The need for novel antifungal, antibacterial, and antiparasitic treatments is significant and is especially critical in the medical field. Immunocompromised patients provide perhaps the greatest challenge to modern health care. The development of antifungal, antibacterial, and antiparasitic treatment regimens has been a continuing challenge.

Dihydrofolate reductase (DHFR) is an important enzyme in nucleic acid and amino acid synthesis in all cells. DHFR inhibitors can reduce nucleotide biosynthesis, inhibit DNA biosynthesis, and reduce cell division in pathogens. For example, DHFR is the target of the marketed antibacterial drug trimethoprim. Trimethoprim has a diaminopyrimidine scaffold which has structural constraints and a limited number of hydrogen-bonding residues that can interact with residues in the DHFR active site.

There is a need in the art for improved DHFR inhibitors having greater structural diversity and larger access to DHFR active site residues, thus providing antifungal, antibacterial, and antiparasitic therapies having greater efficacy, bioavailability, and reduced toxicity. SUMMARY

The disclosure features compositions and methods for the treatment of fungal, bacterial, and parasitic infections and inhibition of fungal, bacterial, and parasitic growth. In particular, such

compositions include dihydrofolate reductase (DHFR) inhibitors having a diaminoquinazoline scaffold.

In one aspect, the disclosure features a compound described by formula (I)

wherein X ¹ is–O-(R ^d )p-,–S-(R ^d )p-,–NR ^a -(R ^d )p-,–(R ^d )p-O-,–(R ^d )p-S-,–(R ^d )p-NR ^a -, optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene, or is absent; p is 0 or 1; X ² is O, S, or NR ^b ; R ¹ is H, hydroxyl, optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted C3- C6 heterocycloalkyl, optionally substituted heteroaryl, optionally substituted C1-C3 alkyl aryl, or -SR ^c ; R ² is H, hydroxyl, amino, aminoalkyl, CF3, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, or optionally substituted heteroalkoxy; or R ¹ , R ² , X ² , C ¹ , and C ² together form a fused ring including optionally substituted C3-C6 heterocycloalkyl (e.g., C5-C6 heterocycloalkyl) having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heterocycloalkenyl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C5-C6 cycloalkoxy, or optionally substituted C3-C6 heterocycloalkoxy (e.g., C5-C6 heterocycloalkoxy) having 1 or 2 heteroatoms independently selected from N, O, and S; R ³ is H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; each of R ^a , R ^b , and R ^c , independently, H or optionally substituted C1- C3 alkyl; and R ^d is optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene and R ^d , when present, joins to C ³ ; or a pharmaceutically acceptable salt thereof.

In some embodiments of this aspect, when R ¹ , R ² , X ² , C ¹ , and C ² do not form a fused ring and R ³ is H, X ¹ is not absent.

In some embodiments of this aspect, R ¹ and X ² form an alkoxy and X ¹ is not absent. In some embodiments, X ² is S. In some embodiments, X ² is NR ^b , and R ^b is H or optionally substituted C1-C3 alkyl.

In some embodiments, the compound is described by formula (I-a)

wherein X ¹ is–O-(R ^d )p-,–S-(R ^d )p-,–NR ^a -(R ^d )p-,–(R ^d )p-O-,–(R ^d )p-S-,–(R ^d )p-NR ^a -, optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene, or is absent; X ² is O, S, or NR ^b ; R ¹ is optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted C3-C6

heterocycloalkyl, optionally substituted heteroaryl, or optionally substituted C1-C3 alkyl aryl; R ² is H, hydroxyl, amino, aminoalkyl, CF3, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, or optionally substituted heteroalkoxy; R ³ is acyl, optionally substituted C1-C3 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted C1-C3 heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; and each of R ^a and R ^b is, independently, H or optionally substituted C1-C3 alkyl; and R ^d is optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene and R ^d , when present, joins to C ³ ; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (I-b)

