmustine. In one embodiment, the glioma has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated glioma and has previously 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 Formula V, or a pharmaceutically acceptable salt thereof) before 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 previously received treatment 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 said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated glioma and has previously 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 Formula V, or a pharmaceutically acceptable salt thereof) and a MEK inhibitor before 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 previously received treatment 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), and a MEK inhibitor selected from binimetinib, trametinib, cobinimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 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 selected from encorafenib, dabrafenib and vemurafenib, or a pharmaceutically acceptable salt thereof, and a MEK inhibitor selected from binimetinib, trametinib and cobinimetinib, or a pharmaceutically acceptable salt thereof. In one embodiment, the glioma has become resistant to said prior treatment. In one embodiment, the glioma is a grade 2, grade 3, or grade 4 glioma.

In one embodiment, the subject has a BRAF-associated brainstem ganglioglioma and has previously 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 Formula V, or a pharmaceutical thereof acceptable salt) before 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 previously been 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 has previously been treated with a BRAF inhibitor selected from encorafenib, dabrafenib and vemurafenib or a pharmaceutically acceptable salt thereof. In one embodiment, the ganglioglioma has become resistant to said prior treatment.

Although the genetic basis of tumorigenesis may differ among cancer types, the cellular and molecular mechanisms required for metastasis appear to be the same across all types of solid tumors. 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 tumor cells detaching from the original tumor, entering the bloodstream through the newly formed vasculature, and tumor cells migrating and extravasating to favorable distant sites where they can form colonies. A number of genes have been identified as promoters or suppressors of metastasis.

Accordingly, also provided herein are methods of treating, inhibiting, preventing, helping to prevent, or reducing symptoms of metastasis of BRAF-associated cancer in a subject in need thereof, wherein the method comprises 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 some 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 anticancer treatment, such as surgery (e.g., at least partial tumor resection) and/or radiation therapy and/or treatment with an anticancer agent. In one embodiment, the cancer is a metastatic cancer with metastases to the brain, and 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. In one embodiment, the cancer is a metastatic melanoma with metastases to the brain. In one embodiment, the cancer is metastatic colorectal cancer with metastases to the brain. In one embodiment, the cancer is metastatic non-small cell lung cancer with metastases to the brain. In one embodiment, the cancer is metastatic ovarian cancer with metastases to the brain. In one embodiment, the cancer is metastatic thyroid cancer with metastases to the brain. In one embodiment, the cancer is a neuroblastoma with brain metastases, and 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. In one embodiment, the subject has previously undergone other anticancer treatment, such as surgery (eg, at least partial tumor resection) and/or radiation therapy, and/or treatment with an anticancer agent. In one embodiment, the subject has become resistant to said previous treatment. In one embodiment, the subject receives 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 combination with another anticancer treatment, such as surgery (e.g., at least partial resection tumor) and/or radiation therapy and/or treatment with an anticancer agent.

Also provided herein are methods of inhibiting metastasis in a subject in need thereof, wherein the method comprises 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 some 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 anticancer treatment, such as surgery (e.g., at least partial tumor resection) and/or radiation therapy and/or treatment with an anticancer agent. In one embodiment, the cancer is a metastatic cancer with metastases to the brain. In one embodiment, the cancer is a metastatic melanoma with metastases to the brain. In one embodiment, the cancer is metastatic colorectal cancer with metastases to the brain. In one embodiment, the cancer is metastatic non-small cell lung cancer with metastases to the brain. In one embodiment, the cancer is metastatic ovarian cancer with metastases to the brain. In one embodiment, the cancer is metastatic thyroid cancer with metastases to the brain. In one embodiment, the cancer is a neuroblastoma with brain metastases. In one embodiment, the subject has previously undergone other anticancer treatment, such as surgery (eg, at least partial tumor resection) and/or radiation therapy, and/or treatment with an anticancer agent. In one embodiment, the subject has become resistant to said previous treatment. In one embodiment, the subject receives 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 combination with another anticancer treatment, such as surgery (e.g., at least partial resection tumor) and/or radiation therapy and/or treatment with an additional anticancer agent. In one embodiment, the additional anticancer therapy is an anticancer agent. In one embodiment, the additional anticancer agent is selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, HER2 and/or HER3 inhibitors, Axl inhibitors, PI3K inhibitors, S0S1 inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators, cytotoxic chemotherapy agents, angiogenesis-targeted therapy, and immunotargeted agents. In one embodiment, the additional anticancer agent is a MEK inhibitor. In one embodiment, the MEK inhibitor is binimetinib, trametinib, cobinimetinib, or a pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof.

As used herein, the term “treating metastases” means reducing the size, progression and/or further spread of one or more metastases.

Also provided herein are methods of inhibiting metastasis in a subject in need thereof, wherein the method comprises 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 some 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 anticancer treatment, such as surgery (e.g., at least partial tumor resection) and/or radiation therapy and/or treatment with an anticancer agent. In one embodiment, the cancer is a metastatic cancer with metastases to the brain. In one embodiment, the cancer is a metastatic melanoma with metastases to the brain. In one embodiment, the cancer is metastatic colorectal cancer with metastases to the brain. In one embodiment, the cancer is metastatic non-small cell lung cancer with metastases to the brain. In one embodiment, the cancer is metastatic ovarian cancer with metastases to the brain. In one embodiment, the cancer is metastatic thyroid cancer with metastases to the brain. In one embodiment, the cancer is a neuroblastoma with brain metastases. In one embodiment, the subject has previously undergone other anticancer treatment, such as surgery (eg, at least partial tumor resection) and/or radiation therapy and/or treatment with an anticancer agent. In one embodiment, the subject has become resistant to said previous treatment. In one embodiment, the subject receives 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 combination with another anticancer treatment, such as surgery (e.g., at least partial resection tumor) and/or radiation therapy and/or treatment with an anticancer agent. In one embodiment, the anticancer therapy is an anticancer agent. In one embodiment, the anticancer agent is selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, HER2 and/or HER3 inhibitors, Axl inhibitors, PI3K inhibitors, S0S1 inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators, cytotoxic chemotherapeutic agents , angiogenesis-targeted therapy and immuno-targeted agents. In one embodiment, the anticancer agent is a MEK inhibitor. In one embodiment, the MEK inhibitor is binimetinib, trametinib, cobinimetinib, or a pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof.

As used herein, the term “inhibiting metastasis” means reducing the occurrence (or reoccurrence) of one or more metastases, preventing the occurrence (or reoccurrence) of one or more metastases, or reducing the spread of one or more metastases.

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-associated cancer, which include: selecting, identifying or diagnosing the subject as having a BRAF-associated cancer, and 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 selected, identified or diagnosed as having BRAF-associated cancer. 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-associated cancer, which include 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 BRAF-associated cancer. The reduction in the risk of developing one or more metastases or one or more additional metastases in a subject having a BRAF-associated cancer can be compared with the risk of developing one or more metastases or one or more additional metastases in the subject before treatment, or compared with the subject or population of subjects with similar or the same BRAF-associated cancer who have not received treatment or have received different treatment.

The phrase "risk of developing one or more metastases" means the risk that a subject or subject having a primary tumor will develop an additional tumor (e.g., a solid tumor) at a site distant from the primary tumor in the subject or subject within a specified period of time, where the additional tumor includes the same or similar cancer cells as the primary tumor. Disclosed herein are methods of reducing the risk of developing one or more metastases in a subject or subject having cancer.

The phrase "risk of developing additional metastases" means the risk that a subject or subject having a primary tumor and one or more additional tumors at sites distant from the primary tumor (where one or more additional tumors include the same or similar cancer cells as the primary tumor) will develop one or more additional tumors distant from the primary tumor, where the additional tumors include the same or similar cancer cells as the primary tumor. This document describes ways to reduce the risk of developing additional metastases.

Also provided herein is a method of treating a BRAF-associated tumor, BRAF-associated tumor metastases, or a combination thereof in a subject in need thereof, comprising administering a compound of Formula I, Formula I-A, Formula II, to the subject of Formula III, Formula IV, or Formula V, or pharmaceutically thereof acceptable salt. 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 class I BRAF mutation (eg, a cancer with a BRAF V600 mutation, eg, a cancer with a BRAF V600E and/or BRAF V600K mutation). In one embodiment, the cancer is a cancer having a class II BRAF mutation (eg, the G469A mutation or the BRAF V600E splice variant). In one embodiment, the subject has previously undergone other anticancer treatment, such as surgery (eg, at least partial tumor resection) and/or radiation therapy, and/or treatment with an anticancer agent. In one embodiment, the subject has become resistant to said previous treatment. In one embodiment, the subject receives 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 combination with another anticancer treatment, such as surgery (e.g., at least partial resection tumor) and/or radiation therapy and/or treatment with an anticancer agent. In one embodiment, the anticancer therapy is an anticancer agent selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, S0S1 inhibitors, HER2 and/or HER3 inhibitors, Axl inhibitors, PI3K inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, pathway modulators apoptosis, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapy and immuno-targeted agents. In one embodiment, the anticancer agent is a MEK inhibitor. In one embodiment, the MEK inhibitor is binimetinib, trametinib, cobinimetinib, or a pharmaceutically acceptable salt thereof. In one embodiment, the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject is administered one or more agents to reduce the side effects of treatment (e.g., one or more of corticosteroids, serotonin antagonists, dopamine antagonists, NK-1 inhibitors, cannabinoids, anti-anxiety drugs (e.g., lorazepam or diazepam), antibiotics , antifungal agents, colony stimulating factor, iron supplements, procrit, epoetin alfa, darbepoetin alfa, antiemetic agents, diuretics, NSAIDs, analgesics, methotrexate, antidiuretics, probiotics, blood pressure medications, antiemetic agents, laxatives, etc.).

In one embodiment, the BRAF-associated 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 various forms of treatment for treating a subject with a benign tumor.

In some embodiments, the subject has a CNS tumor and is administered one or more agents to alleviate one or more symptoms associated with the CNS tumor, including, but not limited to, seizures, nausea, headaches, blurred vision, loss of vision, spatial orientation, changes in fine motor skills and drowsiness. Examples of such agents for the relief of one or more symptoms associated with a CNS tumor include corticosteroids, anticonvulsants (eg, cannabidiol, gabapentin, or pregabalin), pain medications (eg, NSAIDs, acetaminophen), and antinausea agents.

Also provided is a method of inhibiting BRAF kinase activity in a mammalian cell, comprising contacting the cell 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 some embodiments, the contact occurs in vitro. In some embodiments, the contact occurs in vivo. In some embodiments, the contact occurs in vivo, where the method includes 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 a cell having BRAF kinase activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer, as described herein. In some embodiments, the cancer cell is a BRAF-associated cancer cell. In some embodiments, the cell is a brain cell (eg, a nerve cell or a glial cell).

As used herein, the term “contact” refers to the connection of these groups in an in vitro system or an in vivo system. For example, “contacting” BRAF kinase with a compound provided herein includes contacting a cell containing BRAF kinase with a compound provided herein, as well as, for example, introducing a compound provided herein into a sample containing cell or purified preparation containing BRAF kinase.

Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting the cell 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, or a pharmaceutical composition thereof. , as defined herein.

As used herein, the term “therapeutically effective amount” of a compound, pharmaceutical composition thereof, or pharmaceutical combination thereof is an amount sufficient to achieve any one or more beneficial or desired results. When used prophylactically, beneficial or desired results include elimination or reduction of risk, reduction in severity, or delay of onset of disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes manifested during the development of the disease. For therapeutic use, the beneficial or desired results include providing a therapeutic effect, which may include reducing tumor size, inhibiting (eg, slowing to some extent, preferably stopping) tumor progression, inhibiting (eg, slowing to some extent, preferably stopping) growth tumors, inhibiting (eg, slowing to some extent, preferably stopping) tumor invasiveness and/or inhibiting (eg, slowing to some extent, preferably stopping) tumor metastasis. One skilled in the art will appreciate that tumor progression in humans can be determined in a variety of ways. For example, the size of a tumor close to the skin can be measured by determining the width and depth of the tumor with a caliper, and then calculating the volume of the tumor. Less accessible tumors, such as lung and central nervous system cancers, can be measured by monitoring images obtained with magnetic resonance imaging (MRI). CNS tumors, such as brain tumors, can be measured using MRI scans and monitoring neurological characteristics. Brain tumor growth is usually associated with a decline in neurological characteristics. Providing a therapeutic effect also includes extending the life expectancy of the subject or subjects beyond what would be expected in the absence of treatment, and/or alleviating to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer. In one embodiment, treatment of a subject or subject with a compound or combination of the invention prolongs survival over that expected in the absence of treatment by 1 or more months, e.g., 3 or more months, e.g., 6 or more months, e.g., 1 or more months. more than years, for example, for 2 or more years, for example, for 3 or more years, for example, for 5 or more years, for example, for 10 or more years. 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 the tumor mass. Providing a therapeutic effect also includes achieving cancer remission. A therapeutically effective amount may be administered in one or more administrations. For purposes of the present invention, the dosage of a therapeutically effective amount of a compound or pharmaceutical composition thereof is an amount sufficient to provide prophylactic or therapeutic treatment directly or indirectly. As understood in a clinical context, dosage of a therapeutically effective amount of a compound or pharmaceutical composition thereof may be achieved in combination with other therapy. Thus, a "therapeutically effective amount" may be considered in the context of the administration of one or more therapies (eg, one or more antineoplastic agents), and one agent may be considered to be administered in a therapeutically effective amount if, in combination with one or more other agents, the desired the result can be achieved or is being achieved. With respect to the treatment of cancer, a therapeutically effective amount may also refer to that amount which has the effect of (1) reducing tumor size, (2) inhibiting (i.e., to some extent slowing, preferably stopping) the occurrence of tumor metastases, (3) inhibiting to some extent (ie, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and/or (4) alleviating to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer. The therapeutic or pharmacological effectiveness of dosages and dosage regimens may also be characterized as the ability to induce, enhance, maintain or prolong disease control and/or overall survival in subjects with these specific tumors, which can be measured as an increase in time to disease progression.

In one embodiment, a subject receiving treatment in accordance with any of the methods described herein may be assessed according to one or more standard response criteria known in the art, including RECIST (Response Evaluation Criteria in Solid Tumors, for example, RECIST version 1.0, RECIST version 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). In one embodiment of any of these criteria, the tumor is assessed using an imaging study (eg, MPT, CT, MDCT or PET). In one embodiment, response to treatment is assessed according to RECIST version 1.1, where: complete response (CR) is defined as complete disappearance of all tumor lesions; partial response (PR) is defined as a decrease in the sum of tumor measurements by at least 30%; Progressive disease (PD) is defined as an increase of at least 20% in the sum of tumor measurements (where development of new lesions or significant progression of off-target lesions is also defined as PD), where an increase of at least 5 mm from baseline is assessed as PD; and stable disease (SD) is defined as neither a decrease sufficient to qualify as PR nor an increase sufficient to qualify as PD, using the smallest sum of diameters during treatment as the reference. In one embodiment, assessments include intracranial response (assessed 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).

In one embodiment, the subject has a CNS tumor and has at least one measurable intracranial tumor. In one embodiment, at least one measurable intracranial tumor is measured using an MRI-CT scan.

A “measurable” tumor (tumor lesion) means a tumor that can be accurately measured in at least one dimension (the longest diameter in the measurement plane is not recorded) with a minimum size of: 10 mm on CT (CT slice thickness no more than 5 mm) ; measuring with a 10 mm caliper during clinical examination; 20 mm on chest x-ray.

When used as pharmaceuticals, 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 as pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical field and can be administered in a variety of ways, depending on whether local or systemic treatment is required and the area being treated. Administration may be local (including percutaneous, epidermal, ophthalmic and mucosal, including intranasal, vaginal and rectal), pulmonary (for example, by inhalation or insufflation of powders or aerosols, including using a nebulizer; intratracheal or intranasal) , oral or parenteral. Oral administration may include a dosage form formulated for once daily or twice daily (BID) administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular administration or injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be administered, for example, using a continuous infusion pump. Pharmaceutical and topical compositions may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

Also provided herein are pharmaceutical compositions that contain as an active ingredient 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 pharmaceutically acceptable 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 some embodiments, the composition is suitable for topical use. In the preparation of the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted with an excipient, or enclosed in such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be a solid, semi-solid or liquid material that acts as a carrier, vehicle or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, wafers, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in the form of a solid or liquid medium), ointments containing, for example, up to 10% by weight active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is a solid oral formulation. In some embodiments, the composition is formulated as a tablet or capsule.

Also provided herein are pharmaceutical compositions comprising a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing as an active ingredient 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 prepared by thoroughly mixing a 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 in accordance with conventional methods for the preparation of pharmaceutical compositions. The carrier may take a variety of forms depending on the desired route of administration (eg, oral, parenteral). In some embodiments, the composition is a solid oral composition.

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.

Methods for formulating pharmaceutical compositions are described in numerous 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.

When preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be used. 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 and the like; for solid oral preparations such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binding agents, disintegrants and the like. Suitable binding agents include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like. Solid oral medications may also be coated with substances such as sugars or have an enteric coating to modulate the primary site of absorption. For parenteral administration, the carrier will generally consist of sterile water, and other ingredients may be added to enhance solubility or preservation. Suspensions or injection solutions can also be prepared using aqueous vehicles along with appropriate additives. The pharmaceutical compositions herein will contain, per dosage unit, for example, tablet, capsule, powder, injection, teaspoon and the like, an amount of active ingredient necessary to deliver a therapeutically effective amount as described herein.

Compositions 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 formulated in unit dosage form, wherein each dose contains from about 5 to about 1000 mg (1 g) ), more often from about 100 to about 500 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human and other subjects, where each unit contains a predetermined amount of active material (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, in combination with a suitable pharmaceutical excipient.

In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of active ingredient. One skilled in the art will recognize that these are 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, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to approximately 50 mg of active ingredient.

In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of active ingredient. One skilled in the art will appreciate that these are 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 some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 80 mg, or about 160 mg of active ingredient.

The daily dosage of a compound of Formula I, Formula I-A, Formula II, Formula III, Formula IV, or Formula V, or a pharmaceutically acceptable salt thereof, may vary widely from 1.0 to 10,000 mg per adult per day or higher, or any range thereof. limits. For oral administration, the compositions are preferably provided in the form of tablets 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 mg of the active ingredient for symptomatic dose adjustment for the subject being treated. A therapeutically effective amount of drug is typically administered at a dosage of from about 0.1 mg/kg to about 1000 mg/kg body weight per day or any other range therein. Preferably, the range is from about 0.5 to about 500 mg/kg body weight per day, or any other range therein. More preferably, from about 1.0 to about 250 mg/kg body weight per day, or any other range therein. More preferably, from about 0.1 to about 100 mg/kg body weight per day, or any other range therein. For example, the range may be from about 0.1 to about 50.0 mg/kg body weight per day, or any other range therein. In another example, the range may be from about 0.1 to about 15.0 mg/kg body weight per day, or any other range therein. In yet another example, the range may be from about 0.5 to about 7.5 mg/kg body weight per day or any amount in this range. Pharmaceutical compositions 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 1 to 4 times daily or as a single daily dose.

The active compound can be effective over a wide range of dosages and is typically administered in a therapeutically effective amount. Optimal dosages for administration can be readily determined by those skilled in the art. Thus, it should be understood that the amount of compound actually administered is generally determined by the physician and will vary depending on the relevant circumstances, including the route of administration, the actual compound administered, the potency of the drug, the condition being treated, and the progression of the disease state. In addition, factors associated with the particular subject being treated, including the subject's response, age, weight, diet, time of administration, and severity of the subject's symptoms, will necessitate dosage adjustments.

In some embodiments, the compounds provided herein can be administered in an amount of from about 1 mg/kg to about 100 mg/kg. In some embodiments, a compound provided herein may be administered in an amount of from about 1 mg/kg to about 20 mg/kg, from about 5 mg/kg to about 50 mg/kg, from about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg. For example, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg kg, approximately 4 5 mg/kg, approximately 5 0 mg/kg, approximately 55 mg/kg, approximately 60 mg/kg, approximately 65 mg/kg, approximately 7 0 mg/kg, approximately 7 5 mg/kg, approximately 8 0 mg/kg, approximately 8 5 mg/kg, approximately 9 0 mg/kg, approximately 95 mg/kg, or approximately 100 mg/kg. In some embodiments, such administration may be once daily (QD) or twice daily (BID). In some embodiments, such administration may be an intermittent administration schedule.

One skilled in the art will appreciate that testing, both in vivo and in vitro, using appropriate, known and accepted cellular and/or animal models can predict the ability of a test compound to treat or prevent a given disorder.

One skilled in the art will also appreciate that clinical trials in humans, including first-in-human trials, dose range and efficacy trials in healthy subjects and/or subjects suffering from the disorder, can be conducted in accordance with methods well known in clinical and medical technology.

Provided herein are pharmaceutical kits useful, for example, for the treatment of BRAF-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition containing a therapeutically effective amount of a compound provided herein. Such kits may further include, if desired, one or more different components of conventional pharmaceutical kits, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be apparent to those skilled in the art. Instructions in the form of inserts or labels indicating the amount of components to be administered, directions for use and/or recommendations for mixing components may also be included in the kit.

Also provided herein are the following embodiments:

Embodiment 1. Compound of Formula I

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, Ar ¹ , Ar ¹ CH ₂ -, hetAr ¹ or hetCyc ¹ ;

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

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring; And

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

provided that the connection does not constitute:

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

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

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

Embodiment 2: Compound of Formula II

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl or C1-C6 fluoroalkyl;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ is C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring; And

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

provided that the connection does not constitute:

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

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

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

Embodiment 3: Compound of Formula III

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, Ar ¹ , Ar ¹ CH ₂ -, hetAr ¹ or hetCyc ¹ ;

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

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₂ CH ₃ , -CH=CH2, F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring; And

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

Embodiment 4: Compound of Formula IV

or a pharmaceutically acceptable salt thereof, where:

L represents NH or O;

R ¹ represents C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH ₂ -, (C1-C6 alkoxy) C1-C6 alkyl-, Ar ¹ , Ar ¹ CH ₂ -, hetAr ¹ or hetCyc ¹ ;

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

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

hetCyc ¹ is a 4-6 membered saturated monocyclic heterocyclic ring having a ring oxygen atom;

R ² represents -CH ₃ , -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Br or CN;

R ³ represents F or Cl;

R ⁴ represents H or F;

R ⁵ represents H, F or Cl;

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl,

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 said ring is optionally substituted 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) a 6-7 membered fused bicyclic ring, optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring; And

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

where if 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 represents -CH ₂ CH ₃ , -CH=CH ₂ , F, Cl, Bt or CN.

Embodiment 5. The compound of any one of Embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C1-C6 alkyl.

Embodiment 6. The compound of Embodiment 5, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl.

Embodiment 7. The compound of any one of Embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein R ¹ is C1-C6 fluoroalkyl.

Embodiment 8. The compound of Embodiment 7, or a pharmaceutically acceptable salt thereof, wherein R ¹ is fluoromethyl.

Embodiment 9. The compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein R ² represents F or C1.

Embodiment 10. The compound of any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein:

R ⁶ represents C1-C6 alkyl, and

R ⁷ represents C1-C6 alkyl, hetCyc ² or C3-C6 cycloalkyl.

Embodiment 11. The compound of any one of embodiments 1-9 or a pharmaceutically acceptable salt thereof, wherein R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a saturated ring system selected from (i) 4-6 membered a 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, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, (ii) 6-7-membered fused a bicyclic ring optionally substituted with 1 or 2 substituents independently selected from F and -CH ₃ , (iii) a 6-7 membered bridged ring, and (iv) a 6-8 membered spirocyclic ring.

Embodiment 12. The compound of Embodiment 11, or a pharmaceutically acceptable salt thereof, wherein R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a saturated 4-6 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, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN.

Embodiment 13. The compound of Embodiment 11, or a pharmaceutically acceptable salt thereof, wherein 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.

Embodiment 14. The compound of any one of Embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein L is O.

Embodiment 15. The compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein L represents NH.

Embodiment 16. The connection of Embodiment 1 selected from:

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide ;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N-ethyl-N-methyl)-sulfamide ;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N,N-dimethyl)-sulfamide ;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-(N-ethyl-N-methyl )-sulfonamide;

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-methoxypyrrolidin- 1-sulfonamide;

(R)-N-(2-chloro-4-fluoro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-methoxypyrrolidin- 1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide;

(R)-N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-methoxypyrrolidine-1 -sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-2-azabicyclo[2,1,1 ]hexane-2-sulfonamide;

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide ;

N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)pyrrolidine-1-sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide;

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

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidin- 1-sulfonamide;

cis-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoro-4- methoxypyrrolidine-1-sulfonamide;

cis-N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-fluoro-4-methoxypyrrolidine -1-sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-azabicyclo[3,1,0 ]hexane-3-sulfonamide;

cis-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoro-4-methoxypyrrolidine -1-sulfonamide;

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide;

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluoropyrrolidin- 1-sulfonamide;

cis-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3,4-difluoropyrrolidin- 1-sulfonamide;

cis-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,4-difluoropyrrolidine-1 -sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3,3-difluoropyrrolidin-1- sulfonamide;

(R)-N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,3-difluoropyrrolidine-1-sulfonamide ;

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(difluoromethoxy )pyrrolidine-1-sulfonamide;

(S)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidin- 1-sulfonamide;

(S)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide;

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(difluoromethoxy) pyrrolidine-1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-azabicyclo[3,1, 0]hexane-3-sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)pyrrolidine-1-sulfonamide;

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-methoxypyrrolidine -1-sulfonamide;

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-fluoropyrrolidine -1-sulfonamide;

(R)-N-(3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)-3-methoxypyrrolidine-1 -sulfonamide;

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-fluoropyrrolidin-1 -sulfonamide;

(R)-N-(3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)-3-fluoropyrrolidin-1 -sulfonamide;

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-methoxypyrrolidine-1 -sulfonamide;

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)pyrrolidine-1-sulfonamide;

N-(2-chloro-4,5-difluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide;

N-(2-chloro-4,5-difluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-azabicyclo[2, 1,1]hexane-2-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-(fluoromethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide;

N-(3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)pyrrolidine-1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)pyrrolidine-1-sulfonamide;

N-(2-chloro-4,5-difluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)phenyl)-(N-ethyl-N-methyl )-sulfonamide;

(R)-N-(2-chloro-4,5-difluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3- fluoropyrrolidine-1-sulfonamide;

(R)-N-(2-chloro-4,5-difluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3- methoxypyrrolidine-1-sulfonamide;

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-methoxypyrrolidin- 1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-2-azabicyclo[2,1, 1]hexane-2-sulfonamide;

N-(2-chloro-3-((5-cyano-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide;

N-(2-chloro-4-fluoro-3-((3-methyl-4-oxo-5-vinyl-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide;

N-(2-chloro-3-((5-ethyl-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide;

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxy- d3)pyrrolidine-1-sulfonamide;

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(methoxy -d3)pyrrolidine-1-sulfonamide;

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxy-d3) pyrrolidine-1-sulfonamide;

(R)-N-(5-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide;

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-(difluoromethoxy)pyrrolidin- 1-sulfonamide;

(R)-N-(5-chloro-2-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidin- 1-sulfonamide;

cis-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3,4-difluoropyrrolidine-1 -sulfonamide;

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-(difluoromethoxy) pyrrolidine-1-sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3,3-difluoropyrrolidine-1-sulfonamide ;

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-ethylpyrrolidin- 1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,3-difluoropyrrolidin-1- sulfonamide;

cis-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,4-difluoropyrrolidin- 1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-azabicyclo[3,1, 0]hexane-3-sulfonamide;

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-(difluoromethoxy )pyrrolidine-1-sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-2-azabicyclo[2,1,1 ]hexane-2-sulfonamide;

6-(2-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-6-fluorophenoxy)-3,5-dimethyl-3,4 dihydroquinazolin-4-one;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)pyrrolidine-1-sulfonamide;

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide ;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N,N-dimethyl)-sulfamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N-methyl-N-(tetrahydrofuran-3 -yl))-sulfamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N-cyclopropyl-N-methyl)-sulfamide ;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N-cyclobutyl-N-methyl)-sulfamide ;

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

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

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

(trans)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoro-4-methoxypyrrolidine -1-sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)morpholine-4-sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N-isopropyl-N-methyl)-sulfamide ;

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

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

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-(N,N-dimethyl)- sulfamide;

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

(trans)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,4-difluoropyrrolidine-1 -sulfonamide;

(S)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide ;

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

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N-isopropyl-N-methyl)-sulfamide ;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N-isopropyl-N-methyl)-sulfamide ;

(cis)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,4-difluoropyrrolidine-1 -sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N-isopropyl-N-methyl)-sulfamide ;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-azabicyclo[3,1,0]hexane -3-sulfonamide;

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

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-ethylpyrrolidine-1-sulfonamide;

cis-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3,4-difluoropyrrolidin-1 -sulfonamide;

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

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-(N-ethyl-N-methyl) -sulfamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-(N,N-dimethyl)-sulfamide ;

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-methoxypyrrolidin-1 -sulfonamide;

cis-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-fluoro-4-methoxypyrrolidine -1-sulfonamide;

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

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-azabicyclo[3,1,0 ]hexane-3-sulfonamide;

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

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

(R)-N-(5-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide ;

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-ethylpyrrolidin-1 -sulfonamide;

(S)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-azabicyclo[3,1,0 ]hexane-3-sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-(N-ethyl-N-methyl) -sulfamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-(N,N-dimethyl)-sulfamide ;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-(N,N-dimethyl)- sulfamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-(N-ethyl-N-methyl )-sulfonamide;

N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4-difluorophenyl)pyrrolidine-1-sulfonamide;

(R)-N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1-sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1- sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-(methoxymethyl)azetidine-1 -sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluoroazetidine-1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-methoxyazetidine-1-sulfonamide;

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

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

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoroazetidine-1-sulfonamide;

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

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-methoxyazetidin-1-sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1-sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1- sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(methoxymethyl)azetidine-1 -sulfonamide;

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

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,3-difluoroazetidine-1-sulfonamide ;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3,3-difluoroazetidin-1- sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-((difluoromethoxy)methyl)azetidine-1 -sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-((difluoromethoxy)methyl)azetidine -1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-((difluoromethoxy)methyl) azetidine-1-sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)-3-methylazetidine-1 -sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-ethoxyazetidine-1-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-ethoxyazetidin-1-sulfonamide;

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(difluoromethoxy)azetidine-1- sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(difluoromethoxy)azetidine-1 -sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoro-3-(methoxymethyl)azetidine- 1-sulfonamide;

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

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

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-6-fluoro-3-azabicyclo[3,1 ,0]hexane-3-sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-1-fluoro-3-azabicyclo[3,1 ,0]hexane-3-sulfonamide;

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

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

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-5-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide ;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-2-azabicyclo[3,1,0]hexane -2-sulfonamide;

N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,5-difluorophenyl)pyrrolidine-1-sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoro-3-methylazetidine-1-sulfonamide ;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-((trifluoromethoxy)methyl)azetidine-1 -sulfonamide;

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

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-2-azaspiro[3,3]heptane -2-sulfonamide;

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-azaspiro[3,3] heptane-2-sulfonamide;

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

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(difluoromethoxy)azetidine-1-sulfonamide;

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(trifluoromethoxy)azetidine-1-sulfonamide;

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

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-((fluoromethoxy)methyl)azetidine-1 -sulfonamide;

or a pharmaceutically acceptable salt thereof.

Embodiment 17: Compound of Formula V

or a pharmaceutically acceptable salt thereof, where:

L represents NH;

R ¹ represents C1-C6 alkyl;

R ² represents F or C1;

R ³ represents C1;

R ⁴ represents F;

R ⁵ represents H;

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 said ring is optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN, and (iii) a 6-7 membered bridging ring.

Embodiment 18. The compound of Embodiment 17, wherein R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 4-6 membered monocyclic ring, optionally having a second ring heteroatom that is O, wherein said ring optionally substituted with 1 or 2 substituents independently selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, - CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , -OCH ₂ CH ₃ and CN.

Embodiment 19. The compound of Embodiment 18, wherein R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 4-6 membered monocyclic ring, wherein said ring is substituted with a substituent selected from F, -OH, -OCH ₃ , -OCHF ₂ , -OCD ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ F, -CH ₂ OCHF ₂ , -CH ₂ OCF ₃ , -OCF ₃ , - OCH ₂ CH ₃ and CN.

Embodiment 20. The compound of Embodiment 19, wherein ^R6 and ^R7 , together with the nitrogen atom to which they are attached, form a saturated 4-6 membered monocyclic ring substituted with F.

Embodiment 21. A compound which is selected from:

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-azabicyclo[2,1, 1]hexane-2-sulfonamide having the structure:

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidin- 1-sulfonamide and 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, having the structure

And

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide, having structure:

or a pharmaceutically acceptable salt thereof.

Embodiment 22. 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 structure:

or a pharmaceutically acceptable salt thereof.

Embodiment 23. 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 structure:

Embodiment 24. A pharmaceutical composition comprising a compound of any one of Embodiments 1-23 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

Embodiment 25: A method for preparing the compound of Embodiment 1 or a pharmaceutically acceptable salt thereof, comprising:

(a) for the compound of Embodiment 1, wherein L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in Embodiment 1, a combination of a compound having formula (25)

where L, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in embodiment 1, with a compound having formula (16)

where R ⁶ and R ⁷ are as defined in embodiment 1, in the presence of a suitable base; or

(b) for the compound of Embodiment 1, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in Embodiment 1 and L is NH, the reaction of the compound of formula (5)

where R ¹ and R ² are as defined in embodiment 1, with a compound having formula (27)

wherein R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as defined in Embodiment 1, and PG represents an amine protecting group in the presence of a palladium catalyst and ligand followed by removal of the amine protecting group; or

(c) for a compound of formula I wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in Embodiment 1 and L is O, reacting a compound having formula (31)

where R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in embodiment 1, and PG represents an amine protecting group with a reagent having the formula

in the presence of a base followed by removal of the amino protecting group; And

optionally forming a pharmaceutically acceptable salt thereof.

Embodiment 26. A method of treating a BRAF-associated tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-23 or a pharmaceutically acceptable salt thereof.

Embodiment 27. The method of Embodiment 26, wherein said BRAF-associated tumor has a class II BRAF mutation.

Embodiment 28. The method of Embodiment 27, wherein said class II BRAF mutation is a non-V600 BRAF mutation.

Embodiment 29. The method of Embodiment 28, wherein said non-V600 BRAF mutation is BRAF G469A or G469R.

Embodiment 30. The method of Embodiment 29, wherein said class II BRAF mutation is a BRAF V600E splice variant.

Embodiment 31. The method of Embodiment 30, wherein said BRAF V600E splice variant is p61BRAF(V600E).

Embodiment 32. The method as in any one of Embodiments 26-31, wherein said BRAF-associated tumor is a cancer selected from lung cancer, melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendix cancer, small bowel cancer, neuroendocrine gastrointestinal cancer, squamous cell carcinoma of the head and neck, angiosarcoma, bladder cancer, plasma cell neoplasm, hepatobiliary cancer, hepato-pancreato-biliary carcinoma, ovarian cancer, neuroendocrine cancer , cholangiocarcinoma, esophageal cancer, soft tissue sarcoma, leukemia, non-Hodgkin's lymphoma and central nervous system cancer.

Embodiment 33. The method of any one of embodiments 26-31, wherein said cancer is a metastatic cancer.

Embodiment 34. The method of Embodiment 33, wherein said cancer is a metastatic CNS cancer.

Embodiment 35. The method of any one of embodiments 26-31, wherein said BRAF-associated tumor is a primary tumor.

Embodiment 36. The method of Embodiment 35, wherein said primary brain tumor is a malignant tumor.

Embodiment 37. The method of Embodiment 35, wherein said primary brain tumor is a grade 2 glioma, a grade 3 glioma, or a grade 4 glioma.

Embodiment 38. The method of embodiment 26, wherein said BRAF-associated tumor has a class I BRAF mutation.

Embodiment 38. The method of Embodiment 38, wherein said class I BRAF mutation is BRAF V600E or BRAF V600K.

Embodiment 40. The method of Embodiment 38 or 39, wherein said BRAF-associated tumor is selected from melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, renal cell cancer and metastatic cancers thereof, and primary brain tumors brain

Embodiment 41. The method of embodiment 38 or 39, wherein said BRAF-associated tumor is a CNS tumor.

Embodiment 42. The method of Embodiment 41, wherein said CNS tumor is a malignant tumor.

Embodiment 43. The method of Embodiment 42, wherein said cancer is a metastatic CNS cancer.

Embodiment 44. The method of Embodiment 43, wherein said metastatic CNS cancer is selected from metastatic melanoma, metastatic colorectal cancer, metastatic non-small cell lung cancer, metastatic thyroid cancer, and metastatic ovarian cancer.

Embodiment 45. The method of Embodiment 41, wherein said CNS tumor is an intracranial or extracranial LMD.

Embodiment 46. The method of Embodiment 41, wherein said CNS tumor is a primary brain tumor.

Embodiment 47. The method of Embodiment 46, wherein said primary brain tumor is a malignant tumor.