(I-b), wherein X ¹ is–O-(R ^d )p-,–S-(R ^d )p-,–NR ^a -(R ^d )p-,–(R ^d )p-O-,–(R ^d )p-S-,–(R ^d )p-NR ^a -, optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene, or is absent; X ² is O, S, or NR ^b ; R ³ is H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; R ¹ is optionally substituted C1-C3 alkyl; R ² is optionally substituted C1-C3 alkyl or optionally substituted C1-C3 alkoxy; R ¹ , R ² , X ² , C ¹ , and C ² together form a fused ring including optionally substituted C3-C6 heterocycloalkyl (e.g., C5-C6 heterocycloalkyl) having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heterocycloalkenyl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C5-C6 cycloalkoxy, or optionally substituted C3-C6

heterocycloalkoxy (e.g., C5-C6 heterocycloalkoxy) having 1 or 2 heteroatoms independently selected from N, O, and S; and each of R ^a and R ^b is, independently, H or optionally substituted C1-C3 alkyl; and R ^d is optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene and R ^d , when present, joins to C ³ ; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (I-c)

wherein R ³ is H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; X ¹ is–O-(R ^d )p-,–S-(R ^d )p-,–NR ^a -(R ^d )p-,–(R ^d )p- O-,–(R ^d )p-S-,–(R ^d )p-NR ^a -, optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene, or is absent; R ⁴ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; R ⁵ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; R ⁶ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; R ⁷ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; each of R ⁸ and R ⁹ is, independently, H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; is a single bond or double bond; n is 0 or 1; when n is 0, R ⁸ and R ⁹ are absent; when is a double bond, R ⁴ and R ⁶ are absent; and R ^a is H or optionally substituted C1-C3 alkyl; and R ^d is optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene and R ^d , when present, joins to C ³ ; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (I-d)

wherein R ³ , R ⁵ , R ⁷ , R ⁸ , R ⁹ , X ¹ , and n are defined as in formula (I-c); R ⁴ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; and R ⁶ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound described by formula (I-c) or formula (I-d), n is 1. In some embodiments, n is 0.

In some embodiments of the aforementioned compounds, R ³ is

wherein each R ^f is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5-C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy, -CONR ^f1 , -CN, -R ^f2 CN, or optionally substituted C1-C3 alkyl ester, and is not bonded to a heteroatom; q is an integer from 0 to 5; t is an integer from 0 to 4; u is an integer from 0 to 3; R ^f1 is H or optionally substituted C1-C3 alkyl; R ^f2 is optionally substituted C1-C4 alkylene; each of R ^g1 , R ^g2 , R ^g3 , R ^g4 , R ^g5 , R ^g6 , and R ^g7 , R ^g8 , R ^g9 , R ^g10 , R ^g11 , and R ^g12 is independently CH or N; each of R ^h1 , R ^h2 , R ^h3 is, independently, S or O; each of ring A, ring A ¹ , ring A ² , and ring A ³ is, independently, optionally substituted C5-C6 cycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heterocycloalkyl (e.g., C5-C6 heterocycloalkyl) including 1-4 NR ⁱ , S, or O, optionally substituted C3-C6 heterocycloalkenyl (e.g., C5-C6 heterocycloalkenyl) including 1-4 NR ⁱ , S, or O, or optionally substituted C3-C6 heteroaryl (e.g., C5-C6 heteroaryl) including 1-4 heteroatoms independently selected from N and S; and R ⁱ is H, optionally substituted C1-C3 alkyl, or O.

In some embodiments of the aforementioned compounds, R ³ is

In some embodiments, the compound is described by formula (I-e)

wherein R ³ is H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; and X ¹ is O or is absent; or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound described by formula (I-e), X ¹ is O and R ³ is , wherein each R ^f is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6

heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6

heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6

heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5-C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy, -CONR ^f1 , -CN, -R ^f2 CN, or optionally substituted C1-C3 alkyl ester; R ^f1 is H or optionally substituted C1-C3 alkyl; and R ^f2 is optionally substituted C1-C4 alkylene. In some particular embodiments, the compound has the structure

.

In some embodiments of the compound described by formula (I-e), X ¹ is absent and R ³ is

, wherein each R ^f is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5- C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy, -CONR ^f1 , -CN, -R ^f2 CN, or optionally substituted C1-C3 alkyl ester; R ^f1 is H or optionally substituted C1-C3 alkyl; and R ^f2 is optionally substituted C1-C4 alkylene. In some embodiments, the compound has the structure

,

In some embodiments, the compound is described by formula (I-f)

wherein R ³ is H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; each of R ⁴ , R ⁶ , and R ⁸ is, independently, H or optionally substituted C1-C3 alkyl; and X ¹ is O or is absent; or a pharmaceutically acceptable salt thereof. In some embodiments of the compound described by formula (I-f), X ¹ is absent and R ³ is

, wherein each R ^f is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6

heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6

heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6

heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5-C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy, -CONR ^f1 , -CN, -R ^f2 CN, or optionally substituted C1-C3 alkyl ester; R ^f1 is H or optionally substituted C1-C3 alkyl; and R ^f2 is optionally substituted C1-C4 alkylene. In some particular embodiments, the compound has the structure

.

In some embodiments, the compound is described by formula (I-g)

wherein X ² is O, S, or NR ^b ; R ¹ is H, hydroxyl, optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted heteroaryl, optionally substituted C1-C3 alkyl aryl, or -SR ^c ; R ² is H, hydroxyl, amino, aminoalkyl, CF3, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, or optionally substituted heteroalkoxy; or R ¹ , R ² , X ² , C ¹ , and C ² together form a fused ring comprising optionally substituted C3-C6 heterocycloalkyl (e.g., C5-C6 heterocycloalkyl) having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heterocycloalkenyl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C5-C6 cycloalkoxy, or optionally substituted C3-C6 heterocycloalkoxy (e.g., C5-C6 heterocycloalkoxy) having 1 or 2 heteroatoms independently selected from N, O, and S; each of R ^b and R ^c is, independently, H or optionally substituted C1-C3 alkyl; and is optionally substituted heterocycloalkyl having 1-4 heteroatoms independently selected from N, O, and S, or optionally substituted heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; or a

pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (I-h)

wherein X ² and are defined as in formula (I-g); and R ¹ is optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted heteroaryl, or optionally substituted C1-C3 alkyl aryl; and R ² is H, hydroxyl, amino, aminoalkyl, CF3, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, or optionally substituted heteroalkoxy; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (I-i)

wherein X ² and are defined as in formula (I-g); R is optionally substituted C1-C3 alkyl; R ² is optionally substituted C1-C3 alkyl or optionally substituted C1-C3 alkoxy; and R ¹ , R ² , X ² , C ¹ , and C ² together form a fused ring including optionally substituted C3-C6 heterocycloalkyl (e.g., C5-C6 heterocycloalkyl) having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heterocycloalkenyl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C5-C6 cycloalkoxy, or optionally substituted C3-C6 heterocycloalkoxy (e.g., C3-C6 heterocycloalkoxy) having 1 or 2 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (I-j)

wherein is defined as in formula (I-g); R ⁴ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; R ⁵ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; R ⁶ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; R ⁷ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; each of R ⁸ and R ⁹ is, independently, H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; is a single bond or double bond; n is 0 or 1; when n is 0, R ⁸ and R ⁹ are absent; and when is a double bond, R ⁴ and R ⁶ are absent; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is described by formula (I-k)

wherein , R ⁵ , R ⁷ , R ⁸ , R ⁹ , and n are defined as in formula (I-j); R ⁴ is H, optionally substituted C1- C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; and R ⁶ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound described by formula (I-j) or formula (I-k), n is 1. In some embodiments, n is 0.

In some embodimen f h f r m n i n m n i. . m n escribed by formula

(I-g), (I-h), (I-i), (I-j), or (I-k)), , wherein each Z is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5-C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy; and wherein each Z is not bonded to N.

In some articular embodiments of the aforementioned com ounds i.e. com ounds described

, ,

In some embodiments, the compound is described by formula (I-l)

wherein is defined as in formula (I-g); and each of R ⁴ and R ⁶ is, independently, H or optionally substituted C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound described by formula (I-l), , wherein each Z is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2- C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5-C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy; and wherein each Z is not bonded to N. In some embodiments, the compound has the structure .

In another aspect, the disclosure features a broad-spectrum substituted 1,3-diaminoquinazoline compound having (i) an MIC < 16 µg/ml against a first fungus in the genus Candida and (ii) an MIC < 16 µg/ml against a second fungus, wherein the second fungus is not in the genus Candida.