Embodiment 48. The method of Embodiment 47, wherein said primary brain tumor is a grade 2 glioma, a grade 3 glioma, or a grade 4 glioma.

Embodiment 49. The method of embodiment 26, wherein said BRAF-associated tumor has a class III BRAF mutation.

Embodiment 50. The method of Embodiment 29, wherein said BRAF-associated tumor is a cancer selected from melanoma, small bowel cancer, colorectal cancer, non-small cell lung cancer, endometrial cancer, cervical cancer, leukemia, bladder cancer, non-Hodgkin's lymphoma , glioma, ovarian cancer, prostate cancer, hepatobiliary cancer, esophageal and gastric cancer, soft tissue sarcoma and breast cancer.

Embodiment 51. The method of Embodiment 4 9 or 50, wherein the cancer has the BRAF G466V or BRAF D594G mutation.

Embodiment 52. The method of any one of embodiments 26-51, wherein the subject has not been treated.

Embodiment 53. The method of any one of embodiments 26-52, wherein the method further comprises administering additional anticancer therapy.

Embodiment 54. The method of Embodiment 53, wherein the additional anticancer therapy is selected from one or more of surgery, radiation therapy, and an anticancer agent.

Embodiment 55. The method of Embodiment 54, wherein the additional anticancer therapy is an anticancer agent.

Embodiment 56. The method of Embodiment 55, wherein the additional anticancer agent is selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, HER ² and/or HER ³ inhibitors, Axl inhibitors, PI3K inhibitors, SOS1 inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors points, modulators of the apoptosis pathway, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapy and immuno-targeted agents.

Embodiment 57. The method of Embodiment 56, wherein the additional anticancer agent is a MEK inhibitor.

Embodiment 58. The method of Embodiment 57, wherein the MEK inhibitor is binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4 -difluorobenzamide, 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H, 8H)-dione or a pharmaceutically acceptable salt thereof.

Embodiment 59. The method of Embodiment 58, wherein the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof.

Embodiment 60. The method of Embodiment 56, wherein the additional anticancer agent is an EGFR inhibitor.

Embodiment 61. The method of Embodiment 60, wherein the EGFR inhibitor is cetuximab.

Embodiment 62. A method of treating a subject with BRAF-associated metastatic cancer, wherein the subject has previously been treated with anticancer therapy, wherein the method comprises administering to the subject a therapeutically effective amount of a compound in accordance with any of Embodiments 1-23.

Embodiment 63. The method of embodiment 62, wherein said BRAF-associated cancer has a class II BRAF mutation.

Embodiment 64. The method of Embodiment 63, wherein said class II mutation is a non-V600 mutation.

Embodiment 65. The method of embodiment 62, wherein said BRAF-associated cancer has a class I BRAF mutation.

Embodiment 66. The method of Embodiment 65, wherein said BRAF-associated cancer has a BRAF V600E or V600K mutation.

Embodiment 67. The method of any one of embodiments 62-66, wherein the subject has been previously treated with an anticancer therapy that is one or more anticancer agents independently selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, HER ² and/or HER inhibitors ³ , Axl inhibitors, PI3K inhibitors, SOS1 inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapy and immuno-targeted agents.

Embodiment 68. The method of Embodiment 67, wherein the subject has previously been treated with a BRAF inhibitor.

Embodiment 69. The method of Embodiment 67, wherein the subject has previously been treated with a combination of a BRAF inhibitor and a MEK inhibitor.

Embodiment 70. The method of Embodiment 67, wherein the subject has previously been treated with one or more checkpoint inhibitors.

Embodiment 71. The method of Embodiment 67, wherein the subject has been previously treated with one or more PI3K inhibitors.

Embodiment 72. The method of Embodiment 67, wherein the subject has previously been treated with a combination of a BRAF inhibitor and a checkpoint inhibitor.

Embodiment 73. The method of Embodiment 67, wherein the subject has previously been treated with a combination of a BRAF inhibitor, a MEK inhibitor, and a checkpoint inhibitor.

Embodiment 74. The method of embodiment 67, wherein the subject has previously been treated with one or more alkylating agents.

Embodiment 75. The method of Embodiment 67, wherein the subject has previously been treated with a combination of a BRAF inhibitor, a MEK inhibitor, and an EGFR inhibitor.

Embodiment 76. The method of Embodiment 67, wherein the subject has been previously treated with an EGFR inhibitor.

Embodiment 77. The method of Embodiment 67, wherein the subject has been previously treated with a combination of an EGFR inhibitor and one or more cytotoxic chemotherapeutic agents.

Embodiment 78. The method of Embodiment 67, wherein the subject has been previously treated with a combination of an EGFR inhibitor and a BRAF inhibitor.

Embodiment 79. The method of Embodiment 67, wherein the subject has previously been treated with a combination of a MEK inhibitor and one or more checkpoint inhibitors.

Embodiment 80. The method of Embodiment 67, wherein the subject has previously been treated with one or more cytotoxic chemotherapeutic agents.

Embodiment 81. The method of Embodiment 67, wherein the subject has previously been treated with a combination of antibody therapy and one or more cytotoxic chemotherapeutic agents.

Embodiment 82. The method of Embodiment 67, wherein the subject has been previously treated with a combination of an EGFR inhibitor, a BRAF inhibitor, and one or more cytotoxic chemotherapeutic agents.

Embodiment 83. The method of Embodiment 67, wherein the subject has been previously treated with an EGFR inhibitor and one or more cytotoxic chemotherapeutic agents.

Embodiment 84. The method of any one of Embodiments 67, 68, 69, 72, 73, 75, and 82, wherein the BRAF inhibitor is encorafenib, dabrafenib, vemurafenib, or a pharmaceutically acceptable salt thereof.

Embodiment 85. The method of any one of Embodiments 67, 69, 73, 75, and 79, wherein the MEK inhibitor is binimetinib, trametinib, cobimetinib, or a pharmaceutically acceptable salt thereof.

Embodiment 86. The method of any one of Embodiments 67, 70, 72, 73, and 79, wherein the checkpoint inhibitor is ipilimumab, nivolumab, or pembrolizumab.

Embodiment 87. The method of Embodiment 67 or 71, wherein the one or more PI3K inhibitors are selected from buparlisib and alpelisib.

Embodiment 88. The method of Embodiment 67 or 74, wherein the alkylating agent is selected from temozolomide, fotemustine, lomustine and carmustine.

Embodiment 89. The method as in any one of Embodiments 67, 75, 76, 77, 78, 82, and 83, wherein the EGFR inhibitor is selected from cetuximab, panitumumab, osimertinib, erlotinib, gefitinib, necitumumab, neratinib, lapatinib, vandetanib, and brigatinib.

Embodiment 90. The method as in any one of Embodiments 67, 77, 80, 81, 82, and 83, wherein the one or more cytotoxic chemotherapeutic agents is selected from Nordic FLOX (fluorouracil, folinic acid, and oxaliplatin), oxaliplatin, bevacizumab, irinotecan, FOLFOXIRI

(oxaliplatin, irinotecan and fluorouracil), FOLFIRI (folinic acid, fluorouracil and irinotecan) or CAPEX (capecitabine and oxaliplatin).

Embodiment 91. The method of any one of embodiments 67-90, wherein the subject is resistant to said previous treatment.

Embodiment 92. The method of any one of embodiments 62-91, wherein the subject developed brain metastases during said previous treatment.

Embodiment 93. The method of any one of embodiments 62-92, wherein the method further comprises administering additional anticancer therapy.

Embodiment 94. The method of Embodiment 93, wherein the additional anticancer therapy is selected from one or more of surgery, radiation therapy, and an anticancer agent.

Embodiment 95. The method of Embodiment 94, wherein the additional anticancer therapy is an anticancer agent.

Embodiment 96. The method of Embodiment 95, wherein the additional anticancer agent is selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, HER2 and/or HER3 inhibitors, Axl inhibitors, PI3K inhibitors, SOS1 inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapy and immuno-targeted agents.

Embodiment 97. The method of Embodiment 96, wherein the additional anticancer agent is a MEK inhibitor.

Embodiment 98. The method of Embodiment 97, wherein the MEK inhibitor is binimetinib, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, mirdametinib, 2-(2-chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4 -difluorobenzamide, 3-[2(R),3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H, 8H)-dione or a pharmaceutically acceptable salt thereof.

Embodiment 99. The method of Embodiment 95, wherein the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof.

Embodiment 100. The method of Embodiment 99, wherein the additional anticancer agent is an EGFR inhibitor.

Embodiment 101. The method of Embodiment 100, wherein the EGFR inhibitor is cetuximab.

Embodiment 102. A method of treating BRAF-associated glioma where the subject has previously been treated with another anticancer therapy, wherein the method comprises administering a therapeutically effective amount of a compound in accordance with any of Embodiments 1-23.

Embodiment 103. The method of Embodiment 102, wherein the subject has previously been treated with one or more cytotoxic chemotherapeutic agents.

Embodiment 104. The method of Embodiment 103, wherein the one or more cytotoxic chemotherapeutic agents is selected from cisplatin, pemetrexed, vinorelbine, and paclitaxel.

Embodiment 105 The method of Embodiment 102 wherein the subject has previously been treated with an alkylating agent.

Embodiment 106. The method of Embodiment 102, wherein the subject has previously been treated with an ornithine decarboxylase inhibitor.

Embodiment 107. The method of Embodiment 102, wherein the subject has previously been treated with a combination of an alkylating agent and an ornithine decarboxylase inhibitor.

Embodiment 108. The method of Embodiment 105 or 107, wherein the alkylating agent is selected from temozolomide, lomustine and carmustine.

Embodiment 109. The method of Embodiment 106 or 107, wherein the ornithine decarboxylase inhibitor is racemic eflornithine, D-eflornithine, or L-eflornithine.

Embodiment 110. The method of Embodiment 102, wherein the subject has previously been treated with a BRAF inhibitor.

Embodiment 111. The method of Embodiment 102, wherein the subject has previously been treated with a combination of a BRAF inhibitor and a MEK inhibitor.

Embodiment 112. The method of Embodiment 110 or 111, wherein the BRAF inhibitor is encorafenib, dabrafenib, vemurafenib, or a pharmaceutically acceptable salt thereof.

Embodiment 113. The method of Embodiment 111, wherein the MEK inhibitor is binimetinib, trametinib, cobimetinib, or a pharmaceutically acceptable salt thereof.

Embodiment 114. The method as in any one of embodiments 102-113, wherein the anticancer therapy includes surgery.

Embodiment 115. The method of any one of embodiments 102-114, wherein the anticancer therapy includes radiation therapy.

EXAMPLES

The following examples illustrate the invention.

Biological examples

Example A1

Enzyme assay BRAF V60 0E

A competitive displacement assay is configured for B-Raf that monitors the amount of fluorescently labeled “tracer” bound to B-Raf via TR-FRET from an anti-tag Eu-labeled antibody also bound to B-Raf. For full-length FLAG-tagged B-Raf(V600E), assay mixtures consist of 25 mM K+HEPES, pH 7.4, 10 mM MgCl ₂ , 0.01% Triton X-100, 1 mM DTT, 2% DMSO ( from compound), 50 nM Tracer 1710 (ThermoFisher, PR917 6A), 0.5 nM Eu anti-FLAG (M2)-cryptate Ab (Cisbio, 61FG2KLB) and 5 nM full-length B-Raf(V600E) with N-terminal FLAG- label (Origene Technologies, TP700031). Compounds are typically diluted in DMSO within an 11-point dosing range created using a 3-fold serial dilution protocol at a maximum dose of 10 μM. The assay is performed in 384-well polystyrene untreated white low-volume microtiter plates (Costar 4512) with a final volume of 12 μl. Low control wells include 1 μM potent B-Raf inhibitor as a control. Assays are incubated at ambient temperature (typically 22°C) for 60 min and read on a PerkinElmer Envision microplate reader using standard TRF settings (AEx=320 nm, AEt=615 and 665 nm). Pulses in specified ratios (6 65 nm/615 nm) are converted to fraction of control (POC) using the following equation:

Where

- average non-inhibited control

- medium background

A 4-parameter logistic model fits the POC data for each compound. Based on this correspondence, IC ₅₀ is estimated and defined as the concentration of the compound at which the best fit curve intersects 50 POC. The average IC ₅₀ values of the compounds described herein when tested in this assay are presented in Table A.

Example A2

Cellular phospho-ERK inhibition assays in A375 and H1755 cells

A375 and H1755 cells were obtained from the American Type Culture Collection (ATCC, Rockville, MD). A375 cells are maintained in DMEM growth medium containing 10% FBS. H1755 cells are maintained in RPMI growth medium containing 10% FBS.

Cells were harvested according to standard protocols, counted, and seeded into flat-bottomed 9-well tissue culture plates (Costar #3599) at 2.5 x 10 ⁴ cells/well for A375 cells and 1.5 x 10 ⁴ cells/well for H1755 cells in 100 μl/well of growth medium containing 10% FBS. After incubation overnight at 37°C with 5% CO ₂ , cells are treated for 2 hours at 37°C, 5% CO ₂ with compounds prepared as a 9-point series of 1:3.33 fold dilutions with a final compound concentration in the range from 66 rM-10 µM and a constant DMSO concentration of 0.25%. Control wells contain either 0.25% DMSO alone (uninhibited control) or 10 μM bimetinib (complete inhibition control). Levels of phosphorylated ERK were determined using the In Cell Western protocol: after incubation with compound, the growth medium was removed and cells were fixed with 0.4% formaldehyde in PBS for 20 minutes at room temperature. Cells are permeabilized with 100% methanol for 10 minutes at room temperature. The plates are washed with PBS containing 0.05% Tween-2 0 and blocked for 1 hour at room temperature with LI-COR blocking buffer (LI-COR Biosciences; cat. no. 927-4 0000). The plates are then incubated for 2 hours at room temperature with 50 μl of anti-phospho-ERK1/2 (Thr202/Tyr204) at a dilution of 1:400 (Cell Signaling; cat. no. 9101) and anti-GAPDH at a dilution of 1:1000 (Millipore ; Cat. No. MAB374) in LI-COR blocking buffer containing 0.05% Tween-20. The plates are washed with PBS containing 0.05% Tween-20, then incubated at room temperature for 1 hour with 50 μl of anti-rabbit AlexaFluor 680 at a dilution of 1:1000 (Life Technologies; cat. no. A21109) and anti-mouse IRDye 800CW diluted 1:1000 (LI-COR; cat. no. 92 6-32 210) in LI-COR blocking buffer containing 0.05% Tween-20. The plates are analyzed by reading on an Odyssey CLx infrared scanner. For each well, the phospho-ERK signal is normalized to the GAPDH signal and converted to POC using the following equation:

Where

- average non-inhibited control

- medium control with complete inhibition

IC ₅₀ is calculated using a 4-parameter fit in XLfit software and the values are presented in Table A1.

Example A3

Cellular Phospho-ERK Inhibition Assay

The compounds of Example 13, Example 14 and Example 12 6 were evaluated in a phospho-ERK assay in two class III BRAF mutant cell lines: NCI-H1666 cells (BRAFG466V) and WM3629 cells (BRAF594G/NRASG12D). NCI-H1666 cells were obtained from the American Type Culture Collection (ATCC, Rockville, MD), and WM3629 cells were obtained from Rockland Immunochemicals (Limerick, PA). Cells are maintained in RPMI growth medium containing 10% FBS.

Cells were harvested according to standard protocols, counted, and seeded into flat-bottomed 9-well tissue culture plates (Costar #3599) at 2.5 x 10 ⁴ cells/well in 100 μl/well of growth medium containing 10% FBS. After incubation overnight at 37°C with 5% CO ₂ , cells are treated for 1 hour at 37°C with 5% CO ₂ inhibitors prepared as a series of 9-point 1:3.33-fold dilutions with final concentrations compound 66 pM-10 µM and a constant DMSO concentration of 0.25%. Control wells contain either 0.25% DMSO alone (uninhibited control) or 10 μM bimetinib (complete inhibition control). Levels of phosphorylated ERK were determined using the In Cell Western protocol: after incubation with compound, growth medium was removed and cells were fixed with 0.4% formaldehyde in PBS for 20 minutes at room temperature. Cells are permeabilized with 100% methanol for 10 minutes at room temperature. The plates are washed with PBS containing 0.05% Tween-20 and blocked for 1 hour at room temperature with LI-COR blocking buffer (LI-COR Biosciences; cat. #927-40000). The plates are then incubated for 2 hours at room temperature with 50 μl of anti-phospho-ERK1/2 (Thr202/Tyr204) at a dilution of 1:400 (Cell Signaling; cat. no. 9101) and anti-GAPDH at a dilution of 1:1000 ( Millipore; cat. no. MAB374) in LI-COR blocking buffer containing 0.05% Tween-2 0. The plates are washed with PBS containing 0.05% Tween-2 0, then incubate at room temperature for 1 hour with 5 0 µl of anti-rabbit AlexaFluor 680 at a dilution of 1:1000 (Life Technologies; cat. no. A21109) and anti-mouse IRDye 800CW at a dilution of 1:1000 (LI-COR; cat. no. 926-32210) in LI-COR blocking buffer, containing 0.05% Tween-2 0. The plates are analyzed by reading on an Odyssey CLx infrared scanner. For each well, the phospho-ERK signal is normalized to the GAPDH signal and converted to POC using the following equation:

Where

- average non-inhibited control

- medium control with complete inhibition

IC ₅₀ is calculated using a 4-parameter fit in XLfit software and the results are shown in Table A2.

Example A4

Proliferation assay

The compounds of Examples 13, Examples 14 and Examples 126 were evaluated in a proliferation assay in two BRAF class III mutant cell lines: NCI-H1666 cells (BRAFG4 66V) and WM3629 cells (BRAF594G/NRASG12D). NCI-H1666 cells were obtained from the American Type Culture Collection (ATCC, Rockville, MD), and WM3 62 9 cells were obtained from Rockland Immunochemicals (Limerick, PA). Cells are maintained in RPMI growth medium containing 10% FBS.

Cells were harvested according to standard protocols, counted, and seeded into flat-bottomed 96-well tissue culture plates (Costar #3599) at 2000-5000 cells/well in 100 μl/well growth medium containing 10% FBS. Cells are incubated at 37°C with 5% CO ₂ overnight, then treated with inhibitors prepared as a series of 9-point 1:3.33-fold dilutions with final compound concentrations of 66 pM-10 μM and a constant DMSO concentration of 0.25 %. Control wells contain either 0.25% DMSO only. After 3-5 days of incubation at 37°C, 5% CO _{2 ,} cell viability is determined by adding 100 μl of CellTiter-Glo® reagent (Promega) to each well and incubating for 15 minutes at room temperature. Day 0 controls are determined by running the CellTiter-Glo® assay on DMSO control wells during compound treatment (Day 0 Control=0 POC). Luminescence is measured on a Cytation 5 plate reader (BioTek) and values are converted to POC using the following equation:

Where

- medium DMSO control

- average DMSO control on “day 0”

IC ₅₀ is calculated using a 4-parameter fit in XLfit software and the values are shown in Table A2.

Example B

MDR1 LLC-PK1 and BCRP MDCKII Permeability Assay ^MDR1 -transfected LLC-PK1 and LLC-PK1 cells were cultured and plated according to the manufacturer's recommendations, except that passage medium contained only 2% fetal bovine serum to increase time passage up to seven days.

BCRP-transfected MDCKII cells were cultured and plated according to the manufacturer's recommendations. Assay conditions include the presence and absence of the BCRP-specific inhibitor KO143 at a concentration of 0.3 μM to determine the contribution of BCRP to the efflux value of the test compound.

To assess the functionality of P_gp or BCRP efflux, both positive and negative controls are used in the assays. Stock solutions for control and test sample analysis are prepared in DMSO for final test concentrations of 10 and 1 μM, respectively. The final concentration of organic matter in the analysis is 1%. All dosing solutions contain 10 μM Lucifer yellow to monitor monolayer integrity of LLC PK1 or MDCKII cells.

For apical-basolateral determination (A-B), 75 μl of test sample in transport buffer is added to the apical side of individual transwells, and 250 μl of basolateral medium without compound or Lucifer yellow is added to each well. For basolateral and apical determination (BA), add 250 µl of test sample in transport buffer to each well, and add 7 5 µl of transport buffer without compound or Lucifer yellow to each transwell. All tests were performed in triplicate, and each compound was tested for both apical-basolateral and basolateral-apical transport. The plates are incubated for 2 hours on a Lab-Line Instruments Titer orbital shaker (VWR, West Chester, PA) at 50 rpm and 37°C with 5% CO ₂ . All culture plates are removed from the incubator, and 50 μl of medium is removed from the apical and basolateral portions of each well and added to 150 μl of 1 μM labetalol in 2:1 acetonitrile (acetonitrile): H ₂ O, v/v.

The plates are read using a Gemini fluorometer from Molecular Devices (Sunnyvale, CA) to estimate the concentration of Lucifer yellow at wavelengths

excitation/emission 425/535 nm. These values are accepted when found to be less than 2% for apical-basolateral and 5% basolateral-apical flux through MDR1-transfected LLC-PK1 or BCRP-transfected MDCKII cell monolayers. The plates are sealed and the contents of each well are analyzed by LC-MS/MS. Compound concentrations are determined by the ratio of the peak areas of the compound to the internal standard (labetalol) compared to the dosing solution.

LC-MS analysis

The LC-MS/MS system consists of an HTS-PAL autosampler (Leap Technologies, Carrboro, NC), an HP1200 HPLC (Agilent, Palo Alto, CA), and an MDSSciex 4000 Q Trap system (Applied Biosystems, Foster City, CA). Chromatographic separation of analyte and internal standard is performed at room temperature using a C18 column (Kinetics®, 50 x 300 mm, 2.6 μm particle size, Phenomenex, Torrance, CA) combined with gradient conditions using mobile phases A (water, containing 1% isopropyl alcohol and 0.1% formic acid) and B (0.1% formic acid in acetonitrile). The total operating time, including re-equilibration, for one injection is 1.2 minutes. Mass spectrometric determination of analytes is carried out using positive ion sputtering mode. Analyte responses are measured by monitoring multiple reaction reactions (MRM) transitions unique to each compound (protonated precursor ion and selected product ions for each sample tested and m/z 329 - m/z 162 for labetalol, the internal standard).

The permeability coefficient (Papp) is calculated using the following equation:

P _app =[((C _d *V* (1×10 ⁶ ))/(t*0.12cm ² *C)]

where C _d , V , t and C ₀ represent the detectable concentration (µM), dosing side volume (ml), incubation time (s) and initial dosing concentration (µM), respectively. Calculations of P _arr are made for each repetition and then averaged. Permeability coefficients for compounds of formula I are given in Table B1. In this analysis, a connection is considered to have high permeability if the permeability exceeds 8×10 ^-6 cm/sec, a connection is considered to have medium permeability if the permeability is between 2×10 ^-6 cm/sec and 8×10 ^-6 cm/sec, and the connection is considered to have low permeability if the permeability is less than 2×10 ^-6 cm/sec.

The efflux coefficient is calculated based on the average of the apical-basolateral (A-B) P _arr and the basolateral-apical (BA) P _ap data using the following equation:

Efflux coefficient = P _arr (B-A) / P _arr (A-B)

The efflux coefficients for the compounds described herein when tested in this assay are presented in Table B2.

Example C

RK (free brain to free plasma ratio) (mouse) The ability of typical compounds to penetrate the BBB in mice is determined by assessing the ratio of unbound brain to unbound plasma concentrations (also called free brain and free plasma) in male CD-1 mice.

Levels of compounds in the brain were obtained by oral administration of PK to mice with typical sampling times of 2, 4, 8, 12 and 24 hours after oral gavage at a dose of 10 mg/kg. Brain samples were stored at -20±5°C before analysis. Concentrations of the test compound in mouse brain homogenate were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after protein precipitation with acetonitrile. A 12-point calibration curve ranging from 0.5 to 10,000 ng/mL was prepared in duplicate. A 400 μg/ml solution of test compound in dimethyl sulfoxide (DMSO) is serially diluted (3-fold) in 100% DMSO, and then 2.5 μl of each standard solution is added to 100 μl of male naïve CD-I mouse brain homogenate. To simulate extraction on a standard curve, 2.5 μl of DMSO was added to all test samples. Add 10 μl of IS (1 μg/ml structural analogue) to calibration and test brain homogenate samples. Brain homogenate is prepared by adding 0.75 ml of 4:1 water:MeOH to each brain sample followed by homogenization for 1 minute using ball mill tubes at 6 m/s using MP Fast Preg-24®. Proteins are precipitated from a 100 μl brain homogenate sample by adding 300 μl acetonitrile. Samples were vortexed for 5 minutes and centrifuged in an Allegra X-12R centrifuge (Beckman Coulter, Fullerton, CA; SX4750A rotor) for 15 minutes at approximately 1500 xg at 4°C. A 100-μL aliquot of each supernatant was transferred using a 550-μL personal pipettor (Apricot Designs, Monrovia, CA) into 96-well plates and diluted 1:1 with HPLC-grade water. The resulting plates were sealed with aluminum for LC-MS/MS analysis.

Brain-plasma ratios are calculated using the concentration of the compound measured in the brain divided by the concentration of the compound measured in the plasma. Brain-to-plasma ratios are always obtained from a single animal and at a single time point. Free brain to free plasma ratios are calculated by multiplying the brain to plasma ratio by the in vitro brain homogenate free fraction divided by the in vitro free plasma fraction using the following equation: (B/P)*(Bfu/Pfu). Table C presents the ratios of free brain to free plasma of the compounds described herein.

Synthesis examples

Preparation of synthetic intermediates

Intermediate connection P1

6-bromo-5-methylquinazolin-4(3H)-one

6-Amino-3-bromo-2-methylbenzoic acid (10 g, 43 mmol) and formamidine acetate (5.4 g, 52 mmol) were dissolved in ethanol (172 ml) in a 500 ml reflux flask. The reaction mixture is heated to 80°C for 16 hours. The mixture is cooled to ambient temperature and concentrated in vacuo. The residue is diluted with water (300 ml) and stirred vigorously for 60 minutes. The resulting solid was isolated by filtration and the filter cake was washed with water (500 ml). The solid was dried under vacuum to give 6-bromo-5-methylquinazolin-4(3H)-one (6.9 g, 66%) as a white solid. MS (chiad, m/z)=239.0, 241.0 (M+H).

Intermediate connection P2

6-bromo-3,5-dimethylquinazolin-4(3H)-one

6-Bromo-5-methylquinazolin-4(3H)-one (Intermediate P1) (11 g, 4 6.0 mmol), potassium carbonate (14.0 g, 101 mmol) and iodomethane (13.1 g, 92 .0 mmol) dissolved in anhydrous DMF (250 ml). The reaction mixture is stirred at ambient temperature for 2 hours. The entire reaction mixture is poured directly into 900 ml of water and the resulting suspension is stirred at ambient temperature for 30 minutes. The solid was collected by filtration and dried overnight under high vacuum to give 6-bromo-3,5-dimethylquinazolin-4(3H)-one (10.1 g, 87%) as a white solid. MS (chiad, m/z)=253.0, 255.0 (M+H).

Intermediate P3

6-Amino-3,5-dimethylquinazolin-4(3H)-one

Step 1: Preparation of 6-((4-methoxybenzyl) amino)-3,5-dimethylquinazolin-4(3H)-one. Solution of (4-methoxyphenyl)methanamine (1.20 ml, 9.18 mmol), 6-bromo-3,5-dimethylquinazolin-4(3H)-one (Intermediate P2) (2.02 g, 7.98 mmol ), Pd ₂ (dba) ₃ (0.365 g, 0.399 mmol), Xantphos (0.693 g, 1.20 mmol) and Cs ₂ CO ₃ (7.80 g, 23.9 mmol) in toluene (53.2 ml) placed in a test tube under pressure and purged with argon for 10 minutes. The reaction vessel is sealed and heated to 90°C for 60 hours. Additional Pd ₂ (dba) ₃ (0.365 g, 0.399 mmol) and Xantphos (0.693 g, 1.20 mmol) are added and the solution is again purged with argon for 10 minutes, sealed and heated to 90°C for another 16 hours. The reaction mixture is cooled to ambient temperature, filtered, concentrated and purified by column chromatography, eluting with 5-95% EtOAc/DCM to give 6-((4-methoxybenzyl)amino)-3,5-dimethylquinazolin-4(3H)-one ( 2.4 g, 97%). MS (chiad, m/z)=310.2 (M+H).

Step 2: Preparation of 6-amino-3,5-dimethylquinazolin-4(3H)-one. A solution of 6((4-methoxybenzyl)amino)-3,5-dimethylquinazolin-4(3H)-one (2.4 g, 7.7 6 mmol) was stirred in 5 0 ml DCM and 2 5 ml TFA for 2 hours . The solution is concentrated and the residue is dissolved in 100 ml DCM, 10 ml MeOH and stirred vigorously with 4 g K ₂ CO ₃ for 30 minutes. K ₂ CO ₃ is removed by filtration and the filtrate is concentrated and the residue is purified by column chromatography, eluting 1-10 % MeOH/DCM (1% NH ₄ OH) to give 6-amino-3,5-dimethylquinazolin-4(3H)-one (1.45 g, 99%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.2 (s, 1H), 7.5 (d, 1H), 7.1 (d, 1H), 4.2 (shs, 2H), 3.6 (s, 3H), 2.8 (s, 3H); MS (chiad, m/z)=190.1 (M+H).

Intermediate P4

6-Amino-5-fluoro-3-methylquinazolin-4(3H)-one

Step 1: Preparation of 6-bromo-5-fluoroquinazolin-4(3H)-one. 6-Amino-3-bromo-2-fluorobenzoic acid (4.51 g, 19.3 mmol) was dissolved in EtOH (2 00 ml) and then treated with formamidine acetate (6.02 g, 57.8 mmol) and then heated up to 80°C for 16 hours. The reaction mixture was treated with additional formamidine acetate (3.01 g, 28.9 mmol) and stirred at 80°C for an additional 4 hours. The reaction mixture was cooled to ambient temperature and poured into water and then extracted with EtOAc (3x). The combined organic layers were washed with brine (1x) and then dried over Na ₂ SO ₄ , filtered and concentrated to give 6-bromo-5-fluoroquinazolin-4(3H)-one (4.28 g, 91%). MS (chiad, m/z)=243.0, 245.0 (M+H).

Step 2: Preparation of 6-bromo-5-fluoro-3-methylquinazolin-4(3H)-one. 6-Bromo-5-fluoroquinazolin-4(3H)-one (4.28 g, 17.6 mmol) was dissolved in DMF (70 ml) and then treated with iodomethane (1.32 ml, 21.1 mmol), then carbonate potassium (3.65 g, 2-6.4 mmol) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into water and extracted with EtOAc (3x). The combined organic layers were washed with water (3x) then brine (1x), then dried over Na ₂ SO ₄ , filtered, and concentrated. The resulting residue was purified by silica gel chromatography (DCM/EtOAc) to give 6-bromo-5-fluoro- 3-methylquinazolin-4(3H)-one (3.33 g, 74%). MS (chiad, m/z)=257.0, 259.0 (M+H).

Step 3: Preparation of 6-amino-5-fluoro-3-methylquinazolin-4(3H)-one. 6-Bromo-5-fluoro-3-methylquinazolin-4(3H)-one (3.18 g, 12.37 mmol) was dissolved in toluene (125 ml) and treated with tert-butyl carbamate (1.59410 g, 13. 61 mmol),

tris(dibenzylideneacetone)dipalladium (1.13 g, 1.24 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.79 g, 3.09 mmol) and cesium carbonate (12.09 g , 37.11 mmol) and then purged with argon for several minutes and heated to 110°C under an argon balloon for 16 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (1 L) and stirred for 15 minutes, filtered through a pad of Celite® and concentrated. The resulting residue is dissolved in 1:1 DCM:TFA (20 ml) and stirred at ambient temperature for 1 hour. The reaction mixture is concentrated and then purified by C18 reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated NaHCO ₃ (1x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give 6-amino-5-fluoro-3-methylquinazolin-4(3H)-one (1.57 g, 65.7%). ¹ H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 7.27-7.22 (m, 2H), 5.51 (brs, 2H), 3.40 (s, 3H); MS (chiad, m/z)=194.1 (M+H).

Intermediate P5

6-Amino-5-chloro-3-methylquinazolin-4(3H)-one

6-Amino-3-methylquinazolin-4(3H)-one (3.00 g, 17.1 mmol) was dissolved in THF (170 ml) and then treated with N-chlorosuccinimide (2.40 g, 18.0 mmol) and heated to 50°C for 16 hours. The reaction mixture was treated with additional N-chlorosuccinimide (1.14 g, 8.56 mmol) and stirred at 50°C for an additional 3 hours. The reaction mixture was concentrated and the resulting residue was diluted with 1.0 M HCl and extracted with DCM (3x). The combined DCM combined organic layers were washed with 1.0 M HCl (2x) and the aqueous layer was neutralized with solid NaHCO ₃ to approximately pH 7-8, and then extracted with 4:1 DCM:IPA (2x). The combine DCM:IPA extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give 6-amino-5-chloro-3-methylquinazolin-4(3H)-one (2.47 g, 69%). ^1H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.38-7.36 (d, 2H), 7.29-7.26 (d, 2H), 5.81 (shs , 2H), 3.40 (s, 3H). MS (chiad, m/z)=210.l, 212.1 (M+H).

Intermediate P6

6-Amino-5-bromo-3-methyl-4a,8a-dihydroquinazolin-4(3H)-one

6-Amino-3-methylquinazolin-4(3H)-one (2.00 g, 11.3 mmol) was dissolved in THF (56 ml) and then treated with N-bromosuccinimide (2.11 g, 11.9 mmol) and the mixture is heated to 50°C for 60 minutes. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate (100 ml) and washed with sodium thiosulfate (saturated aqueous solution, 100 ml, 1x), then sodium bicarbonate (saturated aqueous solution, 100 ml, 1x). The combined organic layers are dried over MgSO ₄ , filtered and concentrated. The residue was purified by C18 reverse phase chromatography on silica gel, eluting with water/acetonitrile to give 6-amino-5-bromo-3-methyl-4a,8a-dihydroquinazolin-4(3H)-one (1.01 g, 35%). MS (chiad, m/z)=254.0, 256.0 (M+H).

Intermediate connection P7

Tert-butyl (3-amino-2-chloro-4-fluorophenyl)carbamate

Step 1: Preparation of methyl 3-((tert-butoxycarbonyl)amino)-2-chloro-6-fluorobenzoate. Methyl 3-amino-2-chloro-6-fluorobenzoate (5.06 g, 24.9 mmol) was dissolved in DCM (250 ml) and cooled to 0°C. The reaction mixture was treated sequentially with triethylamine (10.4 ml, 74.6 mmol), 4-(dimethylamino)pyridine (0.304 g, 2.49 mmol) and di-tert-butyl dicarbonate (13.6 g, 62.1 mmol) and stir at ambient temperature for 16 hours. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel, eluting with hexane/acetone to give methyl 3-((tert-butoxycarbonyl)amino)-2-chloro-6-fluorobenzoate (7.55 g, 100%) which was used immediately next stage in the form of a mixture of mono/bis-Boc products.

Step 2: Preparation of 3-((tert-butoxycarbonyl)amino)-2-chloro-6-fluorobenzoic acid. Methyl 3-((tert-butoxycarbonyl)amino)-2-chloro-6-fluorobenzoate (7.55 g, 24.9 mmol) was dissolved in 1:1 THF/MeOH (120 ml) and then treated with 2.0 M aqueous NaOH (37.3 mL, 74.6 mmol) and stir at ambient temperature for 16 hours. The reaction mixture is diluted with additional water and extracted with Et20 (2×250 ml). Et ₂ O combined organic layers are combined and washed with 1.0 M NaOH (1×50 ml). The combined aqueous layers were acidified to approximately pH 4 using 4.0 M HCl, and then extracted with 4:1 DCM/IPA (2×250 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated to give 3-((tert-butoxycarbonyl)amino)-2-chloro-6-fluorobenzoic acid (5.53 g, 77%) which was used immediately in the next step. without cleaning.

Step 3: Preparation of tert-butyl (3-amino-2-chloro-4-fluorophenyl)carbamate.

3-(T-Butoxycarbonyl)amino)-2-chloro-6-fluorobenzoic acid (5.53 g, 19.1 mmol) was dissolved in DMF (100 ml) and treated sequentially with triethylamine (7.98 ml, 57.27 mmol ) and diphenylphosphoryl azide (6.17 ml, 28.63 mmol) and stir at ambient temperature for 1 hour. The reaction mixture is treated with water (20 ml) and heated to 80°C for 16 hours. The reaction mixture is cooled to ambient temperature and diluted with additional water (50 ml) and then extracted with EtOAc (2×250 ml). The organic extracts are combined and washed with water (3×100 ml) and brine (1×50 ml) then dried over Na ₂ SO ₄ , filtered, and concentrated. The residue is purified by chromatography on silica gel, eluting with hexane/acetone and then again with hexane/MTBE to give tert-butyl (3-amino-2-chloro-4-fluorophenyl)carbamate (1.05 g, 21%). ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.41 (s, 1H), 6.99-6.94 (m, 1H), 6.69-6.66 (m, 1H), 5, 34 (s, 2H), 1.43 (s, 9H).