In some embodiments, the substituted 1,3-diaminoquinazoline compound is described by formula (II)

wherein each of R ^AA , R ^BB , and R ^CC is, independently, H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted heteroalkenyl, optionally substituted heterocycloalkenyl, OH, SH, OR ^C , or SR ^D ; each of R ^C and R ^D is, independently, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted heteroalkenyl, or optionally substituted heterocycloalkenyl; or R ^AA , R ^BB , C ¹ , and C ² together form a fused ring comprising optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted heteroaryl, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted aryloxy, or optionally substituted heteroaryloxy; or a pharmaceutically acceptable salt thereof.

In some embodiments of this aspect, the second fungus is in the genus Aspergillus,

Cryptococcus, Fusarium, or Scedosporium, or in the order Mucorales.

In some embodiments of this aspect, the first fungus is Candida albicans. In some embodiments of this aspect, the second fungus is selected from the group consisting of Aspergillus fumigatus, Cryptococcus neoformans, Fusarium solani, Fusarium verticillioides, Fusarium oxysporum, Scedosporium apiospermum, Mucor circinelloides, Absidia corymbifera, Rhizopus oryzae, Cunninghamella bertholletiae, and Rhizomucor pusillus. In another aspect, the disclosure features a substituted 1,3-diaminoquinazoline compound having an MIC < 8 µg/ml against a fungus in the order Mucorales. In a related aspect, the disclosure features a broad-spectrum substituted 1,3-diaminoquinazoline compound having (i) an MIC < 8 µg/ml against a first fungus in the order Mucorales and (ii) an MIC < 16 µg/ml against a second fungus, wherein the second fungus is not in the order Mucorales. In some embodiments of either such aspects, the fungus in the order Mucorales is Mucor circinelloides, Absidia corymbifera, Rhizopus oryzae, Cunninghamella bertholletiae, or Rhizomucor pusillus. In some embodiments of either such aspects, the substituted 1,3- diaminoquinazoline compound is described by formula (II), as described above.

In another aspect, the disclosure features a substituted 1,3-diaminoquinazoline compound against a fungus in the genus Fusarium. In some embodiments, the substituted 1,3-diaminoquinazoline compound against a fungus in the genus Fusarium has an MIC that is, e.g., < 16 µg/ml. In some embodiments, the fungus in the genus Fusarium is Fusarium solani, Fusarium verticillioides, or Fusarium oxysporum.

In another aspect, the disclosure features a substituted 1,3-diaminoquinazoline compound against a fungus in the genus Scedosporium. In some embodiments, the substituted 1,3- diaminoquinazoline compound against a fungus in the genus Scedosporium has an MIC that is, e.g., < 16 µg/ml. In some embodiments, the fungus in the genus Scedosporium is Scedosporium apiospermum.

In another aspect, the disclosure features a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition further includes a dihydropteroate synthase (DHPS) inhibitor (e.g., sulfamethoxazole).

In some embodiments, the pharmaceutical composition further includes an ergosterol synthesis inhibitor.

In some embodiments, the ergosterol synthesis inhibitor is a fungal 14α-demethylase inhibitor. In some embodiments, the fungal 14α-demethylase inhibitor is an azole compound. In particular, the azole compound is VT-1161, fluconazole, albaconazole, bifonazole, butoconazole, clotrimazole, econazole, efinaconazole, fenticonazole, isavuconazole, isoconazole, itraconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, posaconazole, pramiconazole, ravuconazole, sertaconazole, sulconazole, terconazole, tioconazole, or voriconazole.

In some embodiments, the ergosterol synthesis inhibitor is a squalene epoxidase inhibitor. In some embodiments, the squalene epoxidase inhibitor is an allylamine compound. In particular, the allylamine compound is terbinafine, butenafine, naftifine, or amorolfine.

In some embodiments, the pharmaceutical composition further includes a methotrexate rescue compound. In some embodiments, the methotrexate rescue compound is leucovorin, wellcovorin, or fusilev (levoleucovorin).

In another aspect, the disclosure features a method of treating a fungal, bacterial, and/or parasitic infection in a subject by administering to the subject a compound or pharmaceutical composition described herein in an amount sufficient to treat the infection.