Intermediate connection P8

6-((3-Amino-2-chloro-6-fluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one

Step 1: Preparation of tert-butyl (2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)carbamate.

Tert-butyl (3-amino-2-chloro-4-fluorophenyl)carbamate (56.7 mg, 0.217 mmol), 6-bromo-3,5-dimethylquinazolin-4(3H)-one (50 mg, 0.198 mmol) , cesium carbonate (193 mg, 0.593 mmol), Xantphos (17.1 mg, 0.0296 mmol) and tris(dibenzylideneacetone)dipalladium (0) (9.05 mg, 0.0099) are combined in a test tube, then degassed under reduced pressure and back filled with argon gas. Toluene (0.98 8 ml) is added and the solution is purged with argon for 5 minutes, then the tube is sealed and heated to 100°C for 16 hours. The reaction mixture is cooled to ambient temperature and filtered through a pad of Celite® and purified by chromatography on silica gel eluting with DCM/EtOAc to give tert-butyl (2-chloro-3-((3,5-dimethyl-4-oxo-3,4 -dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-carbamate as an off-white solid (81 mg, 95%). MS (chiad, m/z)=333.1 (M-Boc).

Step 2: Preparation of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one.

Tert-butyl (2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)carbamate (81 mg, 0.187 mmol) dissolved in DCM (4.7 ml) and treated with trifluoroacetic acid (1.5 ml), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with DCM/MeOH and 1% NH ₄ OH to give 6-((3-amino-2-chloro-6-fluorophenyl)amino)-3,5-dimethylquinazoline-4( 3H)-one as a light yellow solid (37 mg, 56%). ^1H NMR (400 MHz, _CDCl3 ) δ 7.99 (s, 1H), 7.38 (d, 1H), 7.02 (d, 1H), 6.86 (dd, 1H), 6.51 (dd, 1H), 3.50 (s, 3H), 2.90 (s, 3H); MS (chiad, m/z)=333.1 (M+H).

Intermediate connection P9

Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate

Step 1: Preparation of 2-chloro-4-fluoro-3-iodoaniline.

In a 5 L 4-neck flask equipped with 3 dropping funnels, an internal temperature probe and a magnetic stirrer, 2-chloro-4-fluoroaniline (82.03 mL, 687.0 mmol) was dissolved in THF (1.5 L) under reflux N ₂ and cooled to -78°C. The reaction mixture was treated dropwise with butyllithium (2.5 M in hexane) (299.5 ml, 748.8 mmol) and left stirring at -78°C for 15 minutes after addition was complete. The reaction mixture was treated dropwise with a THF solution (500 ml) of 1,2-bis(chlorodimethylsilyl)ethane (155.3 g, 721.4 mmol) and left stirring at -78° C. for 30 minutes after addition was complete. The reaction mixture was treated dropwise with additional butyllithium (2.5 M in hexane) (299.5 mL, 748.8 mmol) and then the ice bath was removed after addition was complete and the reaction mixture was stirred for 1 hour. The reaction mixture was cooled back to -78°C and treated dropwise with additional butyllithium (2.5 M in hexane) (299.5 ml, 748.8 mmol) and stirred at -78°C for 30 minutes after addition was complete. The reaction mixture was treated dropwise with a THF solution (600 ml) of iodine (249.3 g, 982.4 mmol) and the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture is treated with 1000 ml water, then hydrochloric acid (4.0 M aqueous solution) (601.1 ml, 2404.5 mmol) and stirred at ambient temperature for 1 hour. The reaction mixture is neutralized to approximately pH 8 using solid NaHCO ₃ and then treated with sodium thiosulfate (3.0 M aqueous solution) (801.5 ml, 2404.5 mmol) and stirred at ambient temperature for 30 minutes. The reaction mixture is transferred to an extraction funnel, rinsing the flask with MTBE and water, and then the layers are separated. The organic layer was washed with brine (1x) and dried over Na ₂ SO ₄ , filtered, and concentrated to give 2-chloro-4-fluoro-3-iodoaniline (186.49 g, 100%). ^1H NMR (400 MHz, DMSO) δ 6.97-6.93 (m, 1H), 6.81-6.77 (m, 1H), 5.41 (brs, 2H).

Step 2: Preparation of bis-tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate.

In a 3 L 1 neck flask, 2-chloro-4-fluoro-3-iodoaniline (186.49 g, 686.99 mmol) was dissolved in THF (2.0 L) and treated with 4-(dimethylamino)pyridine (8. 39 g, 68.7 mmol), then add di-tert-butyl dicarbonate (314.87 g, 1442.7 mmol) and then stir at ambient temperature for 1 hour in open air with a Vigreux column. The reaction mixture is concentrated to dryness. The resulting residue was dissolved in DCM (1 L) and diluted with hexane (1 L) and stirred for 15 minutes, then passed through a thin layer of silica, eluting with additional 1:1 DCM:Hexane (2.5 L). The filtrate is concentrated to dryness and the resulting solid is suspended in heptane (500 ml) and stirred at 80°C for 30 minutes. The mixture was cooled to 0°C in an ice bath and filtered, washed with additional cooled (0°C) heptane (500 ml), and the light tan solid was collected to give bis-tert-butyl (2-chloro-4-fluoro -3-iodophenyl)carbamate (145.5 g, 45%). ^1H NMR (400 MHz, DMSO) δ 7.55-7.51 (m, 1H), 7.32-7.28 (m, 1H), 1.33 (s, 18H).

Step 3: Preparation of tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate.

Bis-tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (331.7 g, 703.2 mmol) was dissolved in MeOH (1.8 L) and treated with potassium carbonate (106.9 g, 773 .5 mmol), then heated to 65°C for 1 hour. The reaction mixture is cooled to ambient temperature and poured into 6.0 L of water and stirred for 30 minutes. The mixture was filtered, washed with additional water (1000 ml), and the light tan solid was collected to give tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (258.0 g, 99%). ^1H NMR (400 MHz, DMSO) δ 8.82 (s, 1H), 7.53-7.50 (m, 1H), 7.24-7.20 (m, 1H), 1.42 (s , 9H).

Intermediate connection P10

Tert-butyl (2-chloro-4,5-difluoro-3-iodophenyl)carbamate

Step 1: Preparation of 2-chloro-4,5-difluoro-3-iodoaniline. A solution of 2-chloro-4,5-difluoroaniline (26.0 g, 158.97 mmol) was dissolved in THF (1.0 L) under reflux of N ₂ and cooled to -78°C. The reaction mixture was treated dropwise with butyllithium (2.5 M in hexane) (66.768 ml, 166.92 mmol) and left stirring at -78°C for 15 minutes after addition was complete. The reaction mixture was treated dropwise with a THF solution (250 ml) of 1,2-bis(chlorodimethylsilyl)ethane (35.932 g, 166.92 mmol) and left stirring at -78°C for 30 minutes after addition was complete. The reaction mixture was treated dropwise with additional butyllithium (2.5 M in hexane) (66.768 mL, 166.92 mmol). The ice bath is removed after addition is complete and the reaction mixture is left stirring for 1 hour. The reaction mixture was cooled back to -78°C and treated dropwise with additional butyllithium (2.5 M in hexane) (66.768 ml, 166.92 mmol) and left to stir at -78°C for 30 minutes after addition was complete. The reaction mixture is treated dropwise with a THF solution (600 ml) of iodine (60.522 g, 238.46 mmol). The ice bath is removed and the reaction mixture is allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture is treated with 500 ml water, then hydrochloric acid (4.0 M aqueous solution) (139.10 ml, 556.40 mmol) and stirred at ambient temperature for 1 hour. The reaction mixture was neutralized to approximately pH 8 with solid NaHCO ₃ and then treated with sodium thiosulfate (3.0 M aqueous solution) (185.47 ml, 556.40 mmol) and stirred at ambient temperature for 30 minutes. The layers are separated and the aqueous layer is extracted with MTBE (1×1000 ml). The combined organic layers were washed with brine (1×500 mL) then dried over Na ₂ SO ₄ , filtered, and concentrated to give 2-chloro-4,5-difluoro-3-iodoaniline (46.0 g, 100%). ^1H NMR (400 MHz, DMSO) δ 6.82-6.77 (m, 1H), 5.68 (brs, 2H).

Step 2: Preparation of bis-tert-butyl (2-chloro-4,5-difluoro-3-iodophenyl)carbamate.

2-Chloro-4,5-difluoro-3-iodoaniline (46.0 g, 159 mmol) was dissolved in THF (1000 ml) and treated with 4-(dimethylamino)pyridine (1.94 g, 15.9 mmol), then di-tert-butyl dicarbonate (72.8 g, 334 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated to dryness and the resulting residue was dissolved in 1:1 DCM:hexane (500 ml) and stirred for 15 minutes. The mixture is passed through a pad of silica gel, eluting with additional 1:1 DCM:Hexane (1.5 L). The filtrate was concentrated to dryness to give bis-tert-butyl (2-chloro-4,5-difluoro-3-iodophenyl)carbamate (77.8 g, 100% yield). ^1H NMR (400 MHz, DMSO) δ 7.95-7.90 (m, 1H), 1.33 (s, 18H).

Step 3: Preparation of tert-butyl (2-chloro-4,5-difluoro-3-iodophenyl)carbamate.

Bis-tert-butyl (2-chloro-4,5-difluoro-3-iodophenyl)carbamate (77.8 g, 159 mmol) was dissolved in MeOH (650 ml) and treated with potassium carbonate (24.2 g, 175 mmol) , and the reaction mixture is heated to 65°C for 1.5 hours. The reaction mixture is cooled to ambient temperature, then poured into water (2 L) and stirred for 15 minutes. The reaction mixture is filtered, washed with additional water, and the resulting brown solid is collected. The solid is dried under high vacuum for 16 hours and then suspended in heptane (250 ml) and stirred for 15 minutes. The suspension is filtered and the solid is washed with additional heptane to give tert-butyl (2-chloro-4,5-difluoro-3-iodophenyl)carbamate (34.9 g, 56.4%). ^1H NMR (400 MHz, DMSO) δ 8.94 (brs, 1H), 7.76-7.71 (m, 1H), 1.43 (s, 9H).

Intermediate connection P11

Tert-butyl (3-bromo-2,4,5-trifluorophenyl)carbamate

Step A: Preparation of bis-tert-butyl (2-chloro-4,5-difluoro-3-iodophenyl)carbamate.

To a solution of 3-bromo-2,4,5-trifluoroaniline (3.0 g, 13 mmol) in THF (88 ml, 13 mmol) add DMAP (0.16 g, 1.3 mmol) and di-tert-butyl dicarbonate (6.7 g, 31 mmol) and the solution was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel chromatography (50% DCM/hexane) to give bis-tert-butyl (2-chloro-4,5-difluoro-3-iodophenyl)carbamate, which was used directly in the next step.

Step B: Preparation of tert-butyl (3-bromo-2,4,5-trifluorophenyl)carbamate.

To a solution of bis-tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (5.7 g, 13 mmol) in methanol (67 ml) add potassium carbonate (2.03 g, 14.7 mmol) , and the reaction mixture is heated to 65°C for 3 hours. The solution is cooled to room temperature and concentrated. The resulting solid was diluted with water, stirred for 15 minutes, and then filtered, washed with water, and dried overnight to give tert-butyl (3-bromo-2,4,5-trifluorophenyl)carbamate (4.15 g, 95 %). ¹ H NMR (400 MHz, DMSO) δ 9.4 (brs, 1H), 7.82 (m, 1H), 1.46, (s, 9H).

Intermediate connection P12

Tert-butyl (3-bromo-5-chloro-2-fluorophenyl)carbamate

3-Bromo-5-chloro-2-fluoroaniline (2.43 g, 10.8 mmol) was dissolved in THF (110 ml) and treated with 4-(dimethylamino)pyridine (0.132 g, 1.08 mmol), then di- tert-butyl dicarbonate (4.96 g, 22.7 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated to dryness and the resulting residue was dissolved in MeOH (100 ml) and treated with potassium carbonate (2.99 g, 21.7 mmol) and heated at 70°C for 30 minutes. The reaction mixture is cooled to ambient temperature and concentrated. The residue was dissolved in DCM and washed with water (1x), then dried over Na ₂ SO ₄ , filtered, and concentrated. The resulting residue was purified by silica gel chromatography (Hexane/EtOAc) to give tert-butyl (3-bromo-5-chloro-2 -fluorophenyl)carbamate (2.92 g, 83%). ¹ H NMR (400 MHz, DMSO) δ 9.45 (brs, 1H), 7.81-7.79 (m, 1H), 7.54-7.52 (m, 1H), 1.47 (s , 9H).

Intermediate connection P13

6-((3-Amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one

6-Amino-5-fluoro-3-methylquinazolin-4(3H)-one (Intermediate P4; 1.50 g, 7.76 mmol) was dissolved in toluene (78 ml) and treated with tert-butyl (2-chloro- 4-fluoro-3-iodophenyl)carbamate (Intermediate P9; 3.02 g, 8.15 mmol), tris(dibenzylideneacetone) dippalladium (0) (0.36 g, 0.39 mmol), Xantphos (0.67 g, 1.16 mmol) and cesium carbonate (5.06 g, 15.53 mmol). The reaction mixture is purged with argon for several minutes and then heated at 110°C for 24 hours under an argon cylinder. The reaction mixture is cooled to ambient temperature and diluted with DCM (1 L) and stirred for 15 minutes, then filtered through a pad of Celite® and concentrated. The resulting residue is dissolved in 1:1 DCM:TFA (20 ml) and stirred at ambient temperature for 1 hour. The reaction mixture is concentrated and purified by C18 reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated NaHCO ₃ (1x) and then dried over Na ₂ SO ₄ , filtered, and concentrated to give 6-((3-amino-2-chloro-6-fluorophenyl) amino)-5-fluoro-3-methylquinazolin-4(3H)-one (1.26 g, 48%). ^1H NMR (400 MHz, DMSO) δ 8.14 (s, 1H), 7.78 (s, 1H), 7.31-7.29 (d, 1H), 7.05-7.00 (t , 1H), 6.94-6.89 (t, 1H), 6.70-6.67 (m, 1H), 5.28 (shs, 2H), 3.43 (s, 3H). MS (chiad, m/z)=337.1, 339.1 (M+H).

Intermediate connection P14

6-((3-Amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one

6-Amino-5-chloro-3-methylquinazolin-4(3H)-one (2.35 g, 11.2101 mmol) was dissolved in toluene (110 ml) and treated with tert-butyl (2-chloro-4-fluoro- 3-iodophenyl)carbamate (4.37 g, 11.77 mmol), tris(dibenzylideneacetone) dippalladium (0) (0.51 g, 0.56 mmol), Xantphos (0.97 g, 1.68 mmol), and cesium carbonate (7.30 g, 22.42 mmol). The reaction mixture is purged with argon for several minutes and then heated, stirred at 110°C under an argon cylinder for 60 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (1 L) and stirred for 15 minutes, then filtered through a pad of Celite® and concentrated. The resulting residue is purified by chromatography on silica gel (DCM/Acetone). The isolated product is dissolved in 1:1 DCM:TFA (20 ml) and stirred at ambient temperature for 1 hour. The reaction mixture is concentrated and then purified by C18 reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated NaHCO ₃ (1x) and then dried over Na ₂ SO ₄ , filtered, and concentrated to give 6-((3-amino-2-chloro-6-fluorophenyl) amino)-5-chloro-3-methylquinazolin-4(3H)-one (2.67 g, 67%). ^1H NMR (400 MHz, DMSO) δ 8.16 (s, 1H), 7.47 (s, 1H), 7.41-7.39 (d, 1H), 7.08-7.03 (t , 1H), 6.76-6.72 (m, 2H), 5.31 (s, 2H), 3.41 (s, 3H). MS (chiad, m/z)=353.0, 355.0 (M+H).

Intermediate connection P15

6-((3-Amino-2-chloro-6-fluorophenyl)amino)-5-bromo-3-methylquinazolin-4(3H)-one

6-Amino-5-bromo-3-methylquinazolin-4(3H)-one (800 mg, 3.15 mmol) was dissolved in toluene (32 ml) and treated with tert-butyl (2-chloro-4-fluoro-3- iodophenyl)carbamate (1.23 g, 3.31 mmol), tris(dibenzylideneacetone) dippalladium (0) (144 mg, 0.16 mmol), Xantphos (273 mg, 0.47 mmol) and cesium carbonate (2.05 g, 6.30 mmol). The reaction mixture is purged with argon for several minutes and then heated and stirred at 110°C under an argon balloon for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (100 ml) and stirred for 15 minutes, then filtered through a pad of Celite® and concentrated. The resulting residue is purified by reverse phase chromatography (5-95% ACN/water, 0.1% TFA). The isolated product is dissolved in DCM and washed with saturated aqueous NaHCO ₃ . The combined organic layers are washed with brine, dried with MgSO ₄ , filtered, and concentrated. The resulting residue is dissolved in 1:1 DCM:TFA (20 ml) and stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and washed with saturated aqueous NaHCO ₃ to give 6-((3-Amino-2-chloro-6-fluorophenyl)amino)-5-bromo-3-methylquinazolin-4(3H)-one (1.2 g, 96%). MS (chiad, m/z)=397.0, 399.0 (M+H).

Intermediate connection P16

6-((3-Amino-2-chloro-5,6-difluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one

6-Amino-5-chloro-3-methylquinazolin-4(3H)-one (1.00 g, 4.77 mmol) was dissolved in toluene (48 ml) and treated with tert-butyl (2-chloro-4,5- difluoro-3-iodophenyl)carbamate (1.95 g, 5.01 mmol), tris(dibenzylideneacetone) dippalladium (0) (218 mg, 0.24 mmol), Xantphos (414 mg, 0.72 mmol) and cesium carbonate (3.89 g, 11.9 mmol). The reaction mixture is purged with argon for several minutes and stirred at 110°C under an argon cylinder for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (100 ml) and stirred for 15 minutes, then filtered through a pad of Celite® and concentrated. The resulting residue is purified by reverse phase chromatography (5-95% ACN/water, 0.1% TFA). The isolated product is dissolved in DCM and washed with saturated aqueous NaHCO ₃ . The combined organic layers are washed with brine, dried with MgSO ₄ , filtered, and concentrated. The resulting residue is dissolved in 1:1 DCM:TFA (35 ml) and stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated, dissolved in DCM (75 ml) and washed with saturated aqueous NaHCO ₃ . The organic residue in DCM is concentrated and purified by silica gel chromatography (55-90% EtOAc/Hexane) to give 6-((3-Amino-2-chloro-5,6-difluorophenyl)amino)-5-chloro-3- methylquinazolin-4(3H)-one (390 mg, 22%). MS (chiad, m/z)=371.0, 373.1 (M+H).

Intermediate connection P17

6-((3-Amino-2-chloro-5,6-difluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one

6-Amino-3,5-dimethylquinazolin-4(3H)-one (2.0 g, 11.0 mmol) was dissolved in toluene (106 ml) and treated with tert-butyl (2-chloro-4,5-difluoro- 3-iodophenyl)carbamate (4.9 g, 13.0 mmol), tris(dibenzylideneacetone) dippalladium (0) (0.97 g, 1.1 mmol), Xantphos (1.5 g, 2.6 mmol) and cesium carbonate (6.9 g, 21.0 mmol). The reaction mixture is purged with argon for several minutes and then stirred at 110°C under an argon balloon for 72 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (500 ml) and stirred for 15 minutes, then filtered through a pad of Celite® and concentrated. The resulting residue is purified by chromatography on silica gel (DCM-EtOAc). The resulting residue was dissolved in 1:1 DCM:TFA (22 ml) and stirred at ambient temperature for 1 hour. The reaction mixture is concentrated and treated with 500 ml NaHCO ₃ and stirred for 30 minutes at ambient temperature. The mixture is extracted with 4:1 DCM:IPA. The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The crude product is purified by silica gel chromatography (DCM/Acetone) to give 6-((3-amino-2-chloro-5,6-difluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one (1,2 g, 32%) as a tan solid. MS (chiad, m/z)=351.0, 353.0 (M+H).

Intermediate connection P18

6-((3-Amino-2-chloro-5;6-difluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one

6-Amino-5-fluoro-3-methylquinazolin-4(3H)-one (1170 mg, 6.05648 mmol) was dissolved in toluene (61 ml) and treated with tert-butyl (2-chloro-4,5-difluoro- 3-iodophenyl)carbamate (2477.37 mg, 6.35931 mmol), tris(dibenzylideneacetone) dippalladium (554.613 mg, 0.605648 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (876.119 mg, 1.51412 mmol) and cesium carbonate (3946.63 mg, 12.1130 mmol). The reaction mixture is purged with argon for several minutes and heated to 110°C for 16 hours under an argon cylinder. The reaction mixture is cooled to ambient temperature and diluted with DCM and stirred for 15 minutes, then filtered through a pad of Celite® and concentrated. The resulting residue was purified by silica gel chromatography (DCM/Acetone) and then the resulting residue was dissolved in 1:1 DCM:TFA (20 ml) and stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated and diluted 4:1 with DCM:IPA and washed with saturated NaHCO ₃ (1x) then dried over Na ₂ SO ₄ , filtered, and concentrated to give 6-((3-amino-2-chloro-5,6-difluorophenyl )amino)-5-fluoro-3-methylquinazolin-4(3H)-one (1.21 g, 56%). MS (chiad, m/z)=355.0, 357.0 (M+H).

Intermediate connection P19

6-((3-Amino-2,5,6-trifluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one

Step A: Preparation of tert-butyl (3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)carbamate.

Solution of 6-amino-5-chloro-3-methylquinazolin-4(3H)-one (200 mg, 0.95 mmol), tert-butyl (3-bromo-2,4,5-trifluorophenyl)carbamate (327 mg, 1.00 mmol), Pd ₂ (dba) ₃ (43.7 mg, 0.0477 mmol), Xantphos (82.8 mg, 0.143 mmol) and cesium carbonate (777 mg, 2.39 mmol) in toluene (9 ,5, ml) purged with argon for 5 minutes and then heated to 110°C under nitrogen for 16 hours. The reaction is cooled to ambient temperature, filtered through Celite®, concentrated, and purified by silica gel chromatography (5-95% DCM/EtOAc) to give tert-butyl (3-((5-chloro-3-methyl-4-oxo- 3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)carbamate (87 mg, 20.0%). MS (chiad, m/z)=455.1 (M+H).

Step B: Preparation of 6-((3-amino-2,5,6-trifluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one.

Tert-Butyl (3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)carbamate solution (87 mg, 0.19 mmol) in dichloromethane (960 µl) and TFA (960 µl) were stirred at ambient temperature for 1 hour. The solution is partitioned between dichloromethane and saturated NaHCO ₃ . The combined organic layers were washed with brine, dried with Na ₂ SO ₄ , filtered, concentrated, and purified by silica gel chromatography (5-95% EtOAc/DCM) to give 6-((3-amino-2,5,6-trifluorophenyl )amino)-5-chloro-3-methylquinazolin-4(3H)-one (65 mg, 96%). MS (chiad, m/z)=355.1 (M+H).

Intermediate P20

6-((3-amino-5-chloro-2-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one

Step A: Preparation of tert-butyl (5-chloro-2-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)carbamate.

Solution of 6-amino-5-fluoro-3-methylquinazolin-4(3H)-one (300 mg, 1.6 mmol), tert-butyl (3-bromo-5-chloro-2-fluorophenyl)carbamate (529 mg, 1.63 mmol), Pd ₂ (dba) ₃ (71.1 mg, 0.0776 mmol), Xantphos (135 mg, 0.233 mmol) and cesium carbonate (1265 mg, 3.88 mmol) in toluene (15.5 ml) purged with argon for 5 minutes and then heated to 110°C under nitrogen for 16 hours. The reaction is cooled to ambient temperature, filtered through Celite®, concentrated, and purified by silica gel chromatography (1-15% MeOH/DCM, 1% NH ₄ OH) to give tert-butyl (5-chloro-2-fluoro-3- ((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)carbamate (189 mg, 27.9%). MS (chiad, m/z)=437.1 (M+H).

Step B: Preparation of 6-((3-amino-5-chloro-2-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one.

Tert-Butyl (5-chloro-2-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)carbamate solution (189 mg, 0.433 mmol ) in dichloromethane (1082 µl) and TFA (1082 µl) were stirred at ambient temperature for 30 minutes. The solution is concentrated and partitioned between DCM and saturated NaHCO ₃ . The combined organic layers were washed with brine, dried with Na ₂ SO ₄ , filtered, concentrated, and purified by silica gel chromatography (1-15% MeOH/DCM, 1% NH ₄ OH) to give 6-((3-amino-5 -chloro-2-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (70 mg, 48.0%). MS (chiad, m/z)=337.1 (M+H).

Intermediate P21

6-((3-amino-5-chloro-2-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one

Step A: Preparation of tert-butyl (5-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-fluorophenyl)carbamate. Solution of 6-amino-5-chloro-3-methylquinazolin-4(3H)-one (820 mg, 2.35 mmol), tert-butyl (3-bromo-5-chloro-2-fluorophenyl)carbamate (800 mg, 2.46 mmol), Pd ₂ (dba) ₃ (107 mg, 0.117 mmol), Xantphos (204 mg, 0.352 mmol), and cesium carbonate (1912 mg, 5.87 mmol) in toluene (23.5 ml) purged argon for 5 minutes and then heated to 110°C under nitrogen for 16 hours. The reaction is cooled to ambient temperature, filtered through Celite®, concentrated, and purified by silica gel chromatography (5-95% DCM/EtOAc) to give tert-butyl (5-chloro-3-((5-chloro-3-methyl- 4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-fluorophenyl)carbamate (525 mg, 49.3%). MS (chiad, m/z)=453.1 (M+H).

Step B: Preparation of 6-((3-amino-5-chloro-2-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one.

Tert-Butyl (5-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-fluorophenyl)carbamate solution (525 mg, 1.16 mmol) in dichloromethane (2895 µl) and TFA (2895 µl) were stirred at ambient temperature for 1 hour. The solution is concentrated and partitioned between dichloromethane and saturated NaHCO ₃ . The combined organic layers were washed with brine, dried with Na ₂ SO ₄ , filtered, concentrated, and purified by silica gel chromatography (5-95% EtOAc/DCM) to give 6-((3-amino-5-chloro-2-fluorophenyl )amino)-5-chloro-3-methylquinazolin-4(3H)-one (260 mg, 63.6%). MS (chiad, t/t.) = 353.1 (M+H).

Intermediate P22

6-((3-amino-5-chloro-2-fluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one

6-Amino-3,5-dimethylquinazolin-4(3H)-one (500 mg, 2.64 mmol) was dissolved in toluene (26 ml) and treated with tert-butyl (3-bromo-5-chloro-2-fluorophenyl) carbamate (1.03 g, 3.17 mmol), tris(dibenzylideneacetone) dippalladium (0) (241.98 mg, 0.26 mmol), Xantphos (382.25 mg, 0.66 mmol) and cesium carbonate (1.721 g, 5.28 mmol). The reaction mixture is purged with argon for several minutes and then heated to 110°C under an argon balloon for 24 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (500 ml) and stirred for 15 minutes, then filtered through a pad of Celite® and concentrated. The resulting residue was purified by silica gel chromatography (DCM/EtOAc) and then dissolved in 1:1 DCM:TFA (10 ml) and stirred at ambient temperature for 1 hour. The reaction mixture is concentrated and treated with 500 ml NaHCO ₃ and stirred for 30 minutes at ambient temperature. The mixture was extracted with 4:1 DCM:IPA and the organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 6-((3-amino-5-chloro-2-fluorophenyl)amino)-3.5 -dimethylquinazolin-4(3H)-one (0.8 g, 90%) as a yellow solid. MS (chiad, m/z)=333.1, 335.1 (M+H).

Intermediate P23

2-Chloro-4-fluoro-3-methoxyaniline

Step 1: Preparation of 2-chloro-4-fluoro-3-methoxybenzaldehyde.

N,N,N'-trimethylethylenediamine (1.77 ml, 13.6 mmol) was dissolved in THF (50 ml) and cooled to -42°C under reflux of nitrogen, then treated with p-butyllithium (2.5 M in hexane , 5.45 ml, 13.6 mmol) and left to stir at -42°C for 30 minutes. The reaction mixture is cooled to -78°C and treated with 50 ml THF solution of 4-fluoro-3-methoxybenzaldehyde (2.0 g, 13.0 mmol) and then warmed to -42°C and stirred for 30 minutes. The reaction mixture was cooled to -78°C and treated with n-butyllithium (2.5 M in hexanes, 5.45 ml, 13.6 mmol) and then warmed to -42°C and allowed to stir for 1 hour. The reaction mixture quickly transfer via cannula into a 50 mL THF hexachloroethane solution (6.14 g, 26.0 mmol) at ambient temperature, and stir at ambient temperature for 2 hours. The reaction mixture is treated with 4.0 M HCl and extracted with Et ₂ O (2×250 ml). The organic phases are combined and washed with 1.0 M NaOH (1 x 100 ml), 1.0 M HCl (1 x 100 ml), and brine (1 x 50 ml) and then dried over Na ₂ SO ₄ , filtered, and concentrate. The residue is purified by C18 reverse phase chromatography (water/acetonitrile with 0.1% TFA) and fractions containing the desired product are combined and partitioned between 4:1 DCM:IPA and saturated NaHCO ₃ (1 x 100 ml), dried over Na ₂ SO ₄ , filter, and concentrate to give 2-chloro-4-fluoro-3-methoxybenzaldehyde (1.12 g, 46%). ^1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.70-7.67 (m, 1H), 7.52-7.48 (t, 1H), 3.94 (s, 3H).

Step 2: Preparation of 2-chloro-4-fluoro-3-methoxybenzoic acid.

2-Chloro-4-fluoro-3-methoxybenzaldehyde (1.07 g, 5.67 mmol) was dissolved in acetonitrile (57 ml) and treated with aqueous 1.0 M sodium phosphate dibasic solution (8.51 ml, 8.51 mmol ) and then cooled to 0°C. The reaction mixture is treated with aqueous 35 wt% hydrogen peroxide solution (0.732 ml, 8.51 mmol) then aqueous 1.0 M sodium chlorite solution (8.51 ml, 8.51 mmol) is added dropwise and then allowed to warm to ambient temperature. medium and stir for 16 hours. The reaction mixture is treated with 3.0 M sodium thiosulfate solution and diluted with 1.0 M NaOH, then washed with Et ₂ O (2×250 ml). The aqueous layer was acidified to approximately pH 2 using 4.0 M HCl and extracted with 4:1 DCM:IPA (2×250 ml). The organic extracts are combined and dried over Na ₂ SO ₄ , filtered, and concentrated to give 2-chloro-4-fluoro-3-methoxybenzoic acid (1.16 g, 99%). ^1H NMR (400 MHz, DMSO-d6) δ 13.45 (brs, 1H), 7.59-7.56 (m, 1H), 7.40-7.36 (t, 1H), 3.89 (s, 3H).

Step 3: Preparation of 2-chloro-4-fluoro-3-methoxyaniline.

2-Chloro-4-fluoro-3-methoxybenzoic acid (1.16 g, 5.670 mmol) was dissolved in DMF (57 ml) and treated with triethylamine (2.37 ml, 17.01 mmol) then diphenylphosphoryl azide (1.83 ml, 8.51 mmol) and stirred at ambient temperature for 1 hour. The reaction mixture is treated with 10 ml of water and heated to 8 0°C for 16 hours. The reaction mixture is cooled to ambient temperature, diluted with water and extracted with EtOAc (2×250 ml). The organic phases are combined and washed with water (3×100 ml) and brine (1×50 ml), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue is purified by chromatography on silica gel (Hexane/EtOAc) to give 2-chloro -4-fluoro-3-methoxyaniline (640.9 mg, 64%). ^1H NMR (400 MHz, DMSO-d6) δ 6.98-6.94 (t, 1H), 6.52-6.49 (m, 1H), 5.24 (shs, 2H), 3.82 (s, 3H).

Intermediate connection P24

3-Amino-2-chloro-6-fluorophenol

To a solution of 2-chloro-4-fluoro-3-methoxyaniline (400 mg, 2.2 mmol) in DCM (10 ml) add BBr ₃ (4.5 ml, 1.0 M in DCM, 4.5 mmol) at 0°C, and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was quenched with methanol (3 ml) and then poured into cold water (75 ml) and extracted with ethyl acetate (100 ml x 2). The organic layers are washed with water (2×50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (10% ethyl acetate in hexanes) to give 3-amino-2-chloro-6-fluorophenol as an off-white solid (220 mg, 60%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.87 (brs, 1H), 6.83 (dd, 1H), 6.22-60.18 (m, 1H), 5.03 (brs, 1H), 2H). MS (m/z)=159.8 (M-H).

Intermediate connection P25

3-Fluoro-2-methyl-6-nitrobenzoic acid

To an ice-cold solution of 3-fluoro-2-methylbenzoic acid (5 g, 32.4 mmol) in concentrated H ₂ SO ₄ (50 ml), concentrated HNO ₃ (3.5 ml) was slowly added and the reaction mixture was stirred at environment for 6 hours. The reaction mixture was poured into ice water and the solid was collected by filtration, washed with water (2×50 ml) and dried under reduced pressure to obtain 3-fluoro-2-methyl-6-nitrobenzoic acid as an off-white solid (3, 0 g, 47%). ^1H NMR (400 MHz, MeOD) δ 8.11-8.07 (m, 1H), 7.34 (t, 1H), 2.32 (s, 3H); MS (m/z)=197.6 (M-H).

Intermediate connection P26

Tert-butyl 3-fluoro-2-methyl-6-nitrobenzoate

Boc ₂ O (1.38 mL, 6 .03 mmol), then DMAP (147 mg, 1.2 mmol), and the reaction mixture was stirred at ambient temperature for 16 hours under nitrogen. The reaction mixture is concentrated and the crude residue is quenched with water (150 ml) and extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with water (2×100 ml), brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 15-20% ethyl acetate in hexane to give tert-butyl 3-fluoro-2-methyl-6-nitrobenzoate as a colorless liquid (600 mg, 60%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.10-8.07 (dd, 1H), 7.34 (t, 1H), 2.30 (s, 3H), 1.60 (s, 9H) .

Intermediate P27

6-(3-Amino-2-chloro-6-fluorophenoxy)-3,5-dimethylquinazolin-4(3H)-one

Step 1: Preparation of methyl 3-fluoro-2-methyl-6-nitrobenzoate. Methyl 3-fluoro-2-methylbenzoate (4.17 g, 24.8 mmol) is dissolved in sulfuric acid (24.1 ml, 248 mmol) and the mixture is cooled to 0°C.

Nitric acid (1.36 mL, 29.8 mmol) was slowly added thereto and the mixture was allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture is poured into 500 ml of ice water and stirred for 15 minutes. The mixture was extracted with EtOAc (2x), the combined organic layers were washed with saturated NaHCO ₃ (2x), brine (1x), dried over Na ₂ SO ₄ , filtered, and concentrated. The crude product was purified by reverse phase chromatography (5->95% water-ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated NaHCO ₃ (1x). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated to give methyl 3-fluoro-2-methyl-6-nitrobenzoate (3.80 g, 72%).

Step 2: Preparation of methyl 3-(3-amino-2-chloro-6-fluorophenoxy)-2-methyl-6-nitrobenzoate.

To a solution of methyl 3-fluoro-2-methyl-6-nitrobenzoate (686 mg, 3.22 mmol) and 3-amino-2-chloro-6-fluorophenol (572 mg, 3.54 mmol) in DMSO (15 ml) potassium carbonate (1112 mg, 8.05 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture is diluted with EtOAc and water. The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography, eluting with 10-50% EtOAc in hexane to give methyl 3-(3-amino-2-chloro-6-fluorophenoxy)-2-methyl-6-nitrobenzoate (950 mg, 83%).

Step 3: Preparation of methyl 3-(3-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-methyl-6-nitrobenzoate.

To a solution of methyl 3-(3-amino-2-chloro-6-fluorophenoxy)-2-methyl-6-nitrobenzoate (683.4 mg, 1.927 mmol) in dioxane (17.8 ml) add TEA (805.6 µl , 5.780 mmol), DMAP (23.54 mg, 0.1927 mmol) and (Boc) _2O (1261 mg, 5.780 mmol), and the reaction mixture was heated to 100°C for 1 hour. The reaction mixture is cooled to ambient temperature and concentrated. The crude product is purified by silica gel chromatography (5->50% Hexane-EtOAc) to give 3-(3-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-methyl-6-nitrobenzoate ( 970 mg, 91%).

Step 4: Preparation of methyl 6-amino-3-(3-(bis(tert-butoxycarbonyl)amino-2-chloro-6-fluorophenoxy)-2-methylbenzoate.

To a solution of methyl 3-(3-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-methyl-6-nitrobenzoate (319 mg, 0.575 mmol) in 1:1 THF/saturated aqueous NH ₄ Cl (10 ml) add iron powder (321 mg, 5.75 mmol) and the reaction mixture is heated to 65°C for 16 hours. The reaction mixture is cooled to ambient temperature and diluted with 20% IPA in DCM and water. The solid was removed by filtration and the filtrate was washed with water (1x), brine (1x), dried over Na ₂ SO ₄ , filtered, and concentrated to give 6-amino-3-(3-(bis(tert-butoxycarbonyl)amino -2-chloro-6-fluorophenoxy)-2-methylbenzoate (260 mg) The crude product was used directly in the next step MS (m/z)=525.2 (M+H).

Step 5: Preparation of tert-butyl (tert-butoxycarbonyl)(2-chloro-4-fluoro-3-((5-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate.

A solution of methyl 6-amino-3-(3-(bis(tert-butoxycarbonyl)amino-2-chloro-6-fluorophenoxy)-2-methylbenzoate (260 mg, 0.495 mmol) and formamidine acetate (61.9 mg, 0.594 mmol ) in EtOH (4 ml) is heated to 70° C. for 24 hours.The reaction mixture is concentrated and the residue is purified by column chromatography, eluting with 25-100% EtOAc in hexane to give tert-butyl (tert-butoxycarbonyl)(2-chloro- 4-fluoro-3-((5-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate (0.244 g, 95%). MS (m/z)=520.1 ( M+N).

Step 6: Preparation of tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate.

To a solution of tert-butyl (tert-butoxycarbonyl)(2-chloro-4-fluoro-3-((5-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate (0.244 g, 0.469 mmol) in DMF was added K ₂ CO ₃ (0.0973 g, 0.704 mmol) then Mel (0.0439 ml, 0.704 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are dried over Na ₂ SO ₄ , filtered and concentrated to give tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6- yl)oxy)-4-fluorophenyl)carbamate. The crude product is used in the next step as is. MS (m/z)=534.2 (M+H).

Step 7: Preparation of 6-(3-amino-2-chloro-6-fluorophenoxy)-3,5-dimethylquinazolin-4(3H)-one.

To a solution of tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (0.251 g , 0.470 mmol) in DCM (4 ml) was added TFA (4 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by column chromatography, eluting with 50-100% EtOAc in hexane to give 6-(3-amino-2-chloro-6-fluorophenoxy)-3,5-dimethylquinazolin-4(3H)-one (0.144 g, 92%). MS (m/z)=334.1 (M+H).

Intermediate P28

6-(3-Amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methyl-3, 4-dihydroquinazolin-4-one

Step 1: Preparation of methyl 2-chloro-3-fluorobenzoate. To a solution of 2-chloro-3-fluorobenzoic acid (3 g, 17.24 mmol) in methanol (60 ml) was added concentrated H ₂ SO ₄ (0.5 ml), and the reaction mixture was heated at 60° C. under a nitrogen atmosphere in within 16 hours. The reaction mixture is cooled to ambient temperature and concentrated under reduced pressure. The reaction mixture is partitioned between ethyl acetate (100 ml) and saturated aqueous NaHCO ₃ (100 ml). The organic phase was separated and washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give methyl 2-chloro-3-fluorobenzoate as a yellow liquid (2.9 g) which was used for next step without further purification ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.70-7.62 (m, 2H), 7.56-7.48 (m, 1H), 3.88 (s, 3H).

Step 2: Preparation of methyl 2-chloro-3-fluoro-6-nitrobenzoate.

To an ice-cooled solution of methyl 2-chloro-3-fluorobenzoate (0.531 g, 2.82 mmol) in concentrated H ₂ SO ₄ (5 ml) add HNO ₃ (0.233 ml, 3.52 mmol, 70% w/w .). The reaction mixture is removed from the ice bath and stirred at ambient temperature for 4 hours. The reaction mixture is poured into ice water (50 ml) and solid Na ₂ CO ₃ is added to adjust the solution to pH 2. The aqueous phase is extracted with DCM (3 x 25 ml) and the combined organic phases are concentrated to give a yellow oil, which is purified by reverse phase chromatography (5-50% ACN/water with 0.1% TFA). The desired fractions are combined and extracted with DCM (3×25 ml). The organic phases are combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give methyl 2-chloro-3-fluoro-6-nitrobenzoate (411 mg, 59.4%) as a clear yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (8.41-8.36, m, 1H), (7.91-7.84, m, 1H), (3.96, s, 3H) .

Step 3: Preparation of methyl 3-(3-amino-2-chloro-6-fluorophenoxy)-2-chloro-6-nitrobenzoate.

To a solution of methyl 2-chloro-3-fluoro-6-nitrobenzoate (85 mg, 0.364 mmol) in DMSO (1.8 ml) add solid K ₂ CO ₃ (126 mg, 0.910 mmol) and 3-amino-2-chloro -6-fluorophenol (64.7 mg, 0.400 mmol). The reaction mixture was stirred at ambient temperature for 16 hours then partitioned between ethyl acetate (25 ml) and water (15 ml). The organic phase is separated and washed with brine (15 ml), then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a brown solid, which is purified by chromatography on silica gel (0-50% hexane/ethyl acetate) to give methyl 3-(3-amino-2-chloro-6-fluorophenoxy)-2-chloro-6-nitrobenzoate (100 mg, 73.3%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (d, 1H), 7.02 (t, 1H), 6.76-6.68 (m, 2H),), 4.09 (shs, 2H), 4.07 (s, 3H).

Step 4: Preparation of methyl 3-(3-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-chloro-6-nitrobenzoate.

To a solution of methyl 3-(3-amino-2-chloro-6-fluorophenoxy)-2-chloro-6-nitrobenzoate (100 mg, 0.267 mmol) in 1,4-dioxane (2.6 ml) add triethylamine (0.112 ml , 0.800 mmol), N,N-dimethylpyridin-4-amine (3.26 mg, 0.0267 mmol) and di-tert-butyl dicarbonate (175 mg, 0.800 mmol). The reaction mixture is heated at 100°C for 1 hour then cooled to ambient temperature and partitioned between ethyl acetate (25 ml) and water (15 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (0-40% hexane/ethyl acetate) to give methyl 3-(3-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-chloro-6-nitrobenzoate ( 128 mg, 84%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, 1H), 7.26-7.22 (m, 2H), 6.63-6.59 (m, 1H), 4.07 ( s, 3H), 1.43 (s, 18H).

Step 5: Preparation of methyl 6-amino-3-(3-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-chlorobenzoate.

To a solution of methyl 3-(3-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-chloro-6-nitrobenzoate (105 mg, 0.182 mmol) in tetrahydrofuran (2 ml) add iron powder (102 mg, 1.82 mmol) and saturated aqueous NH ₄ Cl (2 ml). The reaction mixture is heated at 65°C for 16 hours. The reaction is cooled to ambient temperature and partitioned between ethyl acetate (25 ml) and water (25 ml), then filtered. The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give methyl 6-amino-3-(3-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2- chlorobenzoate as a yellow oil (99 mg), which is used directly in the next step without further purification.

Step 6: Preparation of tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate.

To a solution of methyl 6-amino-3-(3-(bis(tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-chlorobenzoate (99 mg, 0.182 mmol) in ethanol (1 ml) add formamidine acetate (20.0 mg, 0.193 mmol). The reaction mixture is sealed and heated at 100°C in a microwave reactor for 2 hours. The reaction is cooled to ambient temperature then concentrated to give a mixture of tert-butyl(tert-butoxycarbonyl)(2-chloro-3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4 -fluorophenyl)carbamate and tert-butyl (2-chloro-3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate, which is used directly in the next step without further purification. MS (chiad, m/z)=540.l (M+H)

Step 7: Preparation of tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl) carbamate.

To a mixture of tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate and tert-butyl ( 2-chloro-3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (99 mg, 0.183 mmol, calculated using the molecular weight of tert-butyl ( tert-butoxycarbonyl)(2-chloro-3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate) in N,N-dimethylformamide (1 ml) add K ₂ CO ₃ (38.0 mg, 0.275 mmol) and iodomethane (12.5 μl, 0.202 mmol). The reaction mixture was stirred at ambient temperature for 16 hours then partitioned between water (10 ml) and ethyl acetate (10 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a yellow oil, which is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TPA) to give 40 mg of product mixture, containing tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate and tert -butyl (2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (40 mg) as a clear oil, which is used in the next step without further purification. MS (chiad, m/z)=554.1 (M+H).

Step 8: Preparation of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one.

A mixture of tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate and tert -Butyl (2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (40 mg) was dissolved in DCM (1 ml) and trifluoroacetic acid (1 ml). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated to give a white solid, which was purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are diluted with saturated aqueous NaHCO ₃ (15 ml) and extracted with DCM (3×15 ml). The organic phases are combined and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one ( 29.2 mg, 37% from step 5) as a tan solid. MS (chiad, m/z)=354.0 (M+H)

Intermediate P29

6-(3-Amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one

Step 1: Preparation of methyl 2,3-difluorobenzoate. 2,3-difluorobenzoic acid (913.1 mg, 5.775 mmol) was dissolved in MeOH (58 ml) then treated with sulfuric acid (140.2 μl, 1.444 mmol) and the mixture was heated to 70°C for 16 hours. The reaction mixture is cooled to ambient temperature and concentrated. The residue is diluted with DCM and washed with saturated NaHCO ₃ (1x) then dried over Na ₂ SO ₄ , filtered, and concentrated to give methyl 2,3-difluorobenzoate (714.4 mg, 71.9%). ^1H NMR (400 MHz, DMSO) δ 7.74-7.65 (m, 2H), 7.35-7.29 (m, 1H), 3.85 (s, 3H).

Stage 2: Preparation of methyl 2,3-difluoro-6-nitrobenzoatv. To a cold (0°C) solution of methyl 2,3-difluorobenzoate (714.4 mg, 4.150 mmol) in sulfuric acid (4030 µl, 41.50 mmol) add nitric acid (297.8 µl, 4.565 mmol) dropwise. The reaction mixture is stirred at 0°C for 15 minutes and then at ambient temperature for 16 hours. The reaction mixture is poured into ice water (100 ml) and stirred for 15 minutes, then neutralized to approximately pH 8 using solid Na ₂ CO ₃ . The reaction mixture was extracted with EtOAc (2x), and the combined organic layers were washed with water (1x), brine (1x), dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by chromatography on silica gel (Hexane/acetone) to give a 1:1 mixture of methyl 2,3-difluoro-6-nitrobenzoate and methyl 2,3-difluoro-5-nitrobenzoate (665.6 mg, 74%), which was used directly to the next stage without cleaning.

Step 3: Preparation of methyl 3-(3-amino-2-chloro-6-fluorophenoxy)-2-fluoro-6-nitrobenzoate. A mixture of methyl 2,3-difluoro-6-nitrobenzoate and methyl 2,3-difluoro-5-nitrobenzoate (665.6 mg, 3.065 mmol) was dissolved in DMSO (12 ml) and treated with 3-amino-2-chloro-6- fluorophenol (544.8 mg, 3.372 mmol), then potassium carbonate (635.5 mg, 4.598 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture is poured into water and extracted with EtOAc (2x). The combined organic layers were washed with water (3x), brine (1x), dried over Na ₂ SO ₄ , filtered, and concentrated to give a 1:1 mixture of methyl 3-(3-amino-2-chloro-6-fluorophenoxy)- 2-fluoro-6-nitrobenzoate and methyl 2-(3-((bis-tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-3-fluoro-5-nitrobenzoate (860.9 mg, 78%) which is used directly in the next step without purification.

Step 4: Preparation of methyl 3-(3-((bis-tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-fluoro-6-nitrobenzoate. 1:1 mixture of methyl 3-(3-amino-2-chloro-6-fluorophenoxy)-2-fluoro-6-nitrobenzoate and methyl 2-(3-((bis-tert-butoxycarbonyl)amino)-2-chloro- 6-Fluorophenoxy)-3-fluoro-5-nitrobenzoate (860.9 mg, 2.400 mmol) was dissolved in THF (24 ml) and treated with 4-(dimethylamino)pyridine (2 9.32 mg, 0.2 4 00 mmol) , then di-tert-butyl dicarbonate (1100 mg, 5.040 mmol) and the reaction mixture was stirred at ambient temperature for 60 hours. The reaction mixture was concentrated and purified by silica gel chromatography (Hexane/EtOAc) to give methyl 3-(3-((bis-tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-fluoro-6-nitrobenzoate (476 .9 mg, 36%). ^1H NMR (400 MHz, DMSO) δ 8.16-8.13 (dd, 1H), 7.63-7.61 (m, 2H), 7.03-6.99 (t, 1H), 3 .94 (s, 3H), 1.33 (s, 18H).

Step 5: Preparation of methyl 6-amino-3-(3-((bis-tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-fluorobenzoate.

Methyl 3-(3-((bis-tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-fluoro-6-nitrobenzoate (461.7 mg, 0.8261 mmol) dissolved in 1:1 THF : saturated NH ₄ Cl (16.5 ml, 0.05 M) and then treated with iron (922.6 mg, 16.52 mmol) and the reaction mixture was heated to 65°C for 16 hours. The reaction mixture is cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with water (1x), brine (1x), dried over Na ₂ SO ₄ , filtered and concentrated to give a mixture of methyl 6-amino-3-(3-((bis-tert-butoxycarbonyl)amino)-2 -chloro-6-fluorophenoxy)-2-fluorobenzoate and methyl 6-amino-3-(3-((tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-fluorobenzoate (395.1 mg, 90 %).

Step 6: Preparation of bis-tert-butyl

(2-chloro-4-fluoro-3-((5-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate. A mixture of methyl 6-amino-3-(3-((bis-tert-butoxycarbonyl)amino)-2-chloro-6-fluorophenoxy)-2-fluorobenzoate and methyl 6-amino-3-(3-((tert-butoxycarbonyl) )Amino)-2-chloro-6-fluorophenoxy)-2-fluorobenzoate (395.1 mg, 0.7470 mmol) was dissolved in EtOH (15 ml) and treated with formamidine acetate (388.8 mg, 3.735 mmol) and the reaction mixture heated to 100°C for 8 hours using microwaves. The reaction mixture is concentrated and the residue is diluted with EtOAc. The combined organic layers were washed with water (1x), brine (1x), dried over Na ₂ SO ₄ , filtered, and concentrated to give bis-tert-butyl (2-chloro-4-fluoro-3-((5- fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate and tert-butyl (2-chloro-4-fluoro-3-((5-fluoro-4-oxo-3,4- Dihydroquinazolin-6-yl)oxy)phenyl)carbamate (342.4 mg, 88%).

Step 7: Preparation of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one. A mixture of bis-tert-butyl (2-chloro-4-fluoro-3-((5-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate and tert-butyl (2-chloro -4-fluoro-3-((5-fluoro-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate (342.4 mg, 0.6535 mmol) was dissolved in DMF (6.5 ml) and treated with potassium carbonate (117.4 mg, 0.8496 mmol) then iodomethane (44.75 μl, 0.7189 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture is diluted with water and extracted with EtOAc (2x). The combined organic layers are washed with water (3x), brine (1x), dried over Na ₂ SO ₄ , filtered, and concentrated. The resulting residue was dissolved in 1:1 DCM:TFA (5.0 ml) and stirred at ambient temperature for 30 minutes. The reaction mixture is concentrated and purified by C18 reverse phase chromatography (water/ACN with 0.1% TFA). The combined desired fractions are then partitioned between 4:1 DCM:IPA and saturated NaHCO ₃ (1x). The combined organic layers are dried over Na ₂ SO ₄ , filtered, and concentrated to give 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (206.1 mg, 93%). MS (chiad, m/z)=338.1, 340.1 (M+H).

Intermediate connection P30

6-((3-amino-2,6-difluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one

Step 1: Preparation of di-tert-butyl (3-bromo-2,4-difluorophenyl) dicarbamate. 3-Bromo-2,4-difluoroaniline (375 mg, 1.80 mmol) is stirred at ambient temperature with di-tert-butyl dicarbonate (826 mg, 3.79 mmol) and DMAP (44.1 mg, 0.361 mmol) in THF (9.014 ml) for 48 hours. The reaction mixture is diluted with ethyl acetate and washed with saturated aqueous NH ₄ Cl. The combined organic layers are dried over magnesium sulfate, filtered and concentrated. The product is used directly in the next step without purification.

Step 2: Preparation of tert-butyl (3-bromo-2,4-difluorophenyl)carbamate. Di-tert-butyl (3-bromo-2,4-difluorophenyl) dicarbamate (735 mg, 1.80 mmol) was dissolved in MeOH (6.0 mL) and potassium carbonate (113 μL, 1.98 mmol) was added, and the reaction is heated to 65°C for 1 hour. The reaction mixture is cooled to ambient temperature and then filtered through a pad of Celite and concentrated. The crude product was purified by normal phase chromatography (0-20% hexane/EtOAc) to give tert-butyl (3-bromo-2,4-difluorophenyl)carbamate as a white solid (447 mg, 81% in 2 steps).

Step 3: Preparation of 6-((3-amino-2,6-difluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one. 6-Amino-3,5-dimethylquinazolin-4(3H)-one (50 mg, 0.26 mmol), tert-butyl (3-bromo-2,4-difluorophenyl)carbamate (81 mg, 0.26 mmol) , cesium carbonate (172 mg, 0.53 mmol), Pd ₂ (dba) ₃ (24 mg, 0.026 mmol) and Xantphos (38 mg, 0.066 mmol) are dissolved in toluene (2.6 ml) and then heated to 110° C within 24 hours. The reaction mixture is cooled to ambient temperature, filtered through Celite, concentrated, and then reconstituted in 1:1 DCM/TFA (5 ml). The reaction mixture is stirred at ambient temperature for 15 minutes. Volatiles are removed in vacuo and the crude product is purified by reverse phase chromatography (0-30% MeCN/H ₂ O, 0.1% TFA). The resulting product is diluted with DCM, washed with sat. aqueous NaHCO ₃ and concentrated to give 6-((3-amino-2,6-difluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one (32 mg, 38%). MS (chiad, m/z)=317.1 (M+H).

Intermediate connection P31

6-amino-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one

Step 1: 6-chloro-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one. To a solution of 6-chloropyrido[3,2-d]pyrimidin-4(3H)-one (100 mg, 0.551 mmol) and iodomethane (44 μl, 0.71 mmol) in N,N-dimethylformamide (1.1 ml) add potassium carbonate (114 mg, 0.826 mmol) and stir at room temperature for 16 hours. The reaction mixture is then partitioned between ethyl acetate and water, and the organic layer is washed with brine (1x), dried over Na ₂ SO ₄ , filtered, and concentrated. The resulting residue was then purified by silica gel chromatography (5-95% EtOAc/DCM) to give 6-chloro-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one (67 mg, 62% yield). MS (chiad, m/z)=196.1 (M+H).

Step 2: 6-((4-methoxybenzyl)amino)-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one. A solution of 6-chloro-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one (25 mg, 0.128 mmol), (4-methoxyphenyl)methanamine (33 µl, 0.25 mmol), and Huenig's base (33 µl, 0.19 mmol) in DMSO (426 µl) was heated at 90°C for 48 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM and water. The organic layer was washed with brine (1x), dried over Na ₂ SO ₄ , filtered, and concentrated. The resulting residue was purified by silica gel chromatography (1-10% MeOH/DCM, 1% NH ₄ OH) to give crude 6-((4-methoxybenzyl)amino)-3-methylpyrido[3,2-d]pyrimidine-4(3H )-she (25 mg, 66% yield). MS (chiad, m/z)=297.1 (M+H).

Step 3: 6-amino-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one. Crude 6-((4-methoxybenzyl)amino)-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one (25 mg, 0.084 mmol) was stirred in TFA (422 µl) and dichloromethane (422 µl) for 3 hours at ambient temperature. The reaction mixture is then concentrated, dissolved in TFA (422 μl) and then heated in a sealed tube at 60°C for 3 days. The reaction mixture is then concentrated and dissolved in 1 ml of methanol and 1 ml of DCM and then passed through a bicarbonate base resin. The filtrate is then concentrated and purified by silica gel chromatography (1-15% MeOH/DCM, 1% NH ₄ OH) to give 6-amino-3-methylpyrido[3,2-d]pyrimidin-4(3H)-one (7, 0 mg, 47% yield). MS (chiad, m/z)=177.1 (M+H).

Intermediate connection P32

tert-Butyl_(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate

Step 1: Preparation of tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate. 6-(3-Amino-2-chloro-6-fluorophenoxy)-3,5-dimethylquinazolin-4(3H)-one (1.5 g, 4.5 mmol) was dissolved in THF (22 ml) then treated with di- tert-butyl dicarbonate (2.2 g, 9.9 mmol) and N,N-dimethylpyridin-4-amine (55 mg, 0.45 mmol). The reaction mixture is heated to 45°C for 12 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (0-20% DCM/EtOAc) to give tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((3,5-dimethyl-4-oxo-3,4 -dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (2 g, 83%) as a white solid. NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.28 (s, 1H), 7.55-7.54 (d, 1H), 7.53 (s, 1H), 7.47-7, 41 (d, 1H), 6.86-6.78 (d, 1H), 3.46 (s, 3H), 2.92 (s, 3H), 1.36 (s, 18H); MS (chiad, m/z)=534.2, 536.2 (M+H).

Step 2: Preparation of tert-butyl (2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate. Tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (2 g, 3 .7 mmol) dissolved in MeOH (19 ml) and treated with potassium carbonate (0.62 g, 4.5 mmol) then heated to 60°C for 12 hours. The reaction mixture is cooled to ambient temperature, poured into water, treated with ultrasound and filtered. The resulting solid was purified by silica gel column chromatography (0-50% DCM/Acetone) to give tert-butyl (2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl )oxy)-4-fluorophenyl)carbamate (1.5 g, 98%) as a white solid. ^1H NMR (400 MHz, ( _CD3 ) _2SO ) δ 8.89 (s, 1H), 8.27 (s, 1H), 7.53-7.40 (m, 3H), 6.97- 6.92 (d, 1H), 3.46 (s, 3H), 2.91 (s, 3H), 1.45 (s, 9H); MS (chiad, m/z)=434.1, 436.1 (M+H).

Intermediate P33

tert-Butyl_(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate

Step 1: Preparation of tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl) carbamate. 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (1.5 g, 4.2 mmol) was dissolved in THF (21 ml) and treated di-tert-butyl dicarbonate (2.0 g, 9.3 mmol) and N,N-dimethylpyridin-4-amine (52 mg, 0.43 mmol) are then heated to 45°C for 12 hours. The reaction mixture is cooled to ambient temperature and concentrated and purified by silica gel column chromatography (0-20% DCM/EtOAc) to give the intermediate tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((5-chloro-3 -methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (2 g, 85%) as a white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.36 (s, 1H), 7.62-7.54 (m, 3H), 7.02-6.96 (d, 1H), 3.46 (s, 3H), 1.36 (s, 18H); MS (chiad, m/z)=554.2, 556.2 (M+H).

Step 2: Preparation of tert-butyl (2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate. Tert-butyl (tert-butoxycarbonyl)(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (2 g , 3.6 mmol) dissolved in MeOH (18 ml) and treated with potassium carbonate (0.60 g, 4.3 mmol) then heated to 60°C for 12 hours. The reaction is cooled to ambient temperature, poured into water, sonicated and filtered, and the resulting solid is purified by silica gel column chromatography (0-50% DCM/Acetone) to give tert-butyl (2-chloro-3-((5- chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (1.6 g, 100%) as a white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.92 (s, 1H), 8.35 (s, 1H), 7.59-7.53 (m, 2H), 7.49- 7.43 (t, 1H), 7.15-7.11 (m, 1H), 3.46 (s, 3H), 1.46 (s, 9H); MS (chiad, m/z)=454.2, 456.2 (M+H).

Intermediate connection P34

tert-Butyl_(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate

Step 1: Preparation of tert-butyl (tert-butoxycarbonyl)(2-chloro-4-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate . 6-(3-Amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (1.5 g, 4.4 mmol) was dissolved in THF (22 ml) and treated di-tert-butyl dicarbonate (2.1 g, 9.8 mmol) and N,N-dimethylpyridin-4-amine (54 mg, 0.44 mmol) are then heated to 45°C for 12 hours. The reaction is concentrated and purified by silica gel column chromatography (0-20% DCM/EtOAc) to tert-butyl (tert-butoxycarbonyl)(2-chloro-4-3-((5-fluoro-3-methyl-4-oxo-3 ,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate (1.8 g, 75%) as a white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.34 (s, 1H), 7.57-7.53 (d, 2H), 7.49-7.46 (m, 1H), 7.23-7.17 (t, 1H), 3.45 (s, 3H), 1.35 (s, 18H); MS (chiad, m/z)=538.1, 540.1 (M+H).

Step 2: Preparation of tert-butyl (2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate. Tert-butyl (tert-butoxycarbonyl)(2-chloro-4-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate (1.8 g, 3.35 mmol) was dissolved in MeOH (16.7 ml) and treated with potassium carbonate (0.55 g, 4.02 mmol) and the reaction was heated to 60°C for 12 hours. The reaction is cooled to ambient temperature, poured into water, sonicated, and filtered, and the resulting solid is purified by silica gel column chromatography (0-50% DCM/Acetone) to give tert-butyl (2-chloro-4-fluoro-3 -((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate (1.16 g, 80%) as a white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.92 (s, 1H), 8.33 (s, 1H), 7.56-7.51 (m, 1H), 7.48- 7.41 (m, 2H), 7.31-7.25 (t, 1H), 3.46 (s, 3H), 1.45 (s, 9H); MS (chiad, m/z)=438.1, 440.1.

Getting Synthetic Examples

Example 1

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide

Step 1: Preparation of (R)-3-methoxypyrrolidine-1-sulfonyl chloride. A suspension of (R)-3-methoxypyrrolidine hydrochloride (198 mg, 1.44 mmol) and N,N-diisopropylethylamine (376 μl, 2.16 mmol) was stirred in DCM (6 ml) at ambient temperature until the mixture was completely dissolved. The reaction mixture is cooled to 0°C and treated with sulfuryl chloride (349 μl, 4.32 mmol). The cold bath is removed after 30 minutes and the mixture is stirred at ambient temperature for 16 hours. The reaction mixture is diluted with additional DCM and washed with 1.0 M HCl (1x). The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give crude (R)-3-methoxypyrrolidine-1-sulfonyl chloride (212 mg, 74%), which was used as is in the next step.

Step 2: Preparation of (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-methoxypyrrolidine -1-sulfonamide. A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one (50 mg, 0.15 mmol) and (R)-3-methoxypyrrolidin- 1-sulfonyl chloride (212 mg, 1.0 mmol) in pyridine (0.8 ml) was sealed and heated at 65°C for 16 hours. The reaction mixture is cooled to ambient temperature and concentrated. The crude product is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The product is then purified by silica gel column chromatography (50-100% EtOAc/hexane) to give (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6 -yl)amino)-4-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide (40 mg, 54%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.44-7.39 (m, 2H), 7.08-7.02 (m, 2H), 6.88 ( s, 1H), 5.57 (s, 1H), 3.96-3.92 (m, 1H), 3.54 (s, 3H), 3.50-3.41 (m, 4H), 3 .25 (s, 3H), 2.96 (s, 3H), 2.09-2.03 (m, 1H), 1.99-1.90 (m, 1H). MS (chiad, m/z)=496, 1 (M+H).

Example 2

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N-ethyl-N-methyl)-sulfamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (35 mg, 0.10 mmol) and N-ethyl-N- Methyl sulfamoyl chloride (47 mg, 0.30 mmol) in pyridine (0.50 ml) is sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , filtered and concentrated, and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-3-((3,5- dimethyl 4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N-ethyl-N-methyl)-sulfonamide trifluoroacetate (22 mg, 48%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.67 (s, 1H), 7.65 (d, 1H), 7.56-7.52 (m, 1H), 7.17 (t, 1H) , 7.01-6.98 (m, 1H), 6.75 (s, 1H), 6.55 (s, 1H), 3.69 (s, 3H), 3.31-3.26 (m , 2H), 2.87 (s, 3H), 1.15 (t, 1H). MS (chiad, m/z)=474.1 (M+H).

Example 3

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-(N,N-dimethyl)sulfamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (30 mg, 0.08494 mmol) and dimethylsulfamoyl chloride (120 mg, 0.8494 mmol) in pyridine (0.8 ml) is heated at 70°C for 24 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM/EtOAc) then reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl )amino)-4-fluorophenyl)-(N,N-dimethyl)-sulfonamide (13.6 mg, 35%) as an off-white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO): δ 9.47 (s, 1H), 8.21 (s, 1H), 7.76 (s, 1H), 7.53-7.33 (m, 3H), 6.78-6.72 (m, 1H), 3.44 (s, 3H), 2.73 (s, 6H); MS (chiad, m/z)=460.1, 462.1 (M+H).

Example 4

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-(N-ethyl-N-methyl )-sulfamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (28 mg, 0.0832 mmol) and ethyl(methyl)sulfamoyl chloride ( 106 mg, 0.673 mmol) in pyridine (0.8 ml) is heated at 70°C for 24 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue is purified by silica gel column chromatography (DCM/EtOAc) then reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazoline -6-yl)amino)phenyl)-(N-ethyl-N-methyl)-sulfonamide (28 mg, 74%) as an off-white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.33 (s, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.39-7.24 ( m, 3H), 7.01-6.93 (t, 1H), 3.41 (s, 3H), 3.13-3.06 (m, 2H), 2.72 (s, 3H), 1 .02-0.98 (t, 3H); MS (chiad, m/z)=458.1, 460.1 (M+H).

Example 5

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-methoxypyrrolidin- 1-sulfonamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (70 mg, 0.21 mmol) and (R)-3- methoxypyrrolidine-1-sulfonyl chloride (166 mg, 0.83 mmol) in pyridine (2 ml) was sealed and heated at 65°C for 16 hours. The reaction mixture is cooled to ambient temperature and concentrated. The crude product is purified by silica gel column chromatography (30-100% EtOAc/hexane) to give (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6 -yl)amino)-4-fluorophenyl)-(N-isopropyl-N-methyl)-sulfonamide (68 mg, 65%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.54-7.51 (m, 1H), 7.40-7.38 (dd, 1H), 7.14- 7.09 (t, 1H), 7.06-6.99 (m, 1H), 6.90 (s, 1H), 5.91 (s, 1H), 3.96-3.93 (m, 1H), 3.57 (s, 3H), 3.52-3.41 (m, 4H), 3.25 (s, 3H), 2.12-2.05 (m, 1H), 2.00 -1.91 (m, 1H). MS (chiad, m/z)=500.1 (M+H).

Example 6

(R)-N-(2-chloro-4-fluoro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-methoxypyrrolidin- 1-sulfonamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (70 mg, 0.20 mmol) and (R)-3- methoxypyrrolidine-1-sulfonyl chloride (158 mg, 0.79 mmol) in pyridine (2 ml) was sealed and heated at 65°C for 60 hours. The reaction mixture is cooled to ambient temperature and concentrated. The crude product is purified by silica gel column chromatography (30-100% EtOAc/hexane) to give (R)-N-(2-chloro-4-fluoro-3-((5-chloro-3-methyl-4-oxo-3 ,4-dihydroquinazolin-6-yl)amino)phenyl)-3-methoxypyrrolidine-1-sulfonamide (59 mg, 58%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.58-7.54 (m, 1H), 7.50-7.48 (d, 1H), 7.15- 7.11 (t, 1H), 6.97-6.94 (m, 1H), 6.91 (s, 1H), 6.44 (s, 1H), 3.96-3.93 (m, 1H), 3.56 (s, 3H), 3.52-3.41 (m, 4H), 3.25 (s, 3H), 2.11-2.05 (m, 1H), 1.99 -1.90 (m, 1H). MS (chiad, m/z)=516.1 (M+H).

Example 7

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (150 mg, 0.45 mmol) and pyrrolidine-1-sulfonyl chloride ( 190 mg, 1.10 mmol) in pyridine (2.2 ml) are sealed and heated at 70°C for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-4-fluoro-3-((5-fluoro -3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide trifluoroacetate (161 mg, 77%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.56-7.53 (m, 1H), 7.49-7.46 (m, 1H), 7.15 ( t, 1H), 7.09-7.03 (m, 1H), 6.75 (s, 1H), 5.98 (s, 1H), 3.64 (s, 3H), 3.37-3 .34 (m, 4H), 1.91-1.88 (m, 4H). MS (chiad, m/z)=470.1 (M+H).

Example 8

(R)-N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-methoxypyrrolidine-1 -sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-bromo-3-methylquinazolin-4(3H)-one (35 mg, 0.088 mmol) and (R)-3-methoxypyrrolidin- 1-sulfonyl chloride (44 mg, 0.22 mmol) in pyridine (0.44 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(3-((5-bromo-3-methyl -4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide trifluoroacetate (20 mg, 40%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.61-7.57 (m, 1H), 7.15 (t, 1H), 7.00-6.95 ( m, 2H), 6.93 (s, 1H), 6.66 (s, 1H), 3.97-3.95 (m, 1H), 3.62 (s, 3H), 3.53-3 .43 (m, 2H), 3.27 (s, 3H), 2.07-1.93 (m, 4H). MS (chiad, m/z)=560.0, 562.0 (M+H).

Example 9

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-2-azabicyclo[2,1,1 ]hexane-2-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (30 mg, 0.085 mmol) and 2-azabicyclo[2,1, 1]hexane-2-sulfonyl chloride (46 mg, 0.26 mmol) in pyridine (0.43 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuS04. The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-3-((5-chloro-3-methyl -4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-2-azabicyclo[2,1,1]hexane-2-sulfonamide trifluoroacetate (21 mg, 50%). ^1H NMR (400 MHz, CDCL ₃ ) δ 8.46 (s, 1H), 7.64-7.61 (m, 2H), 7.16 (t, 1H), 7.00-6.97 ( m, 1H), 6.82 (s, 1H), 6.51 (s, 1H), 4.27-4.24 (m, 1H), 3.53 (s, 3H), 3.40 (s , 2H), 2.92-2.88 (m, 1H), 1.96-1.94 (m, 2H), 1.55-1.53 (m, 2H). MS (chiad, m/z)=498.1 (M+H).

Example 10

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-3,5-dimethylquinazolin-4(3H)-one (70 mg, 0.21 mmol) and (R)-3-methoxypyrrolidine-1-sulfonyl chloride (167 mg, 0.84 mmol) in pyridine (2 ml) are sealed and heated at 65°C for 60 hours. The reaction mixture is cooled to ambient temperature and concentrated. The crude product is purified by silica gel column chromatography (30-100% EtOAc/hexane) to give (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline-6 -yl)oxy)-4-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide (55 mg, 53%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.58-7.55 (m, 1H), 7.43 (d, 1H), 7.15-7.11 ( t, 1H), 6.93-6.91 (m, 2H), 3.96-3.93 (m, 1H), 3.55 (s, 3H), 3.51-3.40 (m, 4H), 3.26 (s, 3H), 3.01 (s, 3H), 2.12-2.05 (m, 1H), 1.99-1.90 (m, 1H). MS (chiad, m/z)=497.1 (M+H).

Example 11

N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-bromo-3-methylquinazolin-4(3H)-one (250 mg, 0.63 mmol) and pyrrolidine-1-sulfonyl chloride ( 320 mg, 1.89 mmol) in pyridine (3.1 ml) are sealed and heated at 70°C for 18 hours.

The reaction mixture was cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(3-((5-bromo-3-methyl-4-oxo -3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate (202 mg, 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.58-7.54 (m, 1H), 7.51-7.49 (m, 1H), 7.14 ( t, 1H), 6.93-6.90 (m, 1H), 6.64 (s, 1H), 3.57 (s, 3H), 3.36-3.31 (m, 4H), 1 .90-1.86 (m, 4H). MS (chiad, m/z)=530.0, 532.0 (M+H).

Example 12

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (150 mg, 0.42 mmol) and pyrrolidine-1-sulfonyl chloride ( 180 mg, 1.06 mmol) in pyridine (2.1 ml) are sealed and heated at 70°C for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-3-((5-chloro-3-methyl -4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate (179 mg, 87%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.59 (s, 1H), 7.64-7.58 (m, 2H), 7.17 (t, 1H), 7.01-6.97 ( m, 1H), 6.77 (s, 1H), 6.54 (s, 1H), 3.68 (s, 1H), 3.38-3.34 (m, 4H), 1.92-1 .88 (m, 4H). MS (chiad, m/z)=486.1 (M+H).

Example 13

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-azabicyclo[2,1, 1]hexane-2-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.089 mmol) and 2-azabicyclo[2,1, 1]hexane-2-sulfonyl chloride (49 mg, 0.27 mmol) in pyridine (0.45 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-4-fluoro-3-((5-fluoro -3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-azabicyclo[2,1,1]hexane-2-sulfonamide trifluoroacetate (18 mg, 41%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.25 (s, 1H), 7.60-7.56 (m, 1H), 7.47-7.56 (m, 1H), 7.14 ( t, 1H), 7.08-7.03 (m, 1H), 6.80 (s, 1H), 5.96 (s, 1H), 4.26-4.24 (m, 1H), 3 .63 (s, 3H), 3.40 (s, 2H), 2.91-2.88 (m, 1H), 1.96-1.93 (m, 2H), 1.54-1.53 (m, 2H). MS (chiad, m/z)=482.1 (M+H).

Example 14

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidin- 1-sulfonamide and crystalline form of (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

Method A for the preparation of (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3 -fluoropyrrolidine-1-sulfonamide.

6-((3-Amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (Intermediate P13; 139.5 mg, 0.4143 mmol) dissolved in pyridine (4.1 ml) and treated with (3R)-3-fluoropyrrolidine-1-sulfonyl chloride (388.6 mg, 2.071 mmol) and the reaction mixture was heated to 60°C for 16 hours. The reaction mixture is cooled to ambient temperature and then diluted with EtOAc and washed with 10% citric acid (2x) then brine (1x) then dried over Na ₂ SO ₄ , filtered, and concentrated. The resulting residue is purified by silica gel chromatography (DCM/Acetone) then C18 reverse phase chromatography (water/ACN with 0.1% TFA). The combined desired fractions were then partitioned between 4:1 DCM:IPA and saturated NaHCO ₃ (1x) then dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was dissolved in DCM and washed with 1.0 M NaOH (2x), and then the combined aqueous layers were extracted with DCM (1x). The aqueous layer is acidified to about pH 2 using 4.0 M HCl and then extracted with 4:1 DCM:IPA (2x) and then dried over Na ₂ SO ₄ , filtered and concentrated to give (R)-N-(2-chloro -4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidine-1-sulfonamide (74.8 mg, 37 %). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.54 (s, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.42-7.38 ( m, 1H), 7.35-7.30 (m, 2H), 7.03-6.99 (t, 1H), 5.39-5.26 (m, 1H), 3.50-3, 39 (m, 6H), 3.35-3.28 (m, 1H), 2.15-2.00 (m, 2H). MS (chiad, m/z)=488.1, 490.1 (M+H).

Method B for the preparation of (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3 -fluoropyrrolidine-1-sulfonamide.

Step 1: Preparation of tert-butyl (R)-(2-chloro-4-fluoro-3-iodophenyl)((3-fluoropyrrolidin-1-yl)sulfonyl)carbamate. Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (Intermediate P9; 20 g, 54 mmol) was dissolved in THF (269 ml) and cooled to 0°C. The reaction mixture was treated with sodium hydride (4.3 g, 108 mmol, 60 wt%, in mineral oil) in portions, and then the ice bath was removed and the mixture was stirred for 15 minutes. The reaction mixture is treated with (R)-3-fluoropyrrolidine-1-sulfonyl chloride (20 g, 108 mmol) and then heated to 50°C for 12 hours. The reaction mixture is cooled to ambient temperature and poured slowly into a stirred flask with ice water (500 ml) and then extracted with EtOAc (3 x 100 ml). The organic extracts are washed with brine (1×50 ml), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue is purified by chromatography on silica gel (50-100% Hexane/DCM). The desired fractions are combined and concentrated, and the resulting solid is then sonicated with cooled MeOH, filtered, and washed with minimal MeOH to give tert-butyl (R)-(2-chloro-4-fluoro-3-iodophenyl)(3-fluoropyrrolidine -1-yl)sulfonyl)carbamate (21 g, 75%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.38 (m, 1H), 7.07-7.03 (m, 1H), 5.39-5.23 (m, 1H), 4.02-3.72 (m, 4H), 2.36-2.03 (m, 2H), 1.39 (s, 9H).

Step 2: Preparation of tert-butyl (R)-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl) ((3-fluoropyrrolidin-1-yl)sulfonyl)carbamate. 6-Amino-5-fluoro-3-methylquinazolin-4(3H)-one (15.7 g, 81 mmol), tert-butyl (R)-(2-chloro-4-fluoro-3-iodophenyl)(3 -fluoropyrrolidin-1-yl)sulfonyl)carbamate (38.5 g, 73.7 mmol), tri(dibenzylideneacetone)dipalladium (6.74 g, 7.37 mmol), (9,9-dimethyl-9H-xanthene- 4,5-diyl)bis(diphenylphosphane) (10.7 g, 18.4 mmol) and cesium carbonate (72.0 g, 221 mmol) were suspended in toluene (491 ml). The reaction mixture is purged with argon for 15 minutes and then heated to 100°C under an argon balloon for 16 hours. The reaction mixture is cooled to ambient temperature, dissolved in 4:1 DCM:IPA (500 ml) and EtOAc (200 ml) and filtered through a pad of Celite. The Celite is washed with additional 4:1 DCM:IPA (2×50 ml) and the filtrate is concentrated to give crude tert-butyl (R)-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl- 4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)((3-fluoropyrrolidin-1-yl)sulfonyl)carbamate (43.3 g, 100%), which is used directly in the next step. MS (chiad, m/z)=588.1, 590.1 (M+H).

Step 3: Preparation of (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)- 3-fluoropyrrolidine-1-sulfonamide. tert-Butyl (R)-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)((3- fluoropyrrolidin-1-yl)sulfonyl)carbamate (43.3 g, 73.6 mmol) was dissolved in 1:1 DCM:TFA (150 ml) and stirred at ambient temperature for 2 hours. The mixture is concentrated, dissolved in 4:1 DCM:IPA and washed with NaHCO ₃ (2×100 ml) and brine (1×50 ml). The organic phase is washed with 1 N NaOH (3 x 100 ml) and the combined aqueous layers are extracted with DCM (2 x 50 ml). The NaOH aqueous layer was acidified with 4N HCl to pH 1 and extracted with 4:1 DCM:IPA (3×100 ml). DCM: IPA, the organic phase is washed with NaHCO ₃ (1×100 ml) and brine (1×50 ml), dried over Na ₂ SO ₄ , filtered, and concentrated. The resulting residue is purified by silica gel chromatography (0-100% DCM/EtOAc) to give (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3, 4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidine-1-sulfonamide (29.7 g, 83%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.55-7.51 (m, 1H), 7.40-7.38 (m, 1H), 7.15- 7.11 (t, 1H), 7.05-7.00 (m, 1H), 6.79 (s, 1H), 5.92 (s, 1H), 5.30-5.15 (m, 1H), 3.69-3.58 (m, 5H), 3.52-3.45 (m, 2H), 2.31-2.21 (m, 1H), 2.13-1.94 ( m, 1H). MS (chiad, m/z) =488.1, 490.1 (M+H).

Method C. Preparation of crystalline form of (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl )-3-fluoropyrrolidine-1-sulfonamide, forms A. (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazoline- 6-yl)amino)phenyl)-3-fluoropyrrolidine-1-sulfonamide prepared by Method A or Method B (63.7 g, 131 mmol) was treated with EtOAc (76 ml, 0.83 mg/ml) and the mixture was stirred until dissolved . The reaction mixture is stirred for 1 hour until solidified, and then additional EtOAc is added to resume stirring, and the mixture is left to stir for 12 hours at ambient temperature. The solution is diluted with cooled EtOAc (100 ml), filtered, and washed with additional cooled EtOAc (25 ml) to give (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 (52.3 g, 82%) as a white solid as determined by powder x-ray diffraction. Powder X-ray diffraction is performed using a Rigaku MiniFlex 6G diffractometer equipped with a Cu radiation source. Diffracted radiation is determined by a D/teX Ultra2 sensor. The X-ray tube voltage and current are set to 40 kV and 15 mA, respectively. Data are collected on a MiniFlex inclinometer at Cu wavelengths from 3.0 to 45.0° 2-Theta using a step width of 0.01° and a step speed of 3.00°/min. The box with the entrance slot is set to 1.25° and the slot limiting the length is set to 10 mm. The sample is rotated at 10 rpm during collection. Samples are obtained by placing them in a low-background silicone sample holder.

Data are collected and analyzed using SmartLab Studio II software (version 4.3.147.0). The software automatically identifies peaks in the PXRD data file using the second derivative method followed by manual peak selection. Typically, peaks with relative intensity ≥3% are selected. Typical error associated with crystalline material peak position as measured by PXRD as specified in USP is up to +/- 0.2° 2-theta (USP-941). Figure 1 shows the PXRD picture of the crystal structure of (3R)-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, and Table D shows the PXRD crystal pattern peaks of crystal form (3R)-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.

Example 15

cis-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoro-4- methoxypyrrolidine-1-sulfonamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.0891 mmol) and cis-3-fluoro- 4-methoxypyrrolidine-1-sulfonyl chloride (97 mg, 0.445 mmol) in pyridine (0.8 ml) is heated at 70°C for 24 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/EtOAc) then reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give cis-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)phenyl)-3-fluoro-4-methoxypyrrolidine-1-sulfonamide (11.2 mg, 24%) as an off-white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.54-7.46 (m, 1H), 7.43-7.36 (d, 1H), 7.18- 7.09 (t, 1H), 7.09-6.99 (m, 1H), 6.76 (s, 1H), 5.92 (s, 1H), 5.23-4.97 (m, 1H), 3.97-3.82 (m, 1H), 3.82-3.74 (m, 1H), 3.70-3.67 (d, 1H), 3.62-3.58 ( m, 1H), 3.57 (s, 3H), 3.44 (s, 3H), 3.35-3.26 (m, 1H); MS (chiad, m/z)=518.1, 520.1 (M+H).

Example 16

cis-N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-fluoro-4-methoxypyrrolidine -1-sulfonamide trifluoroacetate

Step 1: Preparation of cis-3-fluoro-4-methoxypyrrolidine-1-sulfonyl chloride. A suspension of cis-3-fluoro-4-methoxypyrrolidine hydrochloride (0.834 g, 5.36 mmol) and N,N-diisopropylethylamine (1.40 ml, 8.04 mmol) was stirred in DCM (13 ml) at ambient temperature until completely dissolving the mixture. The reaction mixture is cooled to 0°C and treated with sulfuryl chloride (1.08 ml, 13.4 mmol). The cold bath is removed after 30 minutes and the mixture is stirred at ambient temperature for 18 hours. The reaction mixture is diluted with additional DCM and washed with 1.0 M HCl (1x). The organic layer was separated, dried over anhydrous MgSO ₄ , filtered and concentrated to obtain crude cis-3-fluoro-4-methoxypyrrolidine-1-sulfonyl chloride, which was used as is in the next step.

Step 2: Preparation of cis-N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-fluoro -4-methoxypyrrolidine-1-sulfonamide trifluoroacetate. A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-bromo-3-methylquinazolin-4(3H)-one (35 mg, 0.088 mmol) and cis-3-fluoro-4- methoxypyrrolidine-1-sulfonyl chloride (48 mg, 0.22 mmol) in pyridine (0.44 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give cis-N-(3-((5-bromo-3-methyl-4 -oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-fluoro-4-methoxypyrrolidine-1-sulfonamide trifluoroacetate (3.0 mg, 6%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (s, 1H), 7.59-7.56 (m, 2H), 7.16 (t, 1H), 6.97-6.94 ( m, 1H), 6.78 (s, 1H), 6.65 (s, 1H), 5.20-5.04 (m, 1H), 3.96-3.86 (m, 1H), 3 .81-3.77 (m, 1H), 3.68-3.67 (m, 1H), 3.61 (s, 3H), 3.45 (m, 3H), 3.32-3.27 (m, 1H), 2.10-2.05 (m, 2H). MS (chiad, m/z)=578.0, 580.0 (M+H).

Example 17

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-azabicyclo[3,1,0 ]hexane-3-sulfonamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (35 mg, 0.099 mmol) and 3-azabicyclo[3,1, 0]hexane-3-sulfonyl chloride (72 mg, 0.40 mmol) in pyridine (0.8 ml) was sealed and heated at 65°C for 60 hours. The reaction mixture is cooled to ambient temperature and concentrated. The crude product is purified by silica gel column chromatography (50-100% EtOAc/hexane) followed by reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated NaHCO ₃ . The combined organic layers are separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6- yl)amino)-4-fluorophenyl)-3-azabicyclo[3,1,0]hexane-3-sulfonamide (34 mg, 69%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.51-7.47 (m, 2H), 7.17-7.12 (t, 1H), 6.96- 6.93 (m, 1H), 6.78 (s, 1H), 6.46 (s, 1H), 3.57 (s, 3H), 3.49 (s, 1H), 3.47 (s , 1H), 3.40-3.37 (m, 2H), 1.53-1.50 (m, 2H), 0.64-0.59 (m, 1H), 0.21-0.18 (m, 1H). MS (chiad, m/z)=498.1 (M+H).

Example 18

cis-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoro-4-methoxypyrrolidine -1-sulfonamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (30 mg, 0.0849 mmol) and cis-3-fluoro- 4-methoxypyrrolidine-1-sulfonyl chloride (108 mg, 0.496 mmol) in pyridine (0.8 ml) is heated at 70°C for 24 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (DCM/EtOAc) to give cis-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino) -4-fluorophenyl)-3-fluoro-4-methoxypyrrolidine-1-sulfonamide (45.4 mg, 21%) as an off-white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.58-7.53 (m, 1H), 7.53-7.48 (d, 1H), 7.18- 7.12 (t, 1H), 6.99-6.92 (m, 1H), 6.78 (s, 1H), 6.45 (s, 1H), 5.20-5.02 (m, 1H), 3.96-3.85 (m, 1H), 3.82-3.76 (m, 1H), 3.71-3.66 (d, 1H), 3.63-3.59 ( t, 1H), 3.57 (s, 3H), 3.44 (s, 3H), 3.35-3.25 (m, 1H); MS (chiad m/z)=534.1, 536.1 (M+H).

Example 19

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide

6-((3-Amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (152.6 mg, 0.4321 mmol) was dissolved in pyridine (1, 8 ml), then treated with (3R)-3-fluoropyrrolidine-1-sulfonyl chloride (121.6 mg, 0.6481 mmol) and heated to 60°C for 16 hours. The reaction mixture was treated with additional (3R)-3-fluoropyrrolidine-1-sulfonyl chloride (121.6 mg, 0.6481 mmol) and stirred at 60°C for an additional 3 hours. The reaction mixture is cooled to ambient temperature and diluted with EtOAc and washed with 10% citric acid (2x) and brine (1x), then dried over Na ₂ SO ₄ , filtered, and concentrated. The resulting residue was purified by silica gel chromatography (DCM/EtOAc) to give (R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl) amino)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (93.9 mg, 43%). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.56 (s, 1H), 8.18 (s, 1H), 7.72 (s, 1H), 7.50-7.46 ( m, 1H), 7.41-7.33 (m, 2H), 6.73-6.70 (dd, 1H), 5.36-5.23 (m, 1H), 3.47-3, 30 (m, 7H), 2.12-1.97 (m, 2H). MS (chiad, m/z)=504.0, 506.0 (M+H).

Example 20

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluoropyrrolidin- 1-sulfonamide

To a solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.089 mmol) in pyridine (0.8 ml) add (R )-3-fluoropyrrolidine-1-sulfonyl chloride (67 mg, 0.36 mmol), and the reaction mixture was sealed and stirred at 65°C for 48 hours. The reaction mixture is cooled to ambient temperature and concentrated. The crude product is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) then silica gel column chromatography (50-100% EtOAc/hexane) to give (R)-N-(2-chloro- 4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluoropyrrolidine-1-sulfonamide (28 mg, 64%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.59-7.55 (m, 1H), 7.43-7.40 (dd, 1H), 7.24- 7.20 (t, 1H), 7.14-7.09 (t, 1H), 6.80 (s, 1H), 5.29-5.14 (m, 1H), 3.67-3, 43 (m, 7H), 2.30-2.20 (m, 1H), 2.11-1.92 (m, 1H). MS (chiad, m/z)=489, 1 (M+H).

Example 21

cis-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3,4-difluoropyrrolidin- 1-sulfonamide

Step 1: Preparation of cis-3,4-difluoropyrrolidine-1-sulfonyl chloride. A suspension of cis-3,4-difluoropyrrolidine HCl (1.0 g, 6.97 mmol) and N,N-diisopropylethylamine (376 μL, 2.16 mmol) was stirred in DCM (70 ml) at ambient temperature until the mixture was completely dissolved . The reaction mixture was cooled to 0°C and treated with sulfuryl chloride (1.69 ml, 20.9 mmol). The ice bath is removed after 30 minutes and the mixture is stirred at ambient temperature for 16 hours. The reaction mixture is diluted with additional DCM and washed with 1.0 M HCl (3x). The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give crude cis-3,4-difluoropyrrolidine-1-sulfonyl chloride (1/21 g, 85%) which was used directly in the next step.

Step 2: Preparation of cis-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3, 4-difluoropyrrolidine-1-sulfonamide. A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.0891 mmol) and cis-3,4- Difluoropyrrolidine-1-sulfonyl chloride (92 mg, 0.45 mmol) in pyridine (0.8 ml) is heated at 70°C for 24 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/EtOAc) then reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give cis-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)phenyl)-3,4-difluoropyrrolidine-1-sulfonamide (22 mg, 49%) as an off-white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.70 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.40-7.24 ( m, 3H), 7.05-6.96 (t, 1H), 5.41-5.15 (m, 2H), 3.70-3.56 (m, 2H), 3.48-3, 37 (m, 6H); MS (chiad, m/z)=506.1, 508.1 (M+H).

Example 22

cis-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,4-difluoropyrrolidine-1 -sulfonamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (30 mg, 0.085 mmol) and cis-3,4-difluoropyrrolidin- 1-sulfonyl chloride (87 mg, 0.42 mmol) in pyridine (0.8 ml) is heated at 70°C for 24 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/EtOAc) then reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give cis-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6- yl)amino)-4-fluorophenyl)-3,4-difluoropyrrolidine-1-sulfonamide (22 mg, 50%) as an off-white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.73 (s, 1H), 8.18 (s, 1H), 7.73 (s, 1H), 7.49-7.32 ( m, 3H), 6.77-6.70 (m, 1H), 5.38-5.16 (m, 2H), 3.68-3.55 (m, 2H), 3.46-3, 33 (m, 5H); MS (chiad, m/z)=522.0, 524.0 (M+H).

Example 23

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3,3-difluoropyrrolidin-1- sulfonamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.089 mmol) and 3,3-difluoropyrrolidin-1- sulfonyl chloride (55 mg, 0.27 mmol) in pyridine (0.5 ml) is heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM (25 ml) and 10% aqueous CuSO ₄ (25 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ (15 ml) and DCM (30 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)phenyl)-3,3-difluoropyrrolidine-1-sulfonamide (8 mg, 18%) as a white solid ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H ), 7.51-7.46 (m, 1H), 7.42-7.38 (m, 1H), 7.15 (t, 1H), 7.00 (m, 1H), 6.75 ( s, 1H), 3.71-3.54 (m, 7H), 2.44-2.31 (m, 2H); MS (chiad, m/z)=506.1 (M+H).

Example 24

(R)-N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-bromo-3-methylquinazolin-4(3H)-one (35 mg, 0.088 mmol) and (R)-3-fluoropyrrolidin- 1-sulfonyl chloride (41 mg, 0.22 mmol) in pyridine (0.44 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated, and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(3-((5-bromo-3- Methyl 4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide trifluoroacetate (3.0 mg, 6%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.61-7.52 (m, 2H), 7.16 (t, 1H), 6.95-6.92 ( m, 1H), 6.78 (s, 1H), 6.63 (s, 1H), 5.30-5.15 (m, 1H), 3.66-3.60 (m, 1H), 3 .60 (s, 3H), 3.53-3.45 (m, 1H), 2.35-2.21 (m, 2H), 2.14-2.00 (m, 2H). MS (chiad, m/z)=548.0, 550.0 (M+H).

Example 25

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,3-difluoropyrrolidine-1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (35 mg, 0.099 mmol) and 3,3-difluoropyrrolidin-1- sulfonyl chloride (61 mg, 0.30 mmol) in pyridine (0.50 ml) is sealed and heated at 70°C for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated, and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-3-((5-chloro-3- Methyl 4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,3-difluoropyrrolidine-1-sulfonamide trifluoroacetate (21 mg, 40%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 7.57-7.55 (m, 2H), 7.18 (t, 1H), 6.98-6.95 ( m, 1H), 6.77 (s, 1H), 6.49 (s, 1H), 3.67-3.63 (m, 2H), 3.61 (s, 3H), 3.59-3 .54 (m, 2H), 2.47-2.33 (m, 2H). MS (chiad, m/z)=522.0, 524.0 (M+H).

Example 26

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(difluoromethoxy )pyrrolidine-1-sulfonamide

Step 1: Preparation of (R)-3-(difluoromethoxy)pyrrolidine-1-sulfonyl chloride. To an ice-cold solution of (R)-3-(difluoromethoxy)pyrrolidine (107 mg, 0.780 mmol) and N-ethyl-N-isopropylpropan-2-amine (204 μL, 1.17 mmol) in DCM (6 mL) sulfuryl dichloride (189 μl, 2.34 mmol), and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture is diluted with DCM (20 ml) and washed with aqueous 1M HCl (10 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain (R)-3-(difluoromethoxy)pyrrolidine-1-sulfonyl chloride, which is used directly in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.47-6.09 (m, 1H), 5.00-4.95 (m, 1H), 3.73-3.58 (m, 4H), 2.30-2.20 (m, 2H).

Step 2: Preparation of (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)- 3-(difluoromethoxy)pyrrolidine-1-sulfonamide. A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (50 mg, 0.149 mmol) and (R)-3-(difluoromethoxy )pyrrolidine-1-sulfonyl chloride (174.9 mg, 0.742 mmol) in pyridine (1 ml) was heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM (25 ml) and 10% aqueous CuSO ₄ (25 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product is purified by silica gel chromatography (hexane/ethyl acetate 0-100%), then reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ (15 ml) and DCM (30 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo- 3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(difluoromethoxy)pyrrolidine-1-sulfonamide (28.02 mg, 35%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.55-7.49 (m, 1H), 7.43-7.38 (m, 1H), 7.13 ( t, 1H), 7.08-7.01 (m, 1H), 6.77 (s, 1H), 4.87-4.80 (m, 1H), 3.62-3.43 (m, 7H), 2.17-2.08 (m, 2H); MS (chiad m/z)=536.1 (M+H).

Example 27

(S)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidin- 1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.09 mmol) and (S)-3- Fluoropyrrolidine-1-sulfonyl chloride (50 mg, 0.3 mmol) in pyridine (445 μl, 0.0891 mmol) is heated to 70°C in a sealed tube for 24 hours. The solution is cooled to ambient temperature, concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is lyophilized to give (S)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)- 3-fluoropyrrolidine-1-sulfonamide trifluoroacetate (18.6 mg, 42.8%). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.54 (s, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.42-7.30 ( m, 2H), 7.03-6.99 (t, 1H), 5.32 (d, 1H), 3.50-3.30 (m, 7H), 2.16-1.96 (m, 2H); MS (chiad m/z)=488.1 (M+H).

Example 28

(S)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (30 mg, 0.09 mmol) and (S)-3- Fluoropyrrolidine-1-sulfonyl chloride (48 mg, 0.25 mmol) in pyridine (425 μl, 0.085 mmol) is heated to 70°C in a sealed tube for 24 hours. The solution is cooled to ambient temperature, concentrated and purified by silica gel chromatography (1-10% MeOH/DCM, 1% NH ₄ OH) to give (S)-N-(2-chloro-3-((5-chloro-3 -methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (14 mg, 33%). ^1H NMR (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 7.67-7.63 (m, 1H), 7.43 (d, 1H), 7.28-7.23 (t, 1H), 6.92-6.89 (m, 1H), 5.31-5.15 (m, 1H), 3.61-3.39 (m, 7H), 2.22-2 .00 (m, 2H); MS (chiad m/z)=504.1 (M+H).

Example 29

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(difluoromethoxy) pyrrolidine-1-sulfonamide

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (52 mg, 0.1472 mmol) and (R)-3- (difluoromethoxy)pyrrolidine-1-sulfonyl chloride (173.5 mg, 0.7362 mmol) in pyridine (0.800 ml) was heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM (25 ml) and 10% aqueous CuSO ₄ (25 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (hexane/ethyl acetate 0-100%), then reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ (15 ml) and DCM (30 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(difluoromethoxy)pyrrolidine-1-sulfonamide (27.34 mg, 34%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.59-7.53 (m, 1H), 7.50 (d, 1H), 7.15 (t, 1H) , 6.98-6.94 (m, 1H), 6.77 (s, 1H), 6.46 (s, 1H), 6.35-5.97 (m, 1H), 4.88-4 .81(m, 1H), 3.63-3.44 (m, 7H), 2.17-2.10 (m, 2H); MS (chiad, m/z)=552.0 (M+H).

Example 30

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-azabicyclo[3,1, 0]hexane-3-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.09 mmol) and 3-azabicyclo[3, 1,0]hexane-3-sulfonyl chloride (48 mg, 0.27 mmol) in pyridine (445 μl, 0.0891 mmol) is heated to 70°C in a sealed tube for 24 hours. The solution is cooled to ambient temperature, concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is lyophilized to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-azabicyclo[ 3,1,0]hexane-3-sulfonamide trifluoroacetate (23.5 mg, 54.7%). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.46 (s, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 7.38-7.30 ( m, 3H), 7.03-6.98 (t, 1H), 3.44 (s, 3H), 3.29 (s, 4H), 1.56-1.52 (m, 2H), 0 .60-0.54 (m, 1H), 0.16-0.13 (m, 1H); MS (chiad, m/z)=482.1 (M+H).

Example 31

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-5,6-difluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (100 mg, 0.2694 mmol) and pyrrolidin-1- sulfonyl chloride (114.2 mg, 0.6735 mmol) in pyridine (1.35 ml) was heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM (15 ml) and 10% aqueous CuSO ₄ (15 ml). The organic phase is separated, dried over Mg ₂ SO ₄ , filtered and concentrated. The reaction mixture is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are collected and lyophilized to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)pyrrolidine -1-sulfonamide trifluoroacetate (73.5 mg, 54%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.61 (d, 1H), 7.49-7.45 (m, 1H), 7.06-7.03 ( m, 1H), 6.85 (s, 1H), 6.54 (s, 1H), 3.64 (s, 3H), 3.40-3.36 (m, 4H), 1.95-1 .92 (m, 4H). MS (chiad, m/z)=504.0 (M+H).

Example 32

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-methoxypyrrolidine -1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-5,6-difluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (100 mg, 0.269 mmol) and (R)-3- methoxypyrrolidine-1-sulfonyl chloride (134.5 mg, 0.6735 mmol) in pyridine (1.35 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ (15 ml). The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(2-chloro-3-((5-chloro -3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-methoxypyrrolidine-1-sulfonamide trifluoroacetate (144 mg, 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.60 (d, 1H), 7.53-7.48 (m, 1H), 7.07-7.04 ( m, 2H), 6.54 (s, 1H), 4.00-3.98 (m, 1H), 3.64 (s, 3H), 3.56-3.43 (m, 4H), 3 .29 (s, 3H), 2.18-2.12 (m, 1H), 2.04-1.94 (m, 1H). MS (chiad, m/z)=534.1 (M+H).

Example 33

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-fluoropyrrolidine -1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-5,6-difluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (100 mg, 0.269 mmol) and (R)-3- fluoropyrrolidine-1-sulfonyl chloride (126.4 mg, 0.6735 mmol) in pyridine (1.35 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ (15 ml). The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(2-chloro-3-((5-chloro -3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide trifluoroacetate (141 mg, 43%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.78 (s, 1H), 7.66 (d, 1H), 7.58-7.53 (m, 1H), 7.07-7.05 ( m, 1H), 6.89 (s, 1H), 6.57 (s, 1H), 5.33-5.18 (m, 1H), 3.71 (s, 3H), 3.68-3 .62 (m, 2H), 3.55-3.46 (m, 2H), 2.36-2.26 (m, 1H), 2.18-1.99 (m, 1H). MS (chiad, m/z)=522.1 (M+H).

Example 34

(R)-N-(3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)-3-methoxypyrrolidine-1 -sulfonamide

To a solution of 6-((3-amino-2,5,6-trifluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (15 mg, 0.042 mmol) in pyridine (211 μl, 0.042 mmol ) add (R)-3-methoxypyrrolidine-1-sulfonyl chloride (21 mg, 0.11 mmol) and the reaction mixture is heated in a sealed tube to 70°C for 16 hours. The solution is cooled to ambient temperature, concentrated and purified by silica gel chromatography (1-15% MeOH/DCM, 1% NH ₄ OH) to give (R)-N-(3-((5-chloro-3-methyl-4 -oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)-3-methoxypyrrolidine-1-sulfonamide (12 mg, 55%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.54 (d, 1H), 7.40-7.33 (m, 1H), 7.14-7.10 ( m, 1H), 7.04 (shs, 1H), 6.32 (shs, 1H), 3.58 (s, 3H), 3.55-3.37 (m, 5H), 3.29 (s , 3H), 1.99-1.93 (m, 2H); MS (chiad, m/z)=518.1 (M+H).

Example 35

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-fluoropyrrolidin-1 -sulfonamide

A solution of 6-((3-amino-2-chloro-5,6-difluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one (125 mg, 0.35 mmol) and (R)-3- Fluoropyrrolidine-1-sulfonyl chloride (334.3 mg, 1.78 mmol) in pyridine (3.6 ml) is heated at 70°C for 24 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/EtOAc) then reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x), and the organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give (R)-N-(2-chloro- 3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4,5-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (50 mg, 28%) as off-white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.49-7.46 (d, 1H), 7.32-7.27 (m, 1H), 7.15- 7.13 (m, 1H), 6.81 (s, 1H), 5.65 (s, 1H), 5.32-5.16 (m, 1H), 3.71-3.47 (m, 7H), 2.96 (s, 3H), 2.34-1.98 (m, 2H); MS (chiad, m/z)=502.1, 504.1 (M+H).

Example 36

(R)-N-(3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide trifluoroacetate

To a solution of 6-((3-amino-2,5,6-trifluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (13 mg, 0.037 mmol) in pyridine (183 μl, 0.037 mmol ) add (R)-3-fluoropyrrolidine-1-sulfonyl chloride (17 mg, 0.092 mmol) and the reaction mixture is heated in a sealed tube to 70°C for 6 hours. The solution is cooled to ambient temperature, concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is lyophilized to give (R)-N-(3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)-3 -fluoropyrrolidine-1-sulfonamide trifluoroacetate (5 mg, 27% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 7.64 (d, 1H), 7.45-7.38 (m, 1H), 7.16-7.12 ( m, 1H), 6.65 (shs, 1H), 6.40 (s, 1H), 5.25 (d, 1H), 3.69 (s, 3H), 3.66-3.44 (m , 4H), 2.35-2.00 (m, 2H); MS (chiad, m/z)=506.1 (M+H).

Example 37

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-methoxypyrrolidine-1 -sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (96 mg, 0.2711 mmol) and (R)-3-methoxypyrrolidin-1 -sulfonyl chloride (270.6 mg, 1.355 mmol) in pyridine (2.2 ml) was heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature, then partitioned between DCM (75 ml) and 10% aqueous CuSO ₄ (75 ml). The organic phase is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (hexane/ethyl acetate 0-100%), then reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ (30 ml) and DCM (15×3 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide (38.53 mg, 27%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.61-7.56 (m, 1H), 7.50 (d, 1H), 7.14 (t, 1H) , 7.04-7.00 (m, 2H), 3.97-3.92 (m, 1H), 3.57 (s, 3H), 3.52-3.37 (m, 4H), 3 .25 (s, 3H), 2.13-2.04 (m, 1H), 2.00-1.87 (m, 1H); MS (chiad, m/z)=517.0 (M+H).

Example 38

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (75 mg, 0.2118 mmol) and (R)-3-fluoropyrrolidin-1 -sulfonyl chloride (119.2 mg, 0.6353 mmol) in pyridine (1.8 ml) was heated at 70°C for 48 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM (50 ml) and 10% aqueous CuSO ₄ (50 ml). The organic phase is dried over Na ₂ SO ₄ , filtered and then concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (hexane/ethyl acetate 0-100%) followed by reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ (15 ml) and DCM (30 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (39.6 mg, 37%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.63-7.58k (m, 1H), 7.50 (d, 1H), 7.15 (t, 1H) , 7.03-6.99 (d, 1H), 6.89 (s, 1H), 5.30-5.13 (m, 1H), 3.68-3.42 (m, 7H), 2 .32-2.18 (m, 1H), 2.13-1.93 (m, 1H); MS (chiad, m/z)=505.0 (M+H).

Example 39

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)pyrrolidine-1-sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (50 mg, 0.141 mmol) and pyrrolidine-1-sulfonyl chloride (120 mg, 0.706 mmol ) in pyridine (1.1 ml) was stirred at 70°C for 48 hours. The reaction mixture is cooled to ambient temperature, then partitioned between DCM (50 ml) and 10% aqueous CuSO ₄ (50 ml). The organic phase is dried over Na ₂ SO ₄ , filtered and then concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (hexane/ethyl acetate 0-100%), then reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ (15 ml) and DCM (30 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6- yl)oxy)-4-fluorophenyl)pyrrolidine-1-sulfonamide (45.6 mg, 66%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.60-7.55 (m, 1H), 7.49 (d, 1H), 7.14 (t, 1H) , 7.00 (d, 1H), 6.93 (s, 1H), 3.57 (s, 3H), 3.36-3.26 (m, 4H), 1.90-1.80 (m , 4H); MS (chiad, m/z)=487.0 (M+H).

Example 40

N-(2-chloro-4,5-difluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-5,6-difluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (35 mg, 0.09867 mmol) and pyrrolidin-1- sulfonyl chloride (41.84 mg, 0.2467 mmol) in pyridine (0.49 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ (15 ml). The DCM extract is dried over MgSO ₄ , concentrated, and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-4,5-difluoro-3-(( 5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide trifluoroacetate (32.4 mg, 67%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 7.54 (d, 1H), 7.46-7.41 (m, 1H), 7.19-7.13 ( m, 1H), 6.85 (s, 1H), 6.05 (s, 1H), 3.68 (s, 3H), 3.40-3.36 (m, 4H), 1.95-1 .92 (m, 4H). MS (chiad, m/z)=488.1 (M+H).

Example 41

N-(2-chloro-4,5-difluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-azabicyclo[2, 1,1]hexane-2-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-5,6-difluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (35 mg, 0.09867 mmol) and 2-azabicyclo[ 2,1,1]hexane-2-sulfonyl chloride (44.80 mg, 0.2467 mmol) in pyridine (0.49 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ (15 ml). The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-4,5-difluoro-3-((5 -fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-azabicyclo[2,1,1]hexane-2-sulfonamide trifluoroacetate (16.4 mg, 33% ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 7.52-7.46 (m, 2H), 7.17-7.11 (m, 1H), 6.88 ( s, 1H), 6.02 (s, 1H), 4.27 (d, 1H), 3.65 (s, 3H), 3.41 (s, 2H), 2.93-2.90 (m , 1H), 1.99-1.95 (m, 2H), 1.56-1.55 (m, 2H). MS (chiad, m/z)=500.1 (M+H).

Example 42

N-(2-chloro-4-fluoro-3-((5-fluoro-3-(fluoromethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide trifluoroacetate

Step 1: Preparation of 6-bromo-5-fluoro-3-(fluoromethyl)quinazolin-4(3H)-one. 6-Bromo-5-fluoroquinazolin-4(3H)-one (0.512 g, 2.107 mmol) was dissolved in N,N-dimethylformamide (5.26 ml) and treated with iodofluoromethane (0.1566 ml, 2.317 mmol) and potassium carbonate ( 0.4367 g, 3.160 mmol). The reaction is maintained at ambient temperature for 16 hours. The crude reaction mixture is diluted with DCM (30 ml) and filtered through Celite®. The filtrate is washed with water (20 ml). The organic layer was collected, dried over MgSO ₄ and concentrated to give 6-bromo-5-fluoro-3-(fluoromethyl)quinazolin-4(3H)-one, which was used in the next step without purification.

Step 2: Preparation of tert-butyl (5-fluoro-3-(fluoromethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)carbamate. 6-Bromo-5-fluoro-3-(fluoromethyl)quinazolin-4(3H)-one (500 mg, 1.82 mmol) was dissolved in toluene (18 ml) and treated with tert-butylcarbamate (224 mg, 1.91 mmol ), tris(dibenzylideneacetone) dippalladium (0) (83.2 mg, 0.0909 mmol), Xantphos (158 mg, 0.273 mmol) and cesium carbonate (1777 mg, 5.45 mmol). The solution is purged with argon for several minutes and then heated and stirred at 110°C under argon for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (30 ml) and stirred for 15 minutes then filtered through Celite® and concentrated. The resulting residue was purified by silica gel chromatography (55-95% EtOAc/Hexane) to give (5-fluoro-3-(fluoromethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)carbamate (270 mg, 47% per two stages). MS (chiad, m/z)=312.1 (M+H).

Step 3: Preparation of 6-amino-5-fluoro-3-(fluoromethyl)quinazolin-4(3H)-one. (5-Fluoro-3-(fluoromethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)carbamate (267 mg, 0.858 mmol) was dissolved in 10 ml of 1:1 TFA/DCM solution and the reaction mixture was stirred at ambient temperature for 15 minutes. The solvent is removed in vacuo. The resulting residue was dissolved in 4:1 DCM/IPA (10 ml) and washed with saturated aqueous NaHCO ₃ (10 ml, x3). The organic layer was dried over MgSO ₄ , filtered and concentrated to give 6-amino-5-fluoro-3-(fluoromethyl)quinazolin-4(3H)-one, which was used without further purification. MS (chiad, m/z)=212.1 (M+H).

Step 4: Preparation of tert-butyl (2-chloro-4-fluoro-3-((5-fluoro-3-(fluoromethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)carbamate. 6-Amino-5-fluoro-3-(fluoromethyl)quinazolin-4(3H)-one (200 mg, 0.947 mmol) was dissolved in toluene (9 ml) and treated with tert-butyl (2-chloro-4-fluoro-3 -iodophenyl)carbamate (370 mg, 0.994 mmol), tris(dibenzylideneacetone) dippalladium (0) (43.4 mg, 0.0474 mmol), Xantphos (82.2 mg, 0.142 mmol) and cesium carbonate (926 mg, 2 .84 mmol). The solution is purged with argon for several minutes and then heated and stirred at 110°C under argon for 6 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and stirred for 15 minutes, then filtered through Celite and concentrated. The resulting residue is purified by chromatography on silica gel (25-75% EtOAc/Hexane) to give tert-butyl (2-chloro-4-fluoro-3-((5-fluoro-3-(fluoromethyl)-4-oxo-3,4 -dihydroquinazolin-6-yl)amino)phenyl)carbamate (332 mg, 75% in two stages). MS (chiad, m/z)=455.1 (M+H).

Step 5: Preparation of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-(fluoromethyl)quinazolin-4(3H)-one. Tert-butyl (2-chloro-4-fluoro-3-((5-fluoro-3-(fluoromethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)carbamate (322 mg, 0.708 mmol) was dissolved in 10 ml of a 1:1 TFA/DCM solution and the reaction mixture was stirred at ambient temperature for 15 minutes. The solvent is removed in vacuo. The resulting residue was dissolved in 4:1 DCM/IPA (10 ml) and washed with saturated aqueous NaHCO ₃ (10 ml, x3). The organic layer was dried over MgSO ₄ , filtered and concentrated to give 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-(fluoromethyl)quinazolin-4(3H)-one (96 mg, 38%) which is used without further purification. MS (chiad, m/z)=355.1 (M+H).

Step 6: Preparation of N-(3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate . A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-(fluoromethyl)quinazolin-4(3H)-one (20 mg, 0.05638 mmol) and 1-pyrrolidine -sulfonyl chloride (23.91 mg, 0.1410 mmol) in pyridine (0.28 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ (15 ml). The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-4-fluoro-3-((5-fluoro -3-(fluoromethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide trifluoroacetate (15.4 mg, 56%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 7.58-7.54 (m, 1H), 7.48-7.46 (m, 1H), 7.16 ( t, 1H), 7.09-7.04 (m, 1H), 6.77 (s, 1H), 6.05 (d, 2H), 6.00 (s, 1H), 3.37-3 .34 (m, 4H), 1.91-1.88 (m, 4H). MS (chiad, m/z)=488.1 (M+H).

Example 43

N-(3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate

To a solution of 6-((3-amino-2,5,6-trifluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (13 mg, 0.037 mmol) in pyridine (183 μl, 0. 0366 mmol) pyrrolidine-1-sulfonyl chloride (10.5 µl, 0.0916 mmol) is added and the reaction mixture is heated in a sealed tube to 70°C for 5 hours. The solution is concentrated and the residue is purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is lyophilized to give N-(3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4,5-trifluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate (9 mg, 50.3%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.60 (s, 1H), 7.67 (d, 1H), 7.39-7.33 (m, 1H), 7.16-7.12 ( m, 1H), 6.58 (shs, 1H), 6.42 (s, 1H), 3.69 (s, 3H), 3.40-3.36 (m, 4H), 1.96-1 .92 (m, 4H); MS (chiad, m/z)=488.1 (M+H).

Example 44

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)pyrrolidine-1-sulfonamide trifluoroacetate

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (85 mg, 0.2517 mmol) and pyrrolidine-1-sulfonyl chloride (106.7 mg, 0.6292 mmol) in pyridine (1.26 ml) is sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ (15 ml). The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-4-fluoro-3-((5-fluoro -3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)pyrrolidine-1-sulfonamide trifluoroacetate (119 mg, 68%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 7.60-4.56 (m, 1H), 7.31-7.27 (m, 1H), 7.14 ( t, 1H), 6.77 (s, 1H), 3.63 (s, 3H), 3.35-3.32 (m, 4H), 1.91-1.87 (m, 4H). MS (chiad, m/z)=471.1 (M+H).

Example 45

N-(2-chloro-4,5-difluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)phenyl)-(N-ethyl-N-methyl )-sulfamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-5,6-difluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.08457 mmol) and N-ethyl- N-methylsulfamoyl chloride (33.32 mg, 0.2114 mmol) in pyridine (0.42 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ (15 ml). The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give N-(2-chloro-4,5-difluoro-3-((5 -fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)phenyl)-(N-ethyl-N-methyl)-sulfonamide trifluoroacetate (26.1 mg, 65%). ^1H NMR ( 400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.52-7.50 (d, 1H), 7.39-7.34 (m, 1H), 7.18-7.12 ( m, 1H), 6.78 (s, 1H), 6.03 (s, 1H), 3.66 (s, 3H), 3.34-3.29 (m, 2H), 2.88 (s , 3H), 1.20-1.16 (t, 3H); MS (chiad, m/z) = 476.1 (M+H).

Example 46

(R)-N-(2-chloro-4,5-difluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3- fluoropyrrolidine-1-sulfonamide trifluoroacetate. A solution of 6-((3-amino-2-chloro-5,6-difluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.08457 mmol) and (R)- 3-fluoropyrrolidine-1-sulfonyl chloride (39.67 mg, 0.2114 mmol) in pyridine (0.42 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ (15 ml). The DCM extract is dried over MgSO ₄ , concentrated, and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(2-chloro-4,5-difluoro- 3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidine-1-sulfonamide trifluoroacetate (24.1 mg, 56%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.52-7.45 (m, 2H), 7.16-7.11 (m, 1H), 6.85 ( s, 1H), 6.01 (s, 1H), 5.32-5.17 (m, 1H), 3.68-3.62 (m, 5H), 3.55-3.47 (m, 2H), 2.35-2.25 (m, 1H), 2.18-1.98 (m, 1H). MS (chiad, m/z)=506.1 (M+H).

Example 47

(R)-N-(2-chloro-4,5-difluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3- methoxypyrrolidine-1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-5,6-difluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.08457 mmol) and (R)- 3-methoxypyrrolidine-1-sulfonyl chloride (42.21 mg, 0.2114 mmol) in pyridine (0.42 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature, diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ (15 ml). The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(2-chloro-4,5-difluoro-3 -((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-methoxypyrrolidine-1-sulfonamide trifluoroacetate (16.4 mg, 37%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 7.53-7.44 (m, 2H), 7.17-7.12 (m, 1H), 7.03 ( s, 1H), 6.03 (s, 1H), 4.00-3.98 (m, 1H), 3.66 (s, 3H), 3.59-3.43 (m, 4H), 3 .29 (s, 3H), 2.18-2.12 (m, 1H), 2.03-1.94 (m, 1H). MS (chiad, m/z)=518.1 (M+H).

Example 48

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-methoxypyrrolidin- 1-sulfonamide trifluoroacetate

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (102 mg, 0.3020 mmol) and (R)-3-methoxypyrrolidin-1 -sulfonyl chloride (150.8 mg, 0.7551 mmol) in pyridine (1.51 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature, diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ (15 ml). The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(2-chloro-4-fluoro-3-( (5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-methoxypyrrolidine-1-sulfonamide trifluoroacetate (78.3 mg, 52%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 7.60-7.57 (m, 1H), 7.48-7.45 (m, 1H), 7.27- 7.23 (m, 1H), 7.13 (t, 1H), 6.94 (s, 1H), 3.97-3.94 (m, 1H), 3.61 (s, 3H), 3 .52-3.40 (m, 4H), 3.27 (s, 3H) 2.13-2.07 (m, 1H), 2.00-1.91 (m, 1H). MS (chiad, m/z)=501.1 (M+H).

Example 49

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-2-azabicyclo[2,1, 1]hexane-2-sulfonamide

Add 2 -azabicyclo[2,1,1]hexane-2-sulfonyl chloride (24 mg, 0.13 mmol), and the reaction mixture was heated in a sealed tube to 70°C for 16 hours. The solution is concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is partitioned between dichloromethane and saturated NaHCO ₃ . The combined organic layers are washed with brine, dried with Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4 -dihydroquinazolin-6-yl)oxy)phenyl)-2-azabicyclo[2,1,1]hexane-2-sulfonamide (7 mg, 33%). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.60-7.56 (m, 1H), 7.44-7.42 (m, 1H), 7.27- 7.14 (m, 1H), 7.14-7.10 (t, 1H), 6.84 (shs, 1H), 4.24-7.22 (m, 1H), 3.58 (s, 3H), 2.89-2.86 (m, 1H), 2.35 (s, 2H), 1.94-1.91 (m, 2H), 1.52-1.50 (m, 2H) ; MS (chiad, m/z)=483.1 (M+H).

Example 50

N-(2-chloro-3-((5-cyano-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate

N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)pyrrolidine-1-sulfonamide 2,2,2 -trifluoroacetate (60 mg, 0.09305 mmol) and copper(I) cyanide (33.34 mg, 0.3722 mmol) in N, N-dimethylformamide (0.93 ml) are sealed in a test tube and heated to 100 ° C within 4 hours. The reaction is allowed to cool to ambient temperature. The crude solution is filtered through a 0.45 μm syringe filter and extracted between H ₂ O and 4:1 DCM/IPA. The combined organic layers are collected, dried over MgSO ₄ and concentrated. The crude mixture is purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA) to give N-(2-chloro-3-((5-cyano-3-methyl-4-oxo-3,4 -dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate (10.8 mg, 24%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.21 (s, 1H), 7.78 (d, 1H), 7.68-7.65 (m, 1H), 7.19 (t, 1H) , 6.78 (s, 1H), 6.69 (s, 1H), 3.68 (s, 3H), 3.37-3.34 (m, 4H), 1.92-1.89 (m , 4H). MS (chiad, m/z)=477.1 (M+H).

Example 51

N-(2-chloro-4-fluoro-3-((3-methyl-4-oxo-5-vinyl-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide trifluoroacetate

N-(3-((5-bromo-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-chloro-4-fluorophenyl)pyrrolidine-1-sulfonamide 2,2,2 β-trifluoroacetate (100 mg, 0.155 mmol) and cesium carbonate (126 mg, 0.388 mmol) are dissolved in 3.2 ml of dioxane and 1.0 ml of water. Pinacol cyclic ester of vinyl boronic acid (65.8 μl, 0.388 mmol) and the addition product of dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium and dichloromethane (3.80 mg, 0.00465 mmol) were added to the solution. The solution is heated to 80°C for 16 hours. The reaction is allowed to cool to ambient temperature. The crude solution is filtered through a 0.45 μm syringe filter and extracted between H ₂ O (5 ml) and DCM (5 ml, x2). The combined organic layers are collected, dried over MgSO ₄ and concentrated. The crude mixture is purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA) to give N-(2-chloro-4-fluoro-3-((3-methyl-4-oxo-5-vinyl -3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide trifluoroacetate (29.0 mg, 39%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 7.63 (d, 1H), 7.56-7.52 (m, 1H), 7.41-7.33 ( m, 1H), 7.14 (t, 1H), 7.00-6.97 (m, 1H), 6.74 (s, 1H), 6.63 (s, 1H), 5.87-5 .84 (m, 1H), 5.66-5.61 (m, 1H), 3.65 (s, 3H), 3.37-3.34 (m, 4H), 1.91-1.88 (m, 4H). MS (chiad, m/z)=478.1 (M+H).

Example 52

N-(2-chloro-3-((5-ethyl-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate

To a solution of N-(2-chloro-4-fluoro-3-((3-methyl-4-oxo-5-vinyl-3,4-dihydroquinazolin-6-yl)amino)phenyl)pyrrolidine-1-sulfonamide 2, 2,2-trifluoroacetate (11 mg, 0.0186 mmol) in methanol (372 μl), add palladium on carbon (10 wt%, 8 mg, 0.00752 mmol) and the reaction mixture is purged with Ar for 5 minutes, then stirred at ambient temperature under a hydrogen cylinder for 30 minutes. The reaction mixture was filtered through a 0.45 μm syringe filter, and the crude solution was purified by reverse phase chromatography (5-95 H ₂ O/ACN, 0.1% TFA) to give N-(2-chloro-3-((5- ethyl 3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate (8.8 mg, 99%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.59 (d, 1H), 7.50-7.46 (m, 1H), 7.13 (t, 1H) , 7.05-7.02 (m, 1H), 6.74 (s, 1H), 5.84 (s, 1H), 3.67 (s, 3H), 3.54-3.48 (m , 2H), 3.38-3.35 (m, 4H), 1.92-1.89 (m, 4H), 1.37 (t, 2H). MS (chiad, m/z)=480.2 (M+H).

Example 53

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxy- d3)pyrrolidine-1-sulfonamide trifluoroacetate

Step 1: Preparation of (3R)-3-(methoxy-d3)pyrrolidine hydrochloride. Tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (1.00 g, 5.34 mmol) was dissolved in N,N-dimethylformamide (26.7 ml, 5.34 mmol) and cooled to 0°C. Sodium hydride (0.214 g, 5.34 mmol) is added and the resulting solution is warmed to ambient temperature and maintained for 10 minutes. Iodomethane-d3 (0.349 mL, 5.61 mmol) was added to the reaction and stirred at ambient temperature for one hour. The reaction is treated with the addition of 20 ml H ₂ O. The solution is extracted with DCM (2×20 ml) and the organic layer is collected and concentrated. The crude product is purified by chromatography on silica gel (0-10% MeOH in DCM). The desired fractions are collected and concentrated. The resulting pyrrolidine is dissolved in DCM (10 ml) and 3 ml of 5N HCl in isopropyl alcohol is added. The reaction is stirred at ambient temperature overnight, then the volatiles are concentrated to give the desired product (605 mg, 81%), which is used as is in the next step.

Step 2: Preparation of (3R)-3-(methoxy-d3)pyrrolidine-1-sulfonyl chloride. A suspension of (3R)-3-(methoxy-d3)pyrrolidine hydrochloride (0.448 g, 4.30 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.12 ml, 6.45 mmol) was stirred in DCM ( 14.3 ml) at ambient temperature until the mixture is completely dissolved. The reaction mixture is cooled to 0°C and treated with sulfuryl chloride (0.70 ml, 8.60 mmol). The mixture is warmed to ambient temperature after 30 minutes and left to stir for 18 hours. The reaction mixture was diluted with additional DCM (20 ml) and washed with 1.0 M HCl (20 ml). The organic layer was separated, dried over anhydrous MgSO ₄ , filtered and concentrated to give crude (3R)-3-(methoxy-d3)pyrrolidine-1-sulfonyl chloride, which was used as is in the next step.

Step 3: Preparation of (R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3 -(methoxy-d3)pyrrolidine-1-sulfonamide trifluoroacetate. A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (25 mg, 0.07079 mmol) and (R)-3- (methoxy-d3)pyrrolidine-1-sulfonyl chloride (28.69 mg, 0.1416 mmol) in pyridine (0.35 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated, and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(2-chloro-3-((5- chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxy-d3)pyrrolidine-1-sulfonamide trifluoroacetate (18.7 mg, 51%) . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 7.61-7.52 (m, 2H), 7.15 (t, 1H), 7.00-6.97 ( m, 1H), 6.93 (s, 1H), 6.49 (s, 1H), 3.97-3.95 (m, 1H), 3.62 (s, 3H), 3.53-3 .42 (m, 4H), 2.14-2.07 (m, 1H), 2.01-1.92 (m, 1H). MS (chiad, m/z)=519.1 (M+H).

Example 54

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(methoxy -d3)pyrrolidine-1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (25 mg, 0.07424 mmol) and (R)-3- (methoxy-d3)pyrrolidine-1-sulfonyl chloride (30.09 mg, 0.1485 mmol) in pyridine (0.37 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , filtered and concentrated, and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(2-chloro-4-fluoro- 3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(methoxy-d3)pyrrolidine-1-sulfonamide trifluoroacetate (16.5 mg, 44%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 7.58-7.55 (m, 1H), 7.48-7.45 (m, 1H), 7.14 ( t, 1H), 7.09-7.04 (m, 1H), 6.92 (s, 1H), 5.97 (s, 1H), 3.97-3.95 (m, 1H), 3 .64 (s, 3H), 3.53-3.42 (m, 4H), 2.13-2.07 (m, 1H), 2.01-1.92 (m, 1H); MS (chiad, m/z)=503.1 (M+H).

Example 55

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxy-d3) pyrrolidine-1-sulfonamide trifluoroacetate

A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one (25 mg, 0.07513 mmol) and (R)-3-(methoxy -d3)pyrrolidine-1-sulfonyl chloride (30.45 mg, 0.1503 mmol) in pyridine (0.37 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated, and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(2-chloro-3-((3, 5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxy-d3)pyrrolidine-1-sulfonamide trifluoroacetate (13.0 mg, 35%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 7.57 (d, 1H), 7.51-7.48 (m, 1H), 7.11 (t, 1H) , 7.09-7.06 (m, 1H), 6.89 (s, 1H), 5.66 (s, 1H), 3.98-3.95 (m, 1H), 3.66 (s , 3H), 3.53-3.43 (m, 4H), 2.96 (s, 3H), 2.13-2.07 (m, 1H), 2.02-1.93 (m, 1H ); MS (chiad, m/z)=499.2 (M+H).

Example 56

(R)-N-(5-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide trifluoroacetate

To a solution of 6-((3-amino-5-chloro-2-fluorophenyl)amino)-5-chloro-3-methylquinazolin-4(3H)-one (20 mg, 0.057 mmol) in pyridine (283 μl, 0.057 mmol ) add (R)-3-fluoropyrrolidine-1-sulfonyl chloride (27 mg, 0.14 mmol) and the reaction mixture is heated in a sealed tube at 70°C for 16 hours. The solution is cooled to ambient temperature, concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is lyophilized to give (R)-N-(5-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2-fluorophenyl)-3 -fluoropyrrolidine-1-sulfonamide trifluoroacetate (11 mg, 39%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (s, 1H), 7.70-7.61 (m, 2H), 7.34-7.32 (m, 1H), 7.03- 7.00 (m, 1H), 6.72 (shs, 1H), 6.55 (shs, 1H), 5.25 (d, 1H), 3.73-3.49 (m, 7H), 2 .36-2.00 (m, 2H); MS (chiad, m/z)=504.1 (M+H).

Example 57

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-(difluoromethoxy)pyrrolidin- 1-sulfonamide trifluoroacetate

To a solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-3,5-dimethylquinazolin-4(3H)-one (30 mg, 0.090 mmol) in pyridine (449 μl) add (R)-3- (difluoromethoxy)pyrrolidine-1-sulfonyl chloride (64 mg, 0.27 mmol), and the reaction mixture was heated in a sealed tube at 70°C for 16 hours. The solution is cooled to ambient temperature, concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is lyophilized to give (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-( difluoromethoxy)pyrrolidine-1-sulfonamide trifluoroacetate (10 mg, 21%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (s, 1H), 7.61-7.54 (m, 2H), 7.20-7.15 (t, 1H), 6.98 ( d, 1H), 6.81 (shs, 1H), 6.45-6.00 (m, 1H), 5.08-4.84 (m, 1H), 3.85-3.45 (m, 7H), 3.01 (s, 3H), 2.28-2.12 (m, 2H); MS (chiad, m/z)=533.1 (M+H).

Example 58

(R)-N-(5-chloro-2-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoropyrrolidin- 1-sulfonamide trifluoroacetate

To a solution of 6-((3-amino-5-chloro-2-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (20 mg, 0.059 mmol) in pyridine (297 μl, 0.059 mmol ) add (R)-3-fluoropyrrolidine-1-sulfonyl chloride (28 mg, 0.15 mmol) and the reaction mixture is heated in a sealed tube at 70°C for 16 hours. The solution is cooled to ambient temperature, concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is lyophilized to give (R)-N-(5-chloro-2-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)- 3-fluoropyrrolidine-1-sulfonamide trifluoroacetate (12 mg, 41%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.67 (s, 1H), 7.71-7.61 (m, 2H), 7.30-7.27 (m, 1H), 6.98- 6.95 (m, 1H), 6.72 (shs, 1H), 5.40-5.20 (m, 1H), 4.00-3.50 (m, 7H), 2.25-2, 00 (m, 2H); MS (chiad, m/z)=488.1 (M+H).

Example 59

cis-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3,4-difluoropyrrolidine-1 -sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (25 mg, 0.071 mmol) and cis-3,4-difluoropyrrolidine-1-sulfonyl chloride (73 mg, 0.35 mmol) in pyridine (0.5 ml) was heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature then partitioned between DCM (25 ml) and saturated aqueous CuSO ₄ (25 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (0-100% EtOAc/hexane), then reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are diluted with saturated aqueous NaHCO ₃ (15 ml) then extracted with DCM (30 ml). The organic phases are combined and dried over Na ₂ SO ₄ , filtered and concentrated to give cis-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl )oxy)-4-fluorophenyl)-3,4-difluoropyrrolidine-1-sulfonamide (18 mg, 49%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.61-7.56 (m, 1H), 7.53 (d, 1H), 7.19 (t, 1H) , 7.03 (d, 1H), 6.80 (s, 1H), 5.21-4.98 (m, 2H), 3.82-3.67 (m, 2H), 3.65-3 .48 (m, 5H); MS (chiad, m/z)=523.0 (M+H).

Example 60

(R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-(difluoromethoxy) pyrrolidine-1-sulfonamide

Step 1: Preparation of (R)-3-(difluoromethoxy)pyrrolidine-1-sulfonyl chloride. To an ice-cold solution of (R)-3-(difluoromethoxy)pyrrolidine (107 mg, 0.780 mmol) and N-ethyl-N-isopropylpropan-2-amine (204 μL, 1.17 mmol) in DCM (6 mL) sulfuryl dichloride (189 μl, 2.34 mmol), and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture is diluted with DCM (20 ml) and washed with aqueous 1M HCl (10 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain (R)-3-(difluoromethoxy)pyrrolidine-1-sulfonyl chloride, which is used directly in the next step without further purification. ^1H NMR (400 MHz, CDCl ₃ ) δ 6.47-6.09 (m, 1H), 5.00-4.95 (m, 1H), 3.73-3.58 (m, 4H), 2.30-2.20 (m, 2H).

Step 2: Preparation of (R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3 -(difluoromethoxy)pyrrolidine-1-sulfonamide. A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (56 mg, 0.158 mmol) and (R)-3-(difluoromethoxy)pyrrolidin- 1-sulfonyl chloride (186 mg, 0.791 mmol) in pyridine (0.800 ml) was heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM (25 ml) and 10% aqueous CuSO ₄ (25 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (hexane/ethyl acetate 0-100%) followed by reverse phase chromatography (5-95% ACN/water with 0.1% TFA). Fractions containing the desired product were combined and partitioned between saturated aqueous NaHCO ₃ (15 ml) and DCM (30 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (R)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-(difluoromethoxy)pyrrolidine-1-sulfonamide (13.9 mg, 16%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.63-7.58 (m, 1H), 7.53 (d, 1H), 7.17 (t, 1H) , 7.03 (d, 1H), 6.78 (s, 1H), 6.39-5.98 (m, 1H), 4.88-4.81 (m, 1H), 3.63-3 .41 (m, 6H), 2.21-2.04 (m, 3H); MS (chiad, m/z)=553.0 (M+H).

Example 61

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3,3-difluoropyrrolidine-1-sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (51 mg, 0.144 mmol) and 3,3-difluoropyrrolidine-1-sulfonyl chloride (148 mg, 0.720 mmol) in pyridine (0.500 ml) is heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM (25 ml) and 10% aqueous CuSO ₄ (25 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (hexane/ethyl acetate 0-100%), then reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ (15 ml) and DCM (30 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6- yl)oxy)-4-fluorophenyl)-3,3-difluoropyrrolidine-1-sulfonamide (21.2 mg, 28%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.60-7.52 (m, 2H), 7.20-7.15 (t, 1H), 7.06- 7.03 (d, 1H), 3.67-3.52 (m, 7H), 2.42-2.32 (m, 2H); MS (chiad, m/z)=523.0 (M+H).

Example 62

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-ethylpyrrolidin- 1-sulfonamide trifluoroacetate

Step 1: Preparation of (3R)-3-ethylpyrrolidine-1-sulfonyl chloride. A suspension of (R)-3-ethylpyrrolidine hydrochloride (150 mg, 1.11 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.289 ml, 1.66 mmol) was stirred in DCM (2.7 ml) at temperature environment until the mixture is completely dissolved. The reaction mixture is cooled to 0°C and treated with sulfuryl chloride (0.179 ml, 2.11 mmol). The mixture is warmed to ambient temperature after 30 minutes and left to stir for 18 hours. The reaction mixture is diluted with additional DCM (5 ml) and washed with 1.0 M HCl (5 ml). The organic layer was separated, dried over anhydrous MgSO ₄ , filtered and concentrated to give crude (3R)-3-ethylpyrrolidine-1-sulfonyl chloride, which was used as is in the next step.

Step 2: Preparation of (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)- 3-ethylpyrrolidine-1-sulfonamide trifluoroacetate. A solution of 6-((3-amino-2-chloro-6-fluorophenyl)amino)-5-fluoro-3-methylquinazolin-4(3H)-one (20 mg, 0.05940 mmol) and (R)-3- ethylpyrrolidine-1-sulfonyl chloride (23.48 mg, 0.1188 mmol) in pyridine (0.30 ml) was sealed and heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM (15 ml) and washed with 10% aqueous CuSO ₄ . The DCM extract is dried over MgSO ₄ , concentrated and the residue is purified by reverse phase chromatography (5-95% ACN/water with 0.1% TFA) to give (R)-N-(2-chloro-4-fluoro-3-( (5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-ethylpyrrolidine-1-sulfonamide trifluoroacetate (18.1 mg, 61%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 7.56-7.52 (m, 1H), 7.48-7.45 (m, 1H), 7.15 ( t, 1H), 7.08-7.03 (m, 1H), 6.75 (s, 1H), 5.97 (s, 1H), 3.64 (s, 3H), 3.55-3 .43 (m, 2H), 3.34-3.28 (m, 1H), 2.94-2.89 (m, 1H), 2.11-2.00 (m, 2H), 1.40 -1.32 (m, 2H), 0.89 (t, 3H). MS (chiad, m/z)=498.2 (M+H).

Example 63

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,3-difluoropyrrolidin-1- sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.08 mmol) and 3,3-difluoropyrrolidine-1-sulfonyl chloride (91.3 mg, 0.44 mmol) was dissolved in pyridine (444 µl, 0.08 mmol) and heated at 70°C for 24 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/EtOAc) then reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x), and the organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-4-fluoro- 3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,3-difluoropyrrolidine-1-sulfonamide (18.1 mg, 40%) in as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.58-7.51 (m, 1H), 7.48-7.41 (m, 1H), 7.30- 7.21 (m, 1H), 7.20-7.10 (t, 1H), 6.75 (s, 1H), 3.69-3.61 (t, 2H), 3.60-3, 53 (m, 5H), 2.45-2.30 (m, 2H); MS (chiad, m/z)=507.1, 509.1 (M+H).

Example 64

cis-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,4-difluoropyrrolidin- 1-sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.08 mmol) and cis-3,4-difluoropyrrolidin-1 -sulfonyl chloride (91.3 mg, 0.44 mmol) is dissolved in pyridine (444 μl, 0.08 mmol) and heated at 70°C for 24 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/EtOAc) then reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x) and the organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give cis-N-(2-chloro-4-fluoro -3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,4-difluoropyrrolidine-1-sulfonamide (10.7 mg, 24%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.57-7.51 (m, 1H), 7.47-7.43 (m, 1H), 7.31- 7.27 (d, 1H), 7.18-7.11 (t, 1H), 6.76 (s, 1H), 5.21-4.98 (m, 2H), 3.77-3, 53 (m, 7H); MS (chiad, m/z)=507.1, 509.1 (M+H).

Example 65

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-azabicyclo[3,1, 0]hexane-3-sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.08 mmol) and 3-azabicyclo[3,1,0 ]hexane-3-sulfonyl chloride (81 mg, 0.44 mmol) is dissolved in pyridine (444 μl, 0.08 mmol) and heated at 70°C for 32 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/EtOAc) then reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x), and the organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-4-fluoro- 3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-azabicyclo[3,1,0]hexane-3-sulfonamide (31 mg, 72%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.53-7.47 (m, 1H), 7.46-7.42 (m, 1H), 7.25- 7.21 (d, 1H), 7.15-7.10 (t, 1H), 6.76 (s, 1H), 3.57 (s, 3H), 3.51-3.44 (d, 2H), 3.42-3.35 (d, 2H), 0.93-0.81 (m, 2H), 0.68-0.59 (m, 1H), 0.23-0.16 ( m, 1H); MS (chiad, m/z)=483.0, 485.0 (M+H).

Example 66

(R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-(difluoromethoxy )pyrrolidine-1-sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.08 mmol) and (R)-3-(difluoromethoxy) Pyrrolidine-1-sulfonyl chloride (105 mg, 0.44 mmol) is dissolved in pyridine (444 μl, 0.08 mmol) and heated at 70°C for 24 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/EtOAc) then reverse phase chromatography (water/ACN with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give (R)-N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3, 4-dihydroquinazolin-6-yl)oxy)phenyl)-3-(difluoromethoxy)pyrrolidine-1-sulfonamide (3.5 mg, 7%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.61-7.55 (m, 1H), 7.48-7.43 (m, 1H), 7.30- 7.27 (d, 1H), 7.17-7.09 (t, 1H), 6.77 (s, 1H), 6.40-6.00 (t, 1H), 4.88-4, 82 (d, 1H), 3.59-3.45 (m, 7H), 2.16-2.10 (m, 2H); MS (chiad, m/z) = 537.0, 539.0 (M+H).

Example 67

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-2-azabicyclo[2,1,11 hexane-2-sulfonamide

Solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (50 mg and 0.1412 mmol), 2-azabicyclo[2,1,1 ]hexane-2-sulfonyl chloride (128.2 mg, 0.7059 mmol) in pyridine (0.700 ml) is heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM (25 ml) and 10% aqueous CuSO ₄ (25 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (hexane/ethyl acetate 0-100%), then reverse phase chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ (15 ml) and DCM (30 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6- yl)oxy)-4-fluorophenyl)-2-azabicyclo[2,1,1]hexane-2-sulfonamide (18.4 mg, 26%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.64-7.58 (m, 1H), 7.53 (d, 1H), 7.16 (t, 1H) , 7.03 (d, 1H), 6.82 (s, 1H), 4.27-4.22 (m, 1H), 3.58 (s, 3H), 3.38 (s, 2H), 2.92-2.86 (m, 1H), 1.98-1.89 (m, 2H), 1.56-1.50 (m, 2H); MS (chiad, m/z) = 499.1 (M+H).

Example 68

6-(2-Chloro-3-{[ethyl(methyl)sulfamoyl]amino}-6-fluorophenoxy)-3,5-dimethyl-3,4 dihydroquinazolin-4-one

To a solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-3,5-dimethylquinazolin-4(3H)-one (160.0 mg, 0.48 mmol) in DCM (10 ml), pyridine was added successively (0.19 ml, 2.39 mmol), ethyl (methyl) sulfamoyl chloride (378 mg, 2.39 mmol) and DMAP (5.8 mg, 0.048 mmol), and the reaction mixture was stirred at ambient temperature for 48 hours under nitrogen. The reaction mixture is concentrated under reduced pressure, diluted with water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (2×25 ml) and brine (25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by reverse phase column chromatography (30-95% ACN/water with 20 mM ammonium bicarbonate) to give 6-(2-chloro-3-{[ethyl(methyl)sulfamoyl]amino}-6-fluorophenoxy)-3 ,5-dimethyl-3,4-dihydroquinazolin-4-one as pale white solid (23 mg, 10%), ^1H NMR (400 MHz, Methanol- _d4 ) δ 8.18 (s, 1H) , 7.56 (dd, 1H), 7.41 (d, 1H), 7.28 (t, 1H), 6.96 (d, 1H), 3.54 (s, 3H), 3.21 ( m, 2H), 2.97 (s, 3H), 2.82 (s, 3H), 1.09 (t, 3H); MS (m/z) = 455.1, 457.1 (M+H).

Example 69

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)pyrrolidine-1-sulfonamide

To a solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-3,5-dimethylquinazolin-4(3H)-one (130.0 mg, 0.39 mmol) in DCM (5 ml) add Et ₃ N (0.75 ml, 5.83 mmol) and pyrrolidine-1-sulfonyl chloride (790 mg, 4.67 mmol), and the mixture was stirred for 16 hours at ambient temperature under nitrogen. The reaction mixture is concentrated under reduced pressure, diluted with water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (2×25 ml) and brine (25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product is purified by reverse phase column chromatography (30-95% ACN/water with 20 mM ammonium bicarbonate) to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazoline -6-yl)oxy)-4-fluorophenyl)pyrrolidine-1-sulfonamide as a white solid (23.4 mg, 13%). ^1H NMR (400 MHz, Methanol- _d4 ) δ 8.18 (s, 1H), 7.60 (dd, 1H), 7.41 (d, 1H), 7.28 (t, 1H), 6 .96 (d, 1H), 3.54 (s, 3H), 3.30 (m, 4H), 2.97 (s, 3H), 1.85 (m, 4H); MS (m/z) = 467.3, 469.3 (M+H).

Example 70

(R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide

To a solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-3,5-dimethylquinazolin-4(3H)-one (119 mg, 0.357 mmol) in pyridine (2 ml) add (R)-3- fluoropyrrolidine-1-sulfonyl chloride (147 mg, 0.784 mmol) and the reaction mixture was stirred at 65°C for 48 hours. The reaction mixture was concentrated and the crude product was purified by reverse phase column chromatography (5-95% MeCN/water with 0.1% TFA) to give (R)-N-(2-chloro-3-((3,5-dimethyl -4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (77 mg, 45%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 1H), 7.59-7.56 (m, 1H), 7.41 (d, 1H), 7.16-7.12 ( t, 1H), 6.91-6.89 (m, 2H), 5.29-5.14 (m, 1H), 3.68-3.44 (m, 7H), 3.00 (s, 3H), 2.31-2.21 (m, 1H), 2.13-1.94 (m, 1H). MS (m/z) = 485.1, 487.1 (M+H).

The compounds in Table 1 were prepared using a procedure similar to that described for the synthesis of (R)-N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino) -4-fluorophenyl)-3-methoxypyrrolidine-1-sulfonamide (Example 1) using the following modifications: in step I, replacement of (R)-3-methoxypyrrolidine hydrochloride with a suitable amine or amine hydrochloride, and in step 2, replacement of 6-( (3-amino-2-chloro-6-fluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one and/or (R)-3-methoxypyrrolidine-1-sulfonyl chloride, suitable quinazolin-4(3H)- it and/or the sulfonyl chloride product from step 1.

Example 107

(S)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoropyrrolidine-1 -sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (51 mg, 0.144 mmol) and (S)-3-fluoropyrrolidine-1-sulfonyl chloride (135 mg, 0.720 mmol) in pyridine (0.50 ml) was heated at 70°C for 18 hours. The reaction mixture is partitioned between DCM (25 ml) and 10% aqueous CuSO ₄ (25 ml) and the organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated. The reaction mixture is purified by silica gel chromatography (0-100% hexane/ethyl acetate) then reverse phase chromatography (5-95% MeCN/water with 0.1% TFA). Fractions containing the desired product were combined and partitioned between saturated aqueous NaHCO ₃ and DCM (30 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated to give (S)-N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6 -yl)oxy)-4-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide (23.5 mg, 32.3% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.64-7.59 (m, 1H), 7.52 (d, 1H), 7.16 (t, 1H) , 7.03 (d, 1H), 6.79 (s, 1H), 5.30-5.14 (m, 1H), 3.70-3.56 (m, 5H), 3.53-3 .43 (m, 2H), 2.33-2.21 (m, 1H), 2.15-1.93 (m, 1H); MS (chiad, m/z) = 505.0.507.0 (M+H).

Example 108

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-azabicyclo[3,1,0 ]hexane-3-sulfonamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (30 mg, 0.085 mmol) and 3-azabicyclo[3,1,0]hexane -3-sulfonyl chloride (46 mg, 0.25 mmol) in pyridine (565 μl, 0.085 mmol) is heated to 70°C for 16 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is partitioned between dichloromethane and saturated NaHCO ₃ . The organic layer is washed with brine, dried with Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product is purified by silica gel chromatography (5-95% EtOAc/DCM) and the product is partitioned between dichloromethane and saturated NaHCO ₃ . The organic layer was washed with brine, dried with Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6- yl)oxy)-4-fluorophenyl)-3-azabicyclo[3,1,0]hexane-3-sulfonamide (13 mg, 31% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.0 (s, 1H), 7.55-7.51 (m, 2H), 7.18-7.14 (t, 1H), 7.03 ( d, 1H), 6.80 (s, 1H), 3.57 (s, 3H), 3.49-3.46 (m, 2H), 3.40-3.36 (m, 2H), 1 .54-1.50 (m, 2H), 0.66-0.60 (m, 1H), 0.22-0.18 (m, 1H); MS (chiad, m/z) = 499.1, 501.1 (M+H).

Example 109

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-(N-ethyl-N-methyl) -sulfamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (50 mg, 0.141 mmol) and (N-ethyl-N-methyl)sulfamoyl chloride ( 86.9 µl, 0.706 mmol) in pyridine (0.5 ml) is heated at 70°C for 8 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM (25 ml) and 10% aqueous CuSO ₄ (25 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (0-100% hexane/EtOAc), then reverse phase HPLC chromatography (5-95% MeCN/water with 0.1% TFA). The desired fractions are divided between saturated aqueous NaHCO ₃ and DCM (20 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy )-4-fluorophenyl)-(N-ethyl-N-methyl)-sulfonamide (32.3 mg, 48.1% yield) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.56-7.49 (m, 2H), 7.16 (t, 1H), 7.03 (d, 1H) , 6.72 (s, 1H), 3.58 (s, 3H), 3.26 (m, 2H), 2.85 (s, 3H), 1.13 (t, 3H); MS (chiad, m/z) = 475.1, 477.1 (M+H).

Example 110

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-(N,N-dimethyl)-sulfamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-chloro-3-methylquinazolin-4(3H)-one (50 mg, 0.1412 mmol) and dimethylsulfamoyl chloride (75.30 μl, 0. 7059 mmol) in pyridine (0.5 ml) is heated at 70°C for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between DCM (25 ml) and 10% aqueous CuSO ₄ (25 ml). The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture is purified by silica gel chromatography (0-100% EtOAc/hexane), then reverse phase HPLC chromatography (5-95% ACN/water with 0.1% TFA). The desired fractions are partitioned between saturated aq. NaHCO ₃ and DCM (20 ml) and the organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((5-chloro-3-methyl- 4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-(N,N-dimethyl)-sulfamide (28.84 mg, 44.28% yield) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.60-7.51 (m, 2H), 7.16 (t, 1H), 7.04 (d, 1H) , 6.68 (s, 1H), 3.58 (s, 3H), 2.87 (s, 6H); MS (chiad, m/z) = 461.1, 463.1 (M+H).

Example 111

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-(N,N-dimethyl)- sulfamide

A solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.08 mmol) and (N,N-dimethyl)sulfamoyl chloride ( 47.7 µl, 0.44 mmol) in pyridine (0.88 ml) is heated at 60°C for 3 days in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with EtOAc and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (30-100% EtOAc/DCM) to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazoline- 6-yl)oxy)phenyl)-(N,N-dimethyl)-sulfonamide (21.3 mg, 54%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.56-7.51 (m, 1H), 7.48-7.43 (m, 1H), 7.29- 7.22 (m, 1H), 7.17-7.08 (t, 1H), 6.67 (s, 1H), 3.57 (s, 3H), 2.86 (s, 6H); MS (chiad, m/z) = 445.0, 447.1 (M+H).

Example 112

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-(N-ethyl-N-methyl )-sulfamide

Solution of 6-(3-amino-2-chloro-6-fluorophenoxy)-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.08 mmol) and (N-ethyl-N-methyl) sulfamoyl chloride (70 mg, 0.44 mmol) in pyridine (0.88 ml) is heated at 60°C for 3 days in a sealed tube. The reaction mixture is cooled to ambient temperature, diluted with EtOAc and washed with 10% citric acid (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (30-100% EtOAc/DCM) then reverse phase chromatography (5-95% MeCN/H ₂ O with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazoline- 6-yl)oxy)phenyl)-(N-ethyl-N-methyl)-sulfonamide (7.1 mg, 17%) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.53-7.48 (m, 1H), 7.47-4.42 (d, 1H), 7.25- 7.20 (m, 1H), 7.16-7.08 (t, 1H), 6.70 (s, 1H), 3.57 (s, 3H), 3.31-3.22 (m, 2H), 2.85 (s, 3H), 1.15-1.10 (t, 3H); MS (chiad, m/z) = 459.0, 461.0 (M+H).

Example 113

N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4-difluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate

6-((3-amino-2,6-difluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one (22 mg, 0.06955 mmol), pyrrolidine-1-sulfonyl chloride (19.93 µl, 0.1739 mmol) and pyridine (347.8 µl, 0.06955 mmol) are added to a 3 ml tube and the reaction is sealed and heated to 70°C for 16 hours. The reaction is cooled to ambient temperature and partitioned between DCM and saturated aqueous CuSO ₄ . The organic layer was concentrated and the resulting residue was purified by reverse phase HPLC (5-95% MeCN/H ₂ O, 0.1% TFA). The desired fractions are lyophilized to give N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4-difluorophenyl)pyrrolidine-1-sulfonamide trifluoroacetate (23 mg , 74% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 7.58 (d, 1H), 7.36-7.30 (m, 1H), 7.16-7.13 ( m, 1H), 7.02-6.97 (m, 1H), 6.43 (s, 1H), 5.48 (s, 1H), 3.64 (s, 3H), 3.37-3 .30 (m, 4H), 2.95 (s, 3H), 1.93-1.88 (m, 4H). MS (chiad, m/z) = 450.1 (M+H).

Example 114

(R)-N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide trifluoroacetate

6-((3-Amino-2,6-difluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one (8.0 mg, 0.0253 mmol), (R)-3-fluoropyrrolidin-1 β-sulfonyl chloride (11.9 mg, 0.0632 mmol) and pyridine (126 µl, 0.0253 mmol) are added to a 3 ml tube and the reaction is sealed and heated to 70°C for 16 hours. The reaction is cooled to ambient temperature and partitioned between DCM and saturated aqueous CuSO ₄ . The organic layer was concentrated and the crude product was purified by reverse phase HPLC (5-95% MeCN/H ₂ O, 0.1% TFA). The desired fractions are lyophilized to give (R)-N-(3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-2,4-difluorophenyl)-3-fluoropyrrolidin- 1-sulfonamide trifluoroacetate (4 mg, 32% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 7.59 (d, 1H), 7.40-7.35 (m, 1H), 7.18-7.15 ( m, 1H), 7.02-6.97 (m, 1H), 6.44 (s, 1H), 5.48 (s, 1H), 5.31-5.17 (m, 1H), 3 .66 (s, 3H), 3.49-3.10 (m, 2H), 2.94 (s, 3H), 2.32-2.22 (m, 2H), 2.16-1.98 (m, 2H). MS (chiad, m/z) = 468.1 (M+H).

Example 115

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1-sulfonamide

Tert-butyl (2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (30 mg, 0.07 mmol) dissolve in THF (0.7 ml), cool to 0°C and treat with sodium hydride (5.5 mg, 0.14 mmol). The reaction is stirred for 10 minutes and then treated with 3-(methoxymethyl)azetidine-1-sulfonyl chloride (28 mg, 0.14 mmol) and then heated to 50°C for 12 hours. The reaction mixture was cooled to ambient temperature and poured into 20 ml of ice water, and the aqueous layer was extracted with DCM (3×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue is dissolved in 1:1 DCM:TFA (5 ml) and stirred at ambient temperature for 30 minutes. The reaction mixture is concentrated, diluted with DCM, washed with saturated NaHCO ₃ (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase chromatography (5-95% water/ACN with 0.1% TFA) and the desired fractions were combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy) -4-fluorophenyl)-3-(methoxymethyl)azetidine-1-sulfonamide (17 mg, 49%) as a white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.72 (s, 1H), 8.28 (s, 1H), 7.55-7.43 (m, 3H), 6.98- 6.94 (d, 1H), 3.90-3.83 (t, 2H), 3.61-3.55 (m, 2H), 3.46 (s, 3H), 3.43-3, 40 (d, 2H), 3.23 (s, 3H), 2.91 (s, 3H), 2.81-2.70 (m, 1H); MS (chiad, m/z) = 497.1, 499.1 (M+H).

Example 116

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide

Tert-butyl (2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (30 mg, 0.07 mmol) dissolve in THF (0.7 ml), cool to 0°C and treat with sodium hydride (5.5 mg, 0.14 mmol). The reaction is stirred for 10 minutes and then treated with 3-fluoroazetidine-1-sulfonyl chloride (24 mg, 0.14 mmol) and heated to 50°C for 12 hours. The reaction mixture is cooled to ambient temperature and poured into 20 ml of ice water. The aqueous layer was extracted with 4:1 DCM/IPA (3×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue is dissolved in 1:1 DCM:TFA (5 ml) and stirred at ambient temperature for 30 minutes. The reaction is concentrated, diluted with DCM, washed with saturated NaHCO ₃ (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase chromatography (5-95% water/ACN with 0.1% TFA) and the desired fractions were combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ . The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy) -4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide (13 mg, 40%) as a white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.96 (s, 1H), 8.28 (s, 1H), 7.52-7.42 (m, 3H), 6.99- 6.94 (d, 1H), 5.46-5.24 (m, 1H), 4.20-4.08 (m, 2H), 4.01-3.89 (m, 2H), 3. 46 (s, 3H), 2.91 (s, 3H); MS (chiad, m/z) = 471.0, 473.0 (M+H).

Example 117

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide

Tert-butyl (2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate (30 mg, 0.07 mmol) dissolve in THF (0.7 ml), cool to 0°C and treat with sodium hydride (5.5 mg, 0.14 mmol). The reaction mixture is stirred for 10 minutes and treated with 3-methoxyazetidine-1-sulfonyl chloride (26 mg, 0.14 mmol) and heated to 50°C for 24 hours. The reaction mixture is cooled to ambient temperature and poured into 20 ml of ice water. The aqueous layer was extracted with DCM (2×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue is dissolved in 1:1 DCM:TFA (5 ml) and stirred at ambient temperature for 30 minutes. The reaction is concentrated, diluted with DCM, washed with saturated NaHCO ₃ (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase chromatography (5-95% water/ACN with 0.1% TFA) and the desired fractions were combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy) -4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide (13 mg, 39%) as an off-white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.82 (s, 1H), 8.28 (s, 1H), 7.54-7.41 (m, 3H), 7.00- 6.94 (d, 1H), 4.18-4.10 (m, 1H), 4.00-3.95 (m, 2H), 3.73-3.67 (m, 2H), 3. 46 (s, 3H), 3.18 (s, 3H), 2.91 (s, 3H); MS (chiad, m/z) = 483.1, 485.1 (M+H).

Example 118

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1- sulfonamide

Tert-Butyl (2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate solution (25 mg, 0.055 mmol) and sodium hydride (4.4 mg, 0.11 mmol) in THF (0.5 ml) were stirred at 0°C for 10 minutes. 3-(methoxymethyl)azetidine-1-sulfonyl chloride (22 mg, 0.11 mmol) was added and the reaction mixture was warmed to ambient temperature and heated at 50° C. for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between water (25 ml) and 4:1 DCM:IPA (25 ml). The organic phase is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reaction mixture was diluted with DCM (5 ml) and TFA (5 ml) added. The reaction mixture was stirred at ambient temperature for 30 minutes, then concentrated and purified by reverse phase HPLC chromatography (5-95% acetonitrile:H ₂ O with 0.1% TFA). Fractions containing the desired product were combined and partitioned between saturated aqueous NaHCO ₃ and DCM (25 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy )-4-fluorophenyl)-3-(methoxymethyl)azetidine-1-sulfonamide (7.7 mg, 27% yield) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.61-7.52 (m, 2H), 7.17 (t, 1H), 7.05 (d, 1H) , 6.67 (s, 1H), 4.01 (t, 2H), 3.82-3.77 (m, 2H), 3.58 (s, 3H), 3.47 (d, 2H), 3.35 (s, 3H), 2.88-2.76 (m, 1H); MS (chiad, m/z) = 517.1, 519.1 (M+H).

Example 119

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide

Tert-Butyl (2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate solution (0.674 ml, 0.0674 mmol) in THF (0.7 ml) and sodium hydride (5.39 mg, 0.135 mmol) were stirred at 0°C for 10 minutes. 3-methoxyazetidine-1-sulfonyl chloride (25.0 mg, 0.135 mmol) was added and the reaction mixture was warmed to ambient temperature then heated to 50° C. for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between water (25 ml) and 4:1 DCM:IPA (25 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated to give a crude mixture which is taken up in DCM (5 ml) and trifluoroacetic acid (5 ml) and stirred at ambient temperature for 30 minutes. The reaction mixture is concentrated and purified by reverse phase HPLC chromatography (5-95% acetonitrile:H ₂ O with 0.1% TFA). The desired fractions are divided between sat. aqueous NaHCO ₃ and DCM (25 ml), and the organic phase is dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3, 4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide (8.3 mg, 24.5% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.17 (s, 1H), 7.61-7.54 (m, 2H), 7.18 (t, 1H), 7.07 (d, 1H) , 6.67 (s, 1H), 4.19-4.04 (m, 3H), 3.93-3.87 (m, 2H), 3.61 (s, 3H), 3.27 (s , 3H); MS (chiad, m/z) = 503.1, 505.1 (M+H).

Example 120

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide

Tert-Butyl (2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)carbamate solution (0.605 ml, 0.0605 mmol) in THF (0.6 ml) and sodium hydride (4.84 mg, 0.121 mmol) stir at 0°C for 10 minutes, then add 3-fluoroazetidine-1-sulfonyl chloride (21.0 mg, 0.121 mmol) , and the reaction mixture is allowed to warm to ambient temperature then heated to 50°C for 18 hours. The reaction mixture is cooled to ambient temperature and partitioned between water (25 ml) and 4:1 DCM:IPA (25 ml). The organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and the reaction mixture is taken up in DCM (5 ml) and TFA (5 ml) and stirred at ambient temperature for 30 minutes. The reaction mixture is concentrated and purified by reverse phase HPLC chromatography (5-95% acetonitrile:H ₂ O with 0.1% TFA). The desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ and DCM (25 ml), and the organic phase is separated and dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((5-chloro-3 -methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide (7.8 mg, 26.2% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.59-7.51 (m, 2H), 7.18 (t, 1H), 7.05 (d, 1H) , 6.68 (s, 1H), 5.35-5.14 (m, 1H), 4.26-4.08 (m, 4H), 3.59 (s, 3H); MS (chiad, m/z) = 491.0, 493.0 (M+H).

Example 121

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-(methoxymethyl)azetidine-1 -sulfonamide

Tert-butyl (2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate (25 mg, 0.06 mmol) dissolved in THF (0.6 ml), cooled to 0°C and treated with sodium hydride (4.6 mg, 0.11 mmol). The reaction is stirred for 10 minutes and treated with 3-(methoxymethyl)azetidine-1-sulfonyl chloride (23 mg, 0.11 mmol) and heated to 50°C for 12 hours. The reaction is cooled to ambient temperature and poured into 20 ml of ice water. The aqueous layer was extracted with 4:1 DCM/IPA (3×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue is dissolved in 1:1 DCM:TFA (5 ml) and stirred at ambient temperature for 30 minutes. The reaction mixture is concentrated, diluted with DCM, washed with saturated NaHCO ₃ (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (0-100% DCM/EtOAc) then reverse phase chromatography (5-95% water/acetonitrile with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x) and the organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-4-fluoro-3 -((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-(methoxymethyl)azetidine-1-sulfonamide (10 mg, 35%) as not completely white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.58-7.54 (m, 1H), 7.47-7.43 (m, 1H), 7.29- 7.22 (m, 1H), 7.17-7.11 (t, 1H), 6.67 (s, 1H), 4.04-3.97 (t, 2H), 3.82-3, 76 (m, 2H), 3.58 (s, 3H), 3.49-3.45 (d, 2H), 3.35 (s, 3H), 2.88-2.77 (m, 1H) ; MS (chiad, m/z) = 501.0, 503.1 (M+H).

Example 122

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluoroazetidine-1-sulfonamide

Tert-butyl (2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate (30 mg, 0.07 mmol) dissolved in THF (0.6 ml), cooled to 0°C and treated with sodium hydride (5.5 mg, 0.14 mmol). The reaction is stirred for 10 minutes and then treated with 3-fluoroazetidine-1-sulfonyl chloride (24 mg, 0.14 mmol). The reaction mixture is heated to 50°C for 12 hours. The reaction is cooled to ambient temperature and poured into 20 ml of ice water, and the aqueous layer is extracted with DCM (3×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue is dissolved in 1:1 DCM:TFA (5 ml) and stirred at ambient temperature for 30 minutes. The reaction is concentrated, diluted with DCM, washed with saturated NaHCO ₃ (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (0-100% DCM/EtOAc) then reverse phase chromatography (5-95% water/acetonitrile with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x) and the organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-4-fluoro-3 -((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-fluoroazetidin-1-sulfonamide (14 mg, 43%) as a white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.99 (s, 1H), 8.33 (s, 1H), 7.55-7.43 (m, 3H), 7.36- 7.29 (t, 1H), 5.45-5.25 (d, 1H), 4.20-4.08 (m, 2H), 3.99-3.88 (m, 2H), 3. 46 (s, 3H); MS (chiad, m/z) = 475.1, 477.1 (M+H).

Example 123

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3-methoxyazetidine-1-sulfonamide

Tert-butyl (2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)carbamate (30 mg, 0.07 mmol) dissolved in THF (0.6 ml), cooled to 0°C and treated with sodium hydride (5.5 mg, 0.14 mmol). The reaction is stirred for 10 minutes and then treated with 3-methoxyazetidine-1-sulfonyl chloride (25 mg, 0.14 mmol) and heated to 50°C for 12 hours. The reaction is cooled to ambient temperature and poured into 20 ml of ice water. The aqueous layer was extracted with DCM (3×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue is dissolved in 1:1 DCM:TFA (5 ml) and stirred at ambient temperature for 30 minutes. The reaction is concentrated, diluted with DCM, washed with saturated NaHCO ₃ (3×50 ml) and brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by silica gel column chromatography (0-100% DCM/EtOAc) then reverse phase chromatography (5-95% water/acetonitrile with 0.1% TFA). The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazoline- 6-yl)oxy)phenyl)-3-methoxyazetidine-1-sulfonamide (14 mg, 42%) as a white solid. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 9.85 (s, 1H), 8.33 (s, 1H), 7.55-7.43 (m, 3H), 7.35- 7.28 (t, 1H), 4.18-4.10 (m, 1H), 4.00-3.93 (m, 2H), 3.73-3.66 (m, 2H), 3. 46 (s, 3H), 3.17 (s, 3H); MS (chiad, m/z) = 487.1, 489.1 (M+H).

Example 124

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)azetidine-1-sulfonamide trifluoroacetate

Step 1: Tert-butyl (azetidin-1-ylsulfonyl)(2-chloro-4-fluoro-3-iodophenyl)carbamate. To a solution of tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (75 mg, 0.20 mmol) in tetrahydrofuran (2.0 ml) at 0°C add sodium hydride (60% in mineral oil, 12 mg, 0.30 mmol) and stir for 10 minutes. Azetidine-1-sulfonyl chloride (63 mg, 0.40 mmol) is added and the solution is heated to 50°C for 4 hours, at which time the reaction stops. The solution is partitioned between dichloromethane and saturated NaHCO ₃ and the organic layer is washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (5-95% DCM/hexane, then washed with 80% EtOAc/hexane) to give tert-butyl (azetidin-1-ylsulfonyl) (2-chloro-4-fluoro-3-iodophenyl)carbamate (64 mg, 65% yield).

Step 2: N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)azetidine-1-sulfonamide trifluoroacetate. 6-Amino-3,5-dimethylquinazolin-4(3H)-one solution (25 mg, 0.13 mmol), tert-butyl (azetidin-1-ylsulfonyl)(2-chloro-4-fluoro-3-iodophenyl) carbamate (64 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium (6 mg, 0.006 mmol), Xantphos (11 mg, 0.019 mmol) and cesium carbonate (86 mg, 0.26 mmol) in toluene (1320 µl) purged with argon and heated to 110°C overnight in a hermetically sealed tube. The next morning, the solution is filtered through Celite®, concentrated and then stirred in 1 ml DCM and 1 ml TFA for 1 hour. The solution is concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA) and the product is lyophilized to give N-(2-chloro-3-((3,5-dimethyl-4-oxo- 3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)azetidine-1-sulfonamide trifluoroacetate (22 mg, 36% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.74 (s, 1H), 7.60 (d, 1H), 7.51-7.47 (m, 1H), 7.16-7.11 ( t, 1H), 7.10-7.06 (m, 1H), 6.60 (shs, 1H), 5.68 (shs, 1H), 4.02-3.98 (t, 4H), 3 .67 (s, 3H), 2.96 (s, 3H), 2.29-2.22 (m, 2H); MS (chiad, m/z) = 452.1, 454.1 (M+H).

Example 125

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide

Step 1: Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-fluoroazetidin-1-yl)sulfonyl)carbamate. Sodium hydride (60% in mineral oil, 16 mg, 0 .40 mmol) and stir for 10 minutes. 3-Fluoroazetidine-1-sulfonyl chloride (70 mg, 0.40 mmol) is added and the solution is heated to 50°C for 5 hours. The solution is then partitioned between dichloromethane and saturated NaHCO ₃ and then the organic layer is washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (5-95% EtOAc/hexane) to give tert-butyl (2- chloro-4-fluoro-3-iodophenyl)((3-fluoroazetidin-1-yl)sulfonyl)carbamate (60 mg, 44% yield).

Step 2: N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide. Solution of 6-amino-3,5-dimethylquinazolin-4(3H)-one (33 mg, 0.17 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-fluoroazetidin-1 -yl)sulfonyl)carbamate (60 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.011 mmol), Xantphos (17 mg, 0.029 mmol) and cesium carbonate (76 mg, 0.23 mmol) in toluene (790 µl) is purged with argon and heated to 110°C overnight in a sealed tube. The solution is filtered through Celite®, concentrated and the filtrate is stirred in 1 ml of DCM and 1 ml of TFA for 30 minutes. The solution is concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA) and the product is partitioned between DCM and saturated NaHCO ₃ . The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl) amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide (32 mg, 58% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.45 (d, 1H), 7.40-7.37 (m, 1H), 7.12-7.04 ( m, 2H), 6.69 (shs, 1H), 5.61 (shs, 1H), 5.33-5.15 (m, 1H), 4.25-4.08 (m, 4H), 3 .54 (s, 3H), 2.98 (s, 3H); MS (chiad, m/z) = 470.1, 472.1 (M+H).

Example 126

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide

Solution of 6-amino-5-chloro-3-methylquinazolin-4(3H)-one (90 mg, 0.42 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl) ((3-fluoroazetidine -1-yl)sulfonyl)carbamate (218 mg, 0.429 mmol), tris(dibenzylideneacetone)dipalladium (39 mg, 0.042 mmol), Xantphos (62 mg, 0.10 mmol) and cesium carbonate (279 mg, 0.858 mmol) in toluene (2860 µl) is purged with argon and heated to 110°C overnight in a sealed tube. The solution is filtered through Celite®, concentrated and the residue is stirred in 1 ml DCM and 1 ml TFA for 1 hour. The solution is concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA) and the product is partitioned between DCM and saturated NaHCO ₃ . The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6- yl)amino)-4-fluorophenyl)-3-fluoroazetidine-1-sulfonamide (78 mg, 37% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.56-7.52 (m, 1H), 7.51 (d, 1H), 7.19-7.14 ( t, 1H), 6.99-6.95 (m, 1H), 6.72 (shs, 1H), 6.47 (shs, 1H), 5.35-5.15 (m, 1H), 4 .25-4.10 (m, 4H), 3.57 (s, 3H); MS (chiad, m/z) = 490.1, 492.1 (M+H).

Example 127

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoroazetidine-1-sulfonamide trifluoroacetate

Solution of 6-amino-5-fluoro-3-methylquinazolin-4(3H)-one (12 mg, 0.062 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl) ((3-fluoroazetidine-1 -yl)sulfonyl)carbamate (31 mg, 0.062 mmol), tris(dibenzylideneacetone)dipalladium (2 mg, 0.003 mmol), Xantphos (5 mg, 0.009 mmol) and cesium carbonate (40 mg, 0.12 mmol) in toluene ( 620 µl) are purged with argon and heated to 110°C in a sealed tube overnight. The solution is filtered through Celite, concentrated and the residue is stirred in 1 ml DCM and 1 ml TFA for 1 hour. The solution is concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA) and the product is lyophilized to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl -4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoroazetidin-1-sulfonamide trifluoroacetate (4 mg, 13% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (s, 1H), 7.56-7.49 (m, 2H), 7.20-7.15 (t, 1H), 7.12- 7.06 (m, 1H), 6.68 (shs, 1H), 6.01 (shs, 1H), 5.34-5.16 (m, 1H), 4.26-4.09 (m, 4H), 3.67 (s, 3H); MS (chiad, m/z) = 475.0, 477.0 (M+H).

Example 128

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide trifluoroacetate

Step 1: tert-butyl (2-chloro-4-fluoro-3-iodophenyl) ((3-methoxyazetidin-1-yl)sulfonyl)carbamate. To a solution of tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (40 mg, 0.11 mmol) in tetrahydrofuran (1070 μl) at 0°C add sodium hydride (60% in mineral oil, 6 mg , 0.2 mmol) and stir for 10 minutes. 3-Methoxyazetidine-1-sulfonyl chloride (40 mg, 0.22 mmol) is added and the solution is heated to 50°C for 2 hours. The solution is partitioned between dichloromethane and saturated NaHCO ₃ and the organic layer is washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (5-95% DCM/hexane, then washed with 80% EtOAc/hexane) to give tert-butyl (2-chloro-4-fluoro-3-iodophenyl) ((3-methoxyazetidin-1-yl)sulfonyl)carbamate (49 mg, 87% yield).

Step 2: N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide trifluoroacetate . Solution of 6-amino-3,5-dimethylquinazolin-4(3H)-one (18 mg, 0.095 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl) ((3-methoxyazetidin-1-yl )sulfonyl)carbamate (49 mg, 0.095 mmol), tris(dibenzylideneacetone)dipalladium (4 mg, 0.004 mmol), Xantphos (8 mg, 0.01 mmol) and cesium carbonate (61 mg, 0.19 mmol) in toluene ( 950 µl) is purged with argon and heated to 110°C in a hermetically sealed tube for 2 hours. The solution is filtered through Celite, concentrated and the residue is stirred in 1 ml DCM and 1 ml TFA for 1 hour. The solution is concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA) and the product is lyophilized to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3 ,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide trifluoroacetate (12 mg, 26% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.68 (s, 1H), 7.58 (d, 1H), 7.50-7.46 (m, 1H), 7.11-7.06 ( m, 2H), 6.63 (shs, 1H), 5.66 (shs, 1H), 4.19-4.13 (m, 1H), 4.11-4.07 (m, 2H), 3 .93-3.89 (m, 2H), 3.66 (s, 3H), 3.26 (s, 3H), 2.97 (s, 3H); MS (chiad, m/z) = 482.2, 484.1 (M+H).

Example 129

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-methoxyazetidine-1-sulfonamide

6-Amino-5-chloro-3-methylquinazolin-4(3H)-one (70 mg, 0.334 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-methoxyazetidin-1- yl)sulfonyl)carbamate (183 mg, 0.351 mmol), cesium carbonate (218 mg, 0.668 mmol), tris(dibenzylideneacetone) dipalladium(0) (30.6 mg, 0.0334 mmol) and (9,9-dimethyl- 9H-xanthene-4,5-diyl)bis(diphenylphosphane) (48.3 mg, 0.0835 mmol) was dissolved in toluene (3.3 ml) and heated at 110°C overnight in a sealed tube. The reaction mixture is allowed to cool to ambient temperature, and the crude reaction mixture is diluted with DCM and filtered through Celite. The solvent is concentrated, then reconstituted in 1:1 DCM:TFA (10 ml) and stirred at ambient temperature for 30 minutes. The crude reaction mixture was concentrated and purified by reverse phase chromatography (5-95%, MeCN/H ₂ O, 0.1% TFA). The desired product was extracted with DCM and saturated aqueous NaHCO ₃ and the DCM layer was concentrated to give the desired product (57 mg, 34% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.58-7.51 (m, 2H), 7.16 (t, 1H), 6.99-6.97 ( m, 1H), 6.67 (s, 1H), 6.47 (s, 1H), 4.18-4.13 (m, 1H), 4.08 (t, 2H), 3.92-3 .89 (m, 2H), 3.58 (s, 3H), 3.27 (s, 3H). MS (chiad, m/z) = 502.1, 504.1 (M+H).

Example 130

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-methoxyazetidine-1-sulfonamide

6-Amino-5-fluoro-3-methylquinazolin-4(3H)-one (84.44 mg, 0.4371 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3- methoxyazetidin-1-yl)sulfonyl)carbamate (239 mg, 0.4590 mmol), cesium carbonate (284.8 mg, 0.8742 mmol), tris(dibenzylideneacetone) dipalladium(0) (40.03 mg, 0.04371 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (63.23 mg, 0.1093 mmol) are dissolved in toluene (4.4 ml) and heated at 110°C overnight in a hermetically sealed tube. The reaction mixture is allowed to cool to ambient temperature and the crude reaction mixture is diluted with DCM and filtered through Celite. The solvent is concentrated, then reconstituted in 1:1 DCM:TFA (10 ml) and stirred at ambient temperature for 30 minutes. The crude reaction mixture was concentrated and purified by reverse phase chromatography (5-95%, MeCN/H ₂ O, 0.1% TFA). The desired product was extracted with DCM and saturated aqueous NaHCO ₃ and the DCM layer was concentrated to give the desired product (98 mg, 46% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.53-7.50 (m, 1H), 7.41-7.39 (m, 1H) 7.16-7 .11 (m, 1H), 7.07-7.02 (m, 1H), 6.68 (s, 1H), 5.90 (s, 1H), 4.14 (t, 1H), 4, 07 (t, 2H), 3.92-3.89 (m, 2H), 3.58 (s, 3H), 3.27 (s, 3H). MS (chiad, m/z) = 486.1, 488.1 (M+H).

Example 131

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1-sulfonamide

Step 1: 3-(methoxymethyl)azetidine-1-sulfonyl chloride. To a solution of 3-(methoxymethyl)azetidine hydrochloride (200 mg, 1.45 mmol) in DCM (3630 μl), add sulfuryl dichloride (290 μl, 3.6 mmol) and Huenig's base (380 μl, 2.2 mmol) dropwise, and the reaction is stirred at ambient temperature for 48 hours. The reaction mixture is partitioned between DCM and 1 N HCl, and the DCM layer is dried over Na ₂ SO ₄ , filtered and concentrated to give 3-(methoxymethyl)azetidine-1-sulfonyl chloride (273 mg, 94.1% yield).

Step 2: tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-(methoxymethyl)azetidin-1-yl)sulfonyl)carbamate. Sodium hydride (60% in mineral oil, 48 mg, 1 .2 mmol) and stir for 10 minutes. 3-(Methoxymethyl)azetidine-1-sulfonyl chloride (242 mg, 1.21 mmol) is added and the solution is heated to 50°C for 16 hours in a sealed tube. The solution is partitioned between DCM and saturated NaHCO ₃ and the organic layer is washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (5-95% EtOAc/hexane) to give the crude product. The crude product is concentrated and purified again by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is partitioned between DCM and saturated NaHCO ₃ and the organic layer is washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give tert-butyl (2-chloro-4-fluoro-3-iodophenyl) ((3-(methoxymethyl) )azetidin-1-yl)sulfonyl)carbamate (232 mg, 53.7% yield).

Step 3: N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1 -sulfonamide. Solution of 6-amino-3,5-dimethylquinazolin-4(3H)-one (83 mg, 0.43 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-(methoxymethyl) azetidin-1-yl)sulfonyl)carbamate (234 mg, 0.438 mmol), tris(dibenzylideneacetone)dipalladium (40 mg, 0.043 mmol), Xantphos (63 mg, 0.10 mmol) and cesium carbonate (285 mg, 0.877 mmol) in toluene (2920 µl) is purged with argon and heated to 110°C for 16 hours in a hermetically sealed tube. The solution is filtered through Celite®, concentrated and the residue is stirred in 1 ml DCM and 1 ml TFA for 1 hour. The solution is concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is partitioned between DCM and saturated NaHCO ₃ and the organic layer is washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3 ,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1-sulfonamide (165 mg, 75.8% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.46-7.39 (m, 2H), 7.12-7.04 (m, 2H), 6.68 ( shs, 1H), 5.60 (shs, 1H), 4.03-3.99 (t, 2H), 3.80-3.76 (m, 2H), 3.54 (s, 3H), 3 .48 (d, 2H), 3.34 (s, 3H), 2.97 (s, 3H), 2.85-2.77 (m, 1H); MS (chiad, m/z) = 496.2, 498.2 (M+H).

Example 132

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1- sulfonamide trifluoroacetate

Solution of 6-amino-5-chloro-3-methylquinazolin-4(3H)-one (20 mg, 0.095 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-(methoxymethyl) azetidin-1-yl)sulfonyl)carbamate (76 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (4 mg, 0.004 mmol), Xantphos (8 mg, 0.01 mmol) and cesium carbonate (6 mg, 0 .1 mmol) in toluene (950 µl) is purged with argon and heated to 110°C in a hermetically sealed tube for 16 hours. The solution is filtered through Celite®, concentrated and the residue is stirred in 1 ml DCM and 1 ml TFA for 1 hour. The solution is concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA) and the product is lyophilized to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo -3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)azetidine-1-sulfonamide trifluoroacetate (2.0 mg, 4.1% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.41 (s, 1H), 7.61-7.57 (m, 2H), 7.20-7.15 (t, 1H), 7.02- 6.99 (m, 1H), 6.67 (shs, 1H), 6.53 (shs, 1H), 4.04-4.00 (t, 1H), 3.82-3.78 (m, 1H), 3.65 (s, 3H), 3.49 (d, 2H), 3.35 (s, 3H), 2.87-2.79 (m, 1H); MS (chiad, m/z) = 516.1, 518.1 (M+H).

Example 133

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(methoxymethyl)azetidine-1 -sulfonamide trifluoroacetate

Solution of 6-amino-5-fluoro-3-methylquinazolin-4(3H)-one (20 mg, 0.10 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-( methoxymethyl)azetidin-1-yl)sulfonyl)carbamate (83 mg, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (4 mg, 0.005 mmol), Xantphos (8 mg, 0.02 mmol) and cesium carbonate (67 mg , 0.20 mmol) in toluene (1030 µl) is purged with argon and heated to 110°C in a sealed tube for 16 hours. The solution is filtered through Celite®, concentrated and the residue is stirred in 1 ml DCM and 1 ml TFA for 1 hour. The solution is concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA) and the product is lyophilized to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl -4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(methoxymethyl)azetidine-1-sulfonamide trifluoroacetate (4.0 mg, 7.7% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 7.58-7.54 (m, 1H), 7.50 (d, 1H), 7.19-7.14 ( t, 1H), 7.11-7.06 (m, 1H), 6.67 (shs, 1H), 6.01 (shs, 1H), 4.04-4.00 (t, 2H), 3 .82-3.78 (m, 2H), 3.67 (s, 3H), 3.50-3.48 (d, 2H), 3.35 (s, 3H), 2.87-2.79 (m, 1H); MS (chiad, m/z) = 500.1, 502.1 (M+H).

Example 134

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,3-difluoroazetidine-1-sulfonamide

Step 1: Tert-butyl (2-chloro-4-fluoro-3-iodophenyl) ((3,3-difluoroazetidin-1-yl)sulfonyl)carbamate. Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (553.3 mg, 1.489 mmol) was dissolved in THF (15 ml) and treated with sodium hydride (60% in mineral oil, 178.7 mg, 4.467 mmol) and stir at ambient temperature for 15 minutes. The reaction mixture is treated with 3,3-difluoroazetidine-1-sulfonyl chloride (855.8 mg, 4.467 mmol) and heated to 60°C for 16 hours. The reaction mixture is cooled to ambient temperature and treated with water and extracted with EtOAc (2x) and the combined organic layer was washed with water (3x), brine (1x) and dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by silica gel chromatography (Hexane/EtOAc) to give tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3,3-difluoroazetidin-1-yl)sulfonyl)carbamate (311.3 mg, 39.7% yield). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 7.68-7.64 (m, 1H), 7.39-7.35 (m, 1H), 4.74-4.67 (t , 2H), 4.46-4.40 (t, 2H), 1.38 (s, 9H).

Step 2: N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,3-difluoroazetidin-1- sulfonamide 6-Amino-3,5-dimethylquinazolin-4(3H)-one (31.5 mg, 0.166475 mmol) was dissolved in toluene (1.7 ml) and treated with tert-butyl (2-chloro-4-fluoro- 3-iodophenyl) ((3,3-difluoroazetidin-1-yl)sulfonyl)carbamate (96.4493 mg, 0.183122 mmol), tris(dibenzylideneacetone) dippalladium (15.2446 mg, 0.0166475 mmol), 4, 5-bis(diphenylphosphino)-9,9-dimethylxanthene (24.0819 mg, 0.0416187 mmol) and cesium carbonate (162.722 mg, 0.499424 mmol), then purged with argon, sealed and heated to 110°C for 16 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM then washed with water (1x) and dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue is purified by chromatography on silica gel (DCM/Acetone). The resulting residue was dissolved in 1:1 DCM:TFA (2.0 ml) and stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated and purified by C18 reverse phase chromatography (water/ACN with 0.1% TFA) and the desired fractions were combined and partitioned between saturated aqueous NaHCO ₃ and 4:1 DCM:IPA. The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl) amino)-4-fluorophenyl)-3,3-difluoroazetidine-1-sulfonamide (33.0 mg, 40.6% yield). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 10.04 (s, 1H), 8.17 (s, 1H), 7.35-7.31 (m, 4H), 6.86- 6.84 (dd, 1H), 4.36-4.30 (t, 4H), 3.43 (s, 3H), 2.81 (s, 3H). MS (chiad, m/z) = 488.1, 490.1 (M+H).

Example 135

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3,3-difluoroazetidine-1-sulfonamide

6-Amino-5-chloro-3-methylquinazolin-4(3H)-one (31.4 mg, 0.149786 mmol) was dissolved in toluene (1.5 ml) and treated with tert-butyl (2-chloro-4- fluoro-3-iodophenyl) ((3,3-difluoroazetidin-1-yl)sulfonyl)carbamate (86.7802 mg, 0.164764 mmol), tris(dibenzylideneacetone) dippalladium (13.7164 mg, 0.0149786 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21.6677 mg, 0.0374464 mmol) and cesium carbonate (146.409 mg, 0.449357 mmol), then purged with argon, sealed and heated to 110°C within 16 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM and washed with water (1x) then dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue is purified by chromatography on silica gel (DCM/Acetone). The resulting residue was dissolved in 1:1 DCM:TFA (2.0 ml) and stirred at ambient temperature for 30 minutes. The reaction mixture is concentrated and purified by C18 reverse phase chromatography (water/ACN with 0.1% TFA) and the desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ and 4:1 DCM:IPA. The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6- yl)amino)-4-fluorophenyl)-3,3-difluoroazetidin-1-sulfonamide (29.0 mg, 38.1% yield). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 10.14 (s, 1H), 8.21 (s, 1H), 7.79 (s, 1H), 7.53-7.49 ( m, 1H), 7.45-7.38 (m, 2H), 6.79-6.76 (dd, 1H), 4.36-4.30 (t, 4H), 3.45 (s, 3H). MS (chiad, m/z) = 508.0, 510.0 (M+H).

Example 136

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3,3-difluoroazetidin-1- sulfonamide

6-Amino-5-fluoro-3-methylquinazolin-4(3H)-one (32.1 mg, 0.166165 mmol) was dissolved in toluene (1.7 ml) and treated with tert-butyl

(2-chloro-4-fluoro-3-iodophenyl)((3,3-difluoroazetidin-1-yl)sulfonyl)carbamate (96.27 mg, 0.183 mmol), tris(dibenzylideneacetone) dippalladium (15.2163 mg, 0 .0166 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24.0371 mg, 0.0415413 mmol) and cesium carbonate (162.419 mg, 0.498 mmol), then purged with argon, sealed and heated to 110°C for 16 hours. The reaction mixture is cooled to ambient temperature and diluted with DCM and washed with water (1x) then dried over Na ₂ SO ₄ , filtered and concentrated. The resulting residue is purified by chromatography on silica gel (DCM/Acetone). The resulting residue was dissolved in 1:1 DCM:TFA (2.0 ml) and stirred at ambient temperature for 30 minutes. The reaction mixture is concentrated and purified by C18 reverse phase chromatography (water/acetonitrile with 0.1% TFA) and the desired fractions are combined and partitioned between saturated aqueous NaHCO ₃ and 4:1 DCM:IPA. The organic phase is separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)phenyl)-3,3-difluoroazetidin-1-sulfonamide (22.6 mg, 27.7% yield). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 10.09 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.40-7.32 ( m, 3H), 7.07-7.02 (t, 1H), 4.37-4.31 (t, 4H), 3.44 (s, 3H). MS (chiad, m/z) = 492.1, 494.1 (M+H).

Example 137

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-((difluoromethoxy)methyl)azetidine-1 -sulfonamide trifluoroacetate

Step 1: Preparation of 3-((difluoromethoxy)methyl)azetidine-1-sulfonyl chloride. 3-((difluoromethoxy)methyl)azetidine (200 mg, 1.46 mmol) was stirred with N-ethyl-N-isopropylpropan-2-amine (379 µl, 2.19 mmol) at ambient temperature in dichloromethane (3646 µl) within 5 minutes. The reaction mixture was cooled to -10°C and then sulfuryl dichloride (295 μl, 3.65 mmol) was added dropwise to the reaction as a pure liquid. The reaction is allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture is diluted with DCM and washed with 1N aq. HCl. The DCM layer is dried over MgSO ₄ , concentrated and used without purification directly in the next step (345 mg, 100%).

Step 2: Preparation of tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-((difluoromethoxy)-methyl)azetidin-1-yl)sulfonyl)carbamate. Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (105 mg, 0.283 mmol) was dissolved in tetrahydrofuran (1413 μl) and cooled to 0°C. Sodium hydride (60% in mineral oil, 17.0 mg, 0.424 mmol) is added and the resulting solution is allowed to warm to ambient temperature, then 3-((difluoromethoxy)-methyl)azetidine-1-sulfonyl chloride (99.9 mg) is added , 0.424 mmol) and the reaction mixture was heated to 60°C for 16 hours. The crude reaction mixture is cooled to ambient temperature, concentrated and purified by silica gel chromatography (Hexane/EtOAc) to give tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-((difluoromethoxy)-methyl)azetidine -1-yl)sulfonyl)carbamate (98 mg, 61%).

Step 3: N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-((difluoromethoxy)methyl) Azetidine-1-sulfonamide trifluoroacetate. 6-amino-3,5-dimethylquinazolin-4(3H)-one (31 mg, 0.164 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-((difluoromethoxy)methyl) azetidin-1-yl)sulfonyl)carbamate (98.2 mg, 0.172 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (14.2 mg, 0.0246 mmol ), cesium carbonate (107 mg, 0.328 mmol) and tris(dibenzylideneacetone) dippalladium(0) (7.50 mg, 0.00819 mmol) are dissolved in toluene (1.6 ml), sealed and heated to 110 ° C in within 16 hours. The reaction mixture is allowed to cool to ambient temperature, filtered through Celite, concentrated and the residue is reconstituted in 1:1 DCM:TFA (2 ml) and stirred at ambient temperature for 30 minutes. Volatiles are removed in vacuo and the crude product is purified by reverse phase chromatography (5-95% MeCN/H ₂ O, 0.1% TFA). The desired fractions are lyophilized to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-((difluoromethoxy) Methyl)azetidine-1-sulfonamide trifluoroacetate (38 mg, 44%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.58 (s, 1H), 7.57 (d, 1H), 7.48-7.44 (m, 1H), 7.13 (t, 1H) , 7.09-7.06 (m, 1H), 6.62 (s, 1H), 6.41-6.04 (m, 1H), 5.66 (s, 1H), 4.05 (t , 2H), 3.98-3.97 (d, 2H), 3.83-3.79 (m, 2H), 3.65 (s, 3H), 2.97 (s, 3H), 2, 93-2.87 (m, 1H). MS (chiad, m/z) = 532.1, 534.1 (M+H).

Example 138

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-((difluoromethoxy)methyl)azetidine -1-sulfonamide trifluoroacetate

6-Amino-5-chloro-3-methylquinazolin-4(3H)-one (28.1 mg, 0.1340 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3- ((difluoromethoxy)methyl)azetidin-1-yl)sulfonyl)carbamate (80.33 mg, 0.1407 mmol), cesium carbonate (87.35 mg, 0.2681 mmol), tris(dibenzylideneacetone)dipalladium(0) ( 6.137 mg, 0.006702 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis-(diphenylphosphane) (9.307 mg, 0.01609 mmol) dissolved in toluene (1.3 ml), seal tightly and heat to 110°C for 16 hours. The reaction mixture is allowed to cool to ambient temperature, filtered through Celite, concentrated and the residue is reconstituted in 1:1 DCM:TFA (2 ml) and stirred at ambient temperature for 30 minutes. Volatiles are removed in vacuo and the crude product is purified by reverse phase chromatography (5-95% MeCN/H ₂ O, 0.1% TFA). The desired fractions are lyophilized to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(( difluoromethoxy)methyl)azetidine-1-sulfonamide trifluoroacetate (33 mg, 44%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 7.61 (d, 1H), 7.60-7.57 (m, 1H), 7.19 (t, 1H) , 7.02-6.99 (m, 1H), 6.66 (s, 1H), 6.53 (s, 1H), 6.41-6.04 (m, 1H), 4.05 (t , 2H), 3.99-3.97 (d, 2H), 3.83-3.80 (m, 2H), 3.67 (s, 3H), 2.96-2.86 (m, 1H ). MS (chiad, m/z) = 552.1, 554.1 (M+H).

Example 139

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-((difluoromethoxy)methyl) Azetidine-1-sulfonamide trifluoroacetate

6-Amino-5-fluoro-3-methylquinazolin-4(3H)-one (25.9 mg, 0.1341 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3- ((difluoromethoxy)methyl)azetidin-1-yl)sulfonyl)carbamate (80.35 mg, 0.1408 mmol), cesium carbonate (87.37 mg, 0.2681 mmol), tris(dibenzylideneacetone)dipalladium(0) ( 6.139 mg, 0.006704 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.309 mg, 0.01609 mmol) dissolved in toluene (1.3 ml), sealed cover and heat to 110°C for 16 hours. The reaction mixture is allowed to cool to ambient temperature, filtered through Celite, concentrated and the residue is reduced in 1:1 DCM/TFA (2 ml). The reaction is stirred at ambient temperature for 30 minutes and volatiles are removed in vacuo. The crude product is purified by reverse phase chromatography (5-95% MeCN/H ₂ O, 0.1% TFA). The desired fractions are lyophilized to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-( (difluoromethoxy)methyl)azetidine-1-sulfonamide trifluoroacetate (39 mg, 55%). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.54 (s, 1H), 7.57-7.50 (m, 2H), 7.17 (t, 1H), 7.12-7.07 ( m, 1H), 6.65 (s, 1H), 6.41-6.04 (m, 1H), 6.01 (s, 1H), 4.05 (t, 2H), 3.98-3 .97 (d, 2H), 3.83-3.79 (m, 2H), 3.68 (s, 3H), 2.96-2.85 (m, 1H). MS (chiad, m/z) = 536.1, 538.1 (M+H).

Example 140

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)-3-methylazetidine-1 -sulfonamide trifluoroacetate

Step 1: 3-(methoxymethyl)-3-methylazetidine-1-sulfonyl chloride. To a solution of 3-(methoxymethyl)-3-methylazetidine hydrochloride (230 mg, 1.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (400 μl, 2 mmol) in dichloromethane (5060 μl) at 0°C sulfuryl dichloride (300 μl, 3.8 mmol) was added and the reaction mixture was warmed to ambient temperature and stirred for 16 hours. The solution was diluted with DCM and washed with 1 N HCl (1x) and the DCM layer was dried over Na ₂ SO ₄ , filtered and concentrated to give 3-(methoxymethyl)-3-methylazetidine-1-sulfonyl chloride (240 mg, 74% yield).

Step 2: tert-butyl (2-chloro-4-fluoro-3-iodophenyl) ((3-(methoxymethyl)-3-methylazetidin-1-yl)sulfonyl)carbamate. To a solution of tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (25 mg, 0.067 mmol) in tetrahydrofuran (340 μl) at 0°C add sodium hydride (60% in mineral oil, 4.0 mg , 0.10 mmol) and stir for 10 minutes. 3-(Methoxymethyl)-3-methylazetidine-1-sulfonyl chloride (22 mg, 0.10 mmol) is added and the solution is heated to 50°C in a sealed tube for 16 hours. The solution is partitioned between dichloromethane and saturated NaHCO ₃ and the organic layer is washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (5-95% EtOAc/hexane) to give tert-butyl (2-chloro- 4-fluoro-3-iodophenyl)((3-(methoxymethyl)-3-methylazetidin-1-yl)sulfonyl)carbamate (34 mg, 92% yield).

Step 3: N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)-3- methylazetidin-1-sulfonamide trifluoroacetate. Solution of 6-amino-3,5-dimethylquinazolin-4(3H)-one (12 mg, 0.063 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)(( 3-(methoxymethyl)-3-methylazetidin-1-yl)sulfonyl)carbamate (34 mg, 0.063 mmol), tris(dibenzylideneacetone) dipalladium (5 mg, 0.00 6 mmol), Xantphos (9 mg, 0.01 mmol ) and cesium carbonate (41 mg, 0.12 mmol) in toluene (420 µl) are purged with argon and heated to 110°C for 16 hours in a sealed tube. The solution is filtered through Celite®, concentrated and stirred in 1 ml DCM and 1 ml TFA for 1 hour. The solution is concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA) and the product is lyophilized to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3 ,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(methoxymethyl)-3-methylazetidine-1-sulfonamide trifluoroacetate (6.0 mg, 19% yield). ^1H NMR (400 MHz, CDCl ₃ ) (8.61 (s, 1H), 7.57 (d, 1H), 7.51-7.47 (m, 1H), 7.15-7.06 ( m, 2H), 6.68 (shs, 1H), 5.67 (shs, 1H), 3.87 (d, 2H), 3.65 (s, 3H), 3.60 (d, 2H), 3.36 (s, 3H), 3.32 (s, 2H), 2.97 (s, 3H), 1.28 (s, 3H); MS (chiad, m/z) = 510.2, 512 ,2 (M+N).

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-ethoxyazetidine-1-sulfonamide

Step 1: tert-butyl 3-ethoxyazetidine-1-carboxylate.

A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (63.5 ml, 12.7 mmol) in 1:1 DMF:THF (60 ml) and sodium hydride (0.7 62 g, 19.1 mmol) was stirred in ice bath for 10 minutes. Iodoethane (3.05 mL, 38.1 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture is diluted with water (100 ml) and extracted with EtOAc (100 ml). The organic phase is dried over Na ₂ SO ₄ , filtered and concentrated to give tert-butyl 3-ethoxyazetidine-1-carboxylate (2.56 g, 100% yield), which is used directly in the next step without further purification.

Step 2: 3-ethoxyazetidine hydrochloride. A solution of tert-butyl 3-ethoxyazetidine-1-carboxylate (2.50 g, 12.4 mmol) in 1:1:3 THF:DMF:EtOAc (150 ml) was stirred at ambient temperature while adding a solution of 5N HCl (74, 5 ml, 373 mmol) in IPA. The reaction mixture was stirred at ambient temperature, then concentrated to give 3-ethoxyazetidine hydrochloride (1.3 g, 76.1% yield) as a red oil, which was used in the following steps without further purification. ^1H NMR (4 00 MHz, D ₄ -Methanol) (4.48-4.40 (m, 1H), 4.33-4.25 (m, 2H), 4.01-3.93 (m, 2H), 3.53 (m, 2H), 1.23 (t, 3H).

Step 3: 3-ethoxyazetidine-1-sulfonyl chloride. A solution of 3-ethoxyazetidine hydrochloride (500 mg, 3.63 mmol) in DCM (30 ml) is cooled to 0°C and treated with N-ethyl-N-isopropylpropan-2-amine (94 9 μl, 5.4 5 mmol), then sulfuryl dichloride (881 µl, 10.9 mmol). The reaction mixture is warmed to ambient temperature and stirred for 18 hours then diluted with DCM (70 ml) and washed with 1N HCl (2 x 50 ml). The organic phases are combined and washed with brine (25 ml), then dried over Na ₂ SO ₄ , filtered and concentrated to give 3-ethoxyazetidine-1-sulfonyl chloride (700 mg, 96.5% yield) as a yellow oil, which is used without further purification. ^1H NMR (400 MHz, CDCl ₃ ) (4.36-4.30 (m, 1H), 4.29-4.22 (m, 2H), 4.04-3.99 (m, 2H), 3.47 (m, 2H), 1.24 (t, 3H).

Step 4: tert-butyl (2-chloro-4-fluoro-3-iodophenyl) ((3-ethoxyazetidin-1-yl)sulfonyl)carbamate. A solution of tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (961 µl, 0.673 mmol) in THF (1 ml) was treated with sodium hydride (53.8 mg, 1.35 mmol, 60% dispersion in mineral oil) and stirred at 0°C for 30 minutes. 3-ethoxyazetidine-1-sulfonyl chloride (269 mg, 1.35 mmol) was added and the reaction mixture was warmed to ambient temperature and heated at 50°C for 96 hours. The reaction mixture was diluted with water (50 ml) and saturated aqueous NaHCO ₃ (50 ml), and the aqueous layer was extracted with 4:1 DCM IPA (3×25 ml). The organic phases are combined and dried over Na ₂ SO ₄ , filtered and concentrated to give a brown oil, which is purified by chromatography on silica gel (0-50% hexane: EtOAc) to give tert-butyl (2-chloro-4-fluoro-3-iodophenyl )((3-ethoxyazetidin-1-yl)sulfonyl)carbamate (279 mg, 77.5% yield). ^1H NMR (400 MHz, CDCl ₃ ) (7.40-7.35 (m, 1H), 7.07-7.01 (m, 1H), 4.40-4.28 (m, 3H), 4.26-4.18 (m, 2H), 3.46 (sq, 2H), 1.43 (s, 9H), 1.23 (t, 3H).

Step 5: N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-ethoxyazetidine-1- sulfonamide Solution of 6-amino-5-chloro-3-methylquinazolin-4(3H)-one (30 mg, 0.143 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-ethoxyazetidine-1 -yl)sulfonyl)carbamate (84.2 mg, 0.157 mmol), Pd ₂ (dba) ₃ (13.1 mg, 0.0143 mmol), cesium carbonate (140 mg, 0.429 mmol) and (9,9-dimethyl -9H-xanthene-4,5-diyl)bis(diphenylphosphane) (20.7 mg, 0.0358 mmol) in toluene (0.9 ml) purged with argon for 5 minutes then heated at 100°C for 18 hours . The reaction mixture is cooled to ambient temperature, then partitioned between water (25 ml) and EtOAc (50 ml). The organic phase is separated and washed with brine (25 ml) then dried over Na ₂ SO ₄ , filtered and concentrated to a brown oil. The crude reaction mixture was dissolved in DCM (25 ml) and TFA (10 ml) and stirred for 20 minutes at ambient temperature then concentrated to a brown oil, which was purified by HPLC (5-95% acetonitrile: H ₂ O with 0. 1% TPA). The desired fractions are combined and the pH is adjusted to 9 with saturated aqueous NaHCO ₃ . The aqueous phase is extracted with DCM (2×50 ml) and the organic phases are combined, dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo -3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-ethoxyazetidine-1-sulfonamide (39.4 mg, 53.3% yield) as a beige solid. ^1H NMR (400 MHz, CDCl ₃ ) (7.93(s, 1H), 7.58-7.48 (m, 2H), 7.15 (t, 1H), 7.01-6.95 ( m, 1H), 6.68 (s, 1H), 6.45 (s, 1H), 4.27-4.19 (m, 1H), 4.10-4.04 (m, 2H), 3 .95-3.88 (m, 2H), 3.57 (s, 3H), 3.41 (m, 2H), 1.19 (t, 3H); MS (chiad, m/z) = 516, 1, 518.1 (M+H).

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-ethoxyazetidine-1-sulfonamide

Solution of 6-amino-5-fluoro-3-methylquinazolin-4(3H)-one (30 mg, 0.155 mmol), tert-butyl (2-chloro-4-fluoro-3-iodophenyl)((3-ethoxyazetidine-1 -yl)sulfonyl)carbamate (91.4 mg, 0.171 mmol), Pd ₂ (dba) ₃ (14.2 mg, 0.0155 mmol), cesium carbonate (152 mg, 0.466 mmol) and (9,9-dimethyl -9H-xanthene-4,5-diyl)bis(diphenylphosphane) (22.5 mg, 0.0388 mmol) in toluene (0.9 ml) was purged with argon for 5 minutes, then heated at 100°C for 18 hours. The reaction mixture is cooled to ambient temperature then partitioned between water (25 ml) and EtOAc (50 ml). The organic phase is separated and washed with brine (25 ml), then dried over Na ₂ SO ₄ , filtered and concentrated to a brown oil. The crude reaction mixture was dissolved in DCM (25 ml) and TFA (10 ml) and stirred for 20 minutes at ambient temperature then concentrated to give a brown oil, which was purified by HPLC (5-95% acetonitrile: H ₂ O with 0. 1% TPA). The desired fractions are combined and the pH is adjusted to 9 with saturated aqueous NaHCO ₃ . The aqueous phase is extracted with DCM (2×50 ml) and the organic phases are combined, dried over Na ₂ SO ₄ , filtered and concentrated to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl -4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-ethoxyazetidine-1-sulfonamide (32.9 mg, 42.4% yield) as a beige solid. ^1H NMR (400 MHz, CDCl ₃ ) (7.90 (s, 1H), 7.54-7.48 (m, 1H), 7.43-7.38 (m, 1H), 7.14 ( t, 1H), 7.08-7.02 (m, 1H), 6.64 (s, 1H), 5.92 (s, 1H), 4.27-4.19 (m, 1H), 4 .10-4.03 (m, 2H), 3.94-3.89 (m, 2H), 3.57 (s, 3H), 3.42 (m, 2H), 1.19 (t, 3H ); MS (chiad, m/z) = 500.1, 502.1 (M+H).

N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(difluoromethoxy)azetidine-1- sulfonamide

Step 1: Preparation of 3-(difluoromethoxy)azetidine-1-sulfonyl chloride. 3-(difluoromethoxy)azetidine hydrochloride (513 mg, 3.21 mmol) was suspended in DCM (15.7 mL) and N,N-diisopropylethylamine (818.7 μL, 4.70 mmol) was added and stirred at ambient temperature. until dissolved. The reaction mixture is cooled to 0°C and treated with sulfuryl dichloride (0.77 ml, 9.64 mmol) dropwise and stirred at ambient temperature for 12 hours. The reaction mixture is diluted with DCM, washed with 10% HCl (3×25 ml), brine (1×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 3-(difluoromethoxy)azetidine-1-sulfonyl chloride ( 366 mg, 51%) as a yellow liquid which is used in the next step without purification. ^1H NMR (400 MHz, CDCl ₃ ) (6.48-6.08 (t, 1H), 5.08-5.01 (m, 1H), 4.41-4.35 (m, 2H), 4.21-4.16 (m, 2H).

Step 2: Preparation of tert-butyl (2-chloro-4-fluoro-3-iodophenyl)(3-(difluoromethoxy)azetidin-1-yl)sulfonyl)carbamate. Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)carbamate (307 mg, 0.826 mmol) was dissolved in THF (4.1 ml), cooled to 0°C and treated with sodium hydride (66.1 mg, 1 .65 mmol). The reaction is stirred at ambient temperature for 15 minutes and treated with 3-(difluoromethoxy)azetidine-1-sulfonyl chloride (366 mg, 1.65 mmol), and then heated to 50°C for 12 hours. The reaction mixture is cooled to ambient temperature and poured into 20 ml of ice water. The aqueous layer was extracted with EtOAc (2×25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue is purified by reverse phase chromatography (5-95% water/ACN with 0.1% TFA) and the desired fractions are combined, partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give tert-butyl (2-chloro-4-fluoro-3-iodophenyl)(3-(difluoromethoxy)azetidin-1-yl)sulfonyl)carbamate (228 mg, 50%) as an off-white semi-solid. ^1H NMR (400 MHz, (CD ₃ ) ₂ SO) (7.62-7.57 (m, 1H), 7.38-7.33 (m, 1H), 6.97-6.60 (t , 1H), 5.07-5.00 (m, 1H), 4.50-4.44 (m, 2H), 4.27-4.18 (m, 2H), 1.39 (s, 9H ).

Step 3: Preparation of N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-(difluoromethoxy) azetidine-1-sulfonamide. Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)(3-(difluoromethoxy)azetidin-1-yl)sulfonyl)carbamate (58.43 mg, 0.11 mmol), 6-amino-5-chloro -3-methylquinazolin-4(3H)-one (22 mg, 0.105 mmol), cesium carbonate (68.4 mg, 0.21 mmol), tris(dibenzylideneacetone) dippalladium (9.6 mg, 0.011 mmol) and (9 ,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (15.2 mg, 0.026 mmol) was suspended in toluene (1.05 ml) and the reaction was purged with argon for 15 minutes, sealed and heated to 110°C for 12 hours. The crude reaction is cooled to ambient temperature, then diluted with DCM and filtered through a short pad of Celite (and concentrated. The residue is dissolved in 1:1 DCM:TFA (5 ml) and stirred at ambient temperature for 30 minutes. The reaction is concentrated, diluted with DCM , washed with saturated NaHCO ₃ (3x50 ml) and brine (1x25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated.The residue was purified by silica gel column chromatography (0-100% DCM/EtOAc), then reverse phase chromatography (5-95% water/acetonitrile with 0.1% TFA) The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x), and the organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filter and concentrate to give N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl) -3-(difluoromethoxy)azetidine-1-sulfonamide (26 mg, 46%) as a light brown solid. ^1H NMR (400 MHz, (CD3)2SO) (9.86 (s, 1H), 8. 21 (s, 1H), 7.77 (s, 1H), 7.54-7.36 (m, 3H), 6.93-6.53 (m, 2H), 4.97-4.88 ( m, 1H), 4.15-4.08 (m, 2H), 3.90-3.82 (m, 2H), 3.44 (s, 3H); MS (chiad, m/z)=539.0.541.0.543.0

(M+N).

N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-(difluoromethoxy)azetidine-1 -sulfonamide

Tert-butyl (2-chloro-4-fluoro-3-iodophenyl)(3-(difluoromethoxy)azetidin-1-yl)sulfonyl)carbamate (61.0 mg, 0.11 mmol), 6-amino-5-fluoro -3-methylquinazolin-4(3H)-one (21 mg, 0.11 mmol), cesium carbonate (71.0 mg, 0.22 mmol), tris(dibenzylideneacetone) dippalladium (10.0 mg, 0.011 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (16 mg, 0.026 mmol) was suspended in toluene (1.08 ml) and the reaction was purged with argon for 15 minutes, sealed and heated to 110°C for 12 hours. The crude reaction is cooled to ambient temperature, then diluted with DCM and filtered through a short pad of Celite (and concentrated. The residue is dissolved in 1:1 DCM:TFA (5 ml) and stirred at ambient temperature for 3 0 minutes. The reaction is concentrated, diluted DCM, washed with saturated NaHCO ₃ (3x50 ml) and brine (1x25 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated.The residue was purified by silica gel column chromatography (0-100% DCM/EtOAc). then reverse phase chromatography (5-95% water/ACN with 0.1% TPA) The desired fractions are combined and partitioned between 4:1 DCM:IPA and saturated aqueous NaHCO ₃ (1x) and the organic layer is separated, dried over anhydrous Na ₂ SO ₄ , filter and concentrate to give N-(2-chloro-4-fluoro-3-((5-fluoro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl) -3-(difluoromethoxy)azetidine-1-sulfonamide (20 mg, 35%) as an off-white solid. ^1H NMR (400 MHz, ( _CD3 ) _2SO ) δ 9.81 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.43-7.29 (m, 3H), 7.08-7.00 (t, 1H), 6.93-6, 53 (t, 1H), 4.97-4.89 (m, 1H), 4.15-4.08 (m, 2H), 3.89-3.82 (m, 2H), 3.43 ( s, 3H); MS (chiad, m/z) = 522.0, 524.0 (M+H).

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoro-3-(methoxymethyl)azetidin- 1-sulfonamide trifluoroacetate

Step 1: tert-butyl 3-fluoro-3-(methoxymethyl)azetidine-1-carboxylate. To a solution of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (600 mg, 2.92 mmol) in tetrahydrofuran (14.6 ml) at 0°C add sodium hydride (60% in mineral oil, 175 mg, 4.39 mmol) and stir at ambient temperature for 10 minutes. Iodomethane (3 64 µl, 5.85 mmol) is added and stirred at ambient temperature for 45 minutes. The solution is partitioned between saturated NaHCO ₃ and DCM, and the organic layer is washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated, then purified by silica gel chromatography (5-75% EtOAc/hexane) to give tert-butyl 3-fluoro -3-(methoxymethyl)azetidine-1-carboxylate (631 mg, 98.4% yield).

Step 2: 3-fluoro-3-(methoxymethyl)azetidine hydrochloride. A solution of tert-butyl 3-fluoro-3-(methoxymethyl)azetidine-1-carboxylate (631 mg, 2.8 8 mmol) in 4 M HCl in dioxane (5.76 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated to give 3-fluoro-3-(methoxymethyl)azetidine hydrochloride (440 mg, 98% yield).

Step 3: 3-fluoro-3-(methoxymethyl) azetidine-1-sulfonyl chloride. To a solution of 3-fluoro-3-(methoxymethyl)azetidine hydrochloride (440 mg, 2.8 3 mmol) and N-ethyl-N-isopropylpropan-2-amine (740 μl, 4.2 4 mmol) in dichloromethane (9, 42 ml) at 0° C. add sulfuryl dichloride (570 µl, 7.07 mmol) and warm to ambient temperature and stir for 16 hours. The solution is diluted with additional DCM and washed with 1 N HCl (1x), then dried over Na ₂ SO ₄ , filtered and concentrated to give 3-fluoro-3-(methoxymethyl)azetidine-1-sulfonyl chloride (601 mg, 97.7% yield) .

Step 4: N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoro-3-(methoxymethyl )azetidine-1-sulfonamide trifluoroacetate. 6-((3-amino-2-chloro-6-fluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one (25 mg, 0.075 mmol), 3-fluoro-3-(methoxymethyl)azetidin- 1-sulfonyl chloride (16 mg, 0.075 mmol) and calcium bis((trifluoromethyl)sulfonyl)amide (45 mg, 0.075 mmol) in toluene (190 μl) are heated to 100°C for 16 hours in a sealed tube. The reaction mixture is cooled to ambient temperature, then filtered, concentrated and purified by reverse phase chromatography (5-95% MeCN/water, 0.1% TFA). The product is concentrated to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluoro-3-( methoxymethyl)azetidine-1-sulfonamide trifluoroacetate (6.0 mg, 16% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.82 (s, 1H), 7.60 (d, 1H), 7.53-7.49 (m, 1H), 7.18-7.14 ( t, 1H), 7.11-7.08 (m, 1H), 6.69 (shs, 1H), 5.73 (shs, 1H), 4.16-4.02 (m, 4H), 3 .73 (s, 3H), 3.65 (d, 2H), 3.43 (s, 3H), 2.95 (s, 3H); MS (chiad, m/z) = 514.1, 516.1 (M+H).

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-cyanoazetidine-1-sulfonamide trifluoroacetate

6-((3-Amino-2-chloro-6-fluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one (25 mg, 0.0751 mmol), 3-cyanoazetidine-1-sulfonyl chloride (13 .6 mg, 0.0751 mmol) and calcium bis((trifluoromethyl)sulfonyl)amide (45.1 mg, 0.0751 mmol) are suspended in toluene (150 μl) in a test tube, sealed and heated at 100 ° C in within 16 hours. The reaction is allowed to cool to ambient temperature and concentrated in vacuo. The crude reaction mixture is purified by reverse phase chromatography (MeCN/H ₂ O, 0.1% TFA). The desired fractions are combined and lyophilized to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-cyanoazetidin- 1-sulfonamide trifluoroacetate (18 mg, 50% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.67 (s, 1H), 7.61-7.58 (m, 1H), 7.15 (t, 1H), 7.12-7.09 ( m, 1H), 6.63 (s, 1H), 5.69 (s, 1H), 4.27-4.18 (m, 4H), 3.66 (s, 3H), 3.50-3 , 43 (m, 1H), 2.97 (s, 3H). MS (chiad, m/z) = 477.1, 479.1 (M+H).

N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-methylazetidine-1-sulfonamide trifluoroacetate

Step 1: Preparation of 3-methylazetidine-1-sulfonyl chloride. 3-Methylazetidine hydrochloride (75 mg, 0.697 mmol) was stirred with N-ethyl-N-isopropylpropan-2-amine (181 µl, 1.05 mmol) at ambient temperature in dichloromethane (1743 µl) for 5 minutes. The reaction mixture is cooled to -10°C (ice/acetone) and sulfuryl dichloride (141 μl, 1.74 mmol) is added dropwise as a pure liquid. The reaction mixture is allowed to warm to ambient temperature and stirred for 16 hours. The solution is diluted with additional DCM and washed with 1 N HCl (1x), then dried over Na ₂ SO ₄ , filtered and concentrated to give 3-methylazetidine-1-sulfonyl chloride (118 mg, 100% yield), which is used directly in the next step.

Step 2: N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-methylazetidine-1-sulfonamide trifluoroacetate . 6-((3-amino-2-chloro-6-fluorophenyl)amino)-3,5-dimethylquinazolin-4(3H)-one (2 0 mg, 0.0 601 mmol), 3-methylazetidine-1-sulfonyl chloride (10.2 mg, 0.0601 mmol) and calcium bis((trifluoromethyl)sulfonyl)amide (36.1 mg, 0.0601 mmol) are suspended in toluene (12 0 μl) in a test tube, sealed and heated at 100 °C for 16 hours. The reaction is allowed to cool to ambient temperature and concentrated in vacuo. The crude reaction mixture is purified by reverse phase chromatography (5-95% MeCN/H ₂ O, 0.1% TFA). The desired fractions are combined and lyophilized to give N-(2-chloro-3-((3,5-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-cyanoazetidin- 1-sulfonamide trifluoroacetate (9.4 mg, 33% yield). ^1H NMR (400 MHz, CDCl ₃ ) δ 8.95 (s, 1H), 7.63 (d, 1H), 7.55-7.51 (m, 1H), 7.16 (t, 1H) , 7.11-7.08 (m, 1H), 6.62 (s, 1H), 5.73 (s, 1H), 4.03 (t, 2H), 3.73 (s, 3H), 3.61 (t, 2H), 2.96 (s, 3H), 2.74-2.65 (m, 1H) 1.23 (d, 3H). MS (chiad, m/z) = 466.l, 468.1 (M+H).

The following compounds are also prepared in accordance with the procedures described herein.

Claims (28)

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 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 structure . 3. A pharmaceutical composition for the treatment of a BRAF-associated tumor, containing a therapeutically effective amount of a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. 4. A method of treating a BRAF-associated tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof. 5. The method according to claim 4, characterized in that said BRAF-associated tumor has a class II BRAF mutation. 6. The method of claim 5, wherein said class II BRAF mutation is a non-V600 BRAF mutation. 7. The method of claim 6, wherein said non-V600 BRAF mutation is BRAF G469A or G469R. 8. The method according to claim 5, characterized in that said class II BRAF mutation is a splice variant BRAF V600E. 9. The method of claim 8, wherein said BRAF V600E splice variant is p61BRAF (V600E). 10. Method according to any one of paragraphs. 4-9, characterized in that said BRAF-associated tumor is a cancer selected from lung cancer, melanoma, colorectal cancer, breast cancer, pancreatic cancer, thyroid cancer, prostate cancer, adenoid cystic carcinoma, appendix cancer , small bowel cancer, squamous cell carcinoma of the head and neck, angiosarcoma, bladder cancer, plasma cell neoplasm, hepatopancreatobiliary carcinoma, ovarian carcinoma, neuroendocrine cancer, cholangiocarcinoma and CNS cancer. 11. Method according to any one of paragraphs. 4-10, characterized in that said cancer is a metastatic cancer. 12. The method according to claim 11, characterized in that said cancer is a metastatic cancer of the central nervous system. 13. Method according to any one of paragraphs. 4-9, characterized in that said BRAF-associated tumor is a primary brain tumor. 14. The method according to claim 13, characterized in that said primary brain tumor is a grade 2 glioma, a grade 3 glioma or a grade 4 glioma. 15. The method according to claim 4, characterized in that said BRAF-associated tumor has a class I BRAF mutation. 16. The method of claim 15, wherein said class I BRAF mutation is BRAF V600E or BRAF V600K. 17. The method according to claim 15 or 16, characterized in that said BRAF-associated tumor is selected from melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, ovarian cancer, renal cell carcinoma and metastatic cancers thereof, and primary brain tumors . 18. Method according to any one of paragraphs. 4-17, further comprising administering additional anticancer therapy. 19. The method of claim 18, wherein the additional anticancer therapy is selected from one or more of surgery, radiation therapy, and an anticancer agent. 20. The method according to claim 19, characterized in that the additional anticancer therapy is an anticancer agent. 21. The method according to claim 20, characterized in that the additional anticancer agent is selected from MEK inhibitors, BRAF inhibitors, EGFR inhibitors, HER2 and/or HER3 inhibitors, Axl inhibitors, PI3K inhibitors, SOS1 inhibitors, signal transduction inhibitors, checkpoint inhibitors , modulators of the apoptosis pathway, cytotoxic chemotherapeutic agents, angiogenesis-targeted therapy and immuno-targeted agents. 22. The method according to claim 21, characterized in that the additional anticancer agent is a MEK inhibitor. 23. The method according to claim 22, characterized in that the MEK inhibitor is binimetinib or a pharmaceutically acceptable salt thereof. 24. The method according to claim 21, characterized in that the additional anticancer agent is an EGFR inhibitor. 25. The method according to claim 24, characterized in that the EGFR inhibitor is cetuximab.