In another aspect, the disclosure features a method of treating a fungal, bacterial, and/or parasitic infection in a subject by administering to the subject a compound or pharmaceutical composition described herein and optionally a DHPS inhibitor, an ergosterol synthesis inhibitor, and/or a methotrexate rescue compound in amounts sufficient to treat the infection.

In some embodiments, the fungal infection is an infection of Candida albicans, C. parapsilosis, C. glabrata, C. guilliermondii, C. krusei, C. tropicalis, C. lusitaniae, Aspergillus fumigatus, A. flavus, A.

terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus, or a fungus in the order Mucorales, or a fungus in the genus Cryptococcus, Fusarium, Cunninghamella, or Scedosporium.

In some embodiments, the fungus in the order Mucorales is in the family Mucoraceae. In some embodiments, the fungus in the order Mucorales and the family Mucoraceae is in a genus selected from the group consisting of Mucor, Rhizopus, Rhizomucor, Absidia, Actinomucor, Apophysomyces,

Backusella, Benjaminiella, Chaetocladium, Circinella, Cokeromyces, Dicranophora, Ellisomyces, Helicostylum, Hyphomucor, Kirkomyces, Parasitella, Pilaira, Pilophora, Pirella, Rhizopodopsis,

Sporodiniella, Syzygites, Thamnidium, Thermomucor, and Zygorhynchus.

In some embodiments, the fungal genus Mucor includes species M. amphibiorum, M.

circinelloides, M. hiemalis, M. hiemalis f. silvaticus, M. indicus, M. mucedo, M. paronychius, M. piriformis, M. plumbeus, and M. racemosus. In some embodiments, the fungal genus Rhizopus includes species Rhizopus azygosporus, R. caespitosus, R. delemar, R. homothallicus, R. microsporus, R. oryzae, R. reflexus, R. schipperae, and R. stolonifer. In some embodiments, the fungal genus Rhizomucor includes species Rhizomucor pusillus. In some embodiments, the fungal genus Absidia includes species Absidia coerulae, A. corymbifera, A. cylindrospora, A. ginsan, A. glauca, and A. spinosa.

In some embodiments, the fungus in the genus Cryptococcus is selected from the group consisting of Cryptococcus neoformans, C. gattii, C. albidus, and C. uniguttulatus. In some

embodiments, the fungus in the genus Fusarium is selected from the group consisting of Fusarium solani, F. avenaceum, F. bubigeum, F. culmorum, F. graminearum, F. langsethiae, F. oxysporum, F. poae, F. sporotrichioides, F. tricinctum, F. verticillioides, and F. virguliforme. In some embodiments, the fungus in the genus Cunninghamella is selected from the group consisting of Cunninghamella africana, C. bainieri, C. bertholletiae, C. binarieae, C. blakesleeana, C. clavata, C. echinulata, C. elegans, C. homothallica, C. intermedia, C. japonica, C. multiverticillata, C. phaeospora, C. polymorpha, C. septata, C. A18, C. CL023, and C. vesiculosa.

In some embodiments, the fungus in the genus Scedosporium is Scedosporium apiospermum or S. prolificans.

In some embodiments, the bacterial infection is an infection of a bacterium in the genus

Staphylococcus. In some embodiments, the bacterium in the genus Staphylococcus is selected from Staphylococcus aureus, S. arlettae, S. agnetis, S. auricularis, S. capitis, S. caprae, S. carnosus, S.

caseolyticus, S. chromogenes, S. cohnii, S. condimenti, S. delphini, S. devriesei, S. epidermidis, S.

equorum, S. felis, S. fleurettii, S. gallinarum, S. haemolyticus, S. hominis, S. hyicus, S. intermedius, S. kloosii, S. leei, S. lentus, S. lugdunensis, S. lutrae, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S. pettenkoferi, S. piscifermentans, S. pseudintermedius, S. pseudolugdunensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleiferi, S. sciuri, S. simiae, S. simulans, S.

stepanovicii, S. succinus, S. vitulinus, S. warneri, and S. xyloses. In some embodiments, the bacterium is Staphylococcus aureus. In another aspect, the disclosure features a method of treating a fungal infection in a subject. The method includes administering to the subject a broad-spectrum substituted 1,3-diaminoquinazoline compound, or a pharmaceutically acceptable salt thereof, wherein the broad-spectrum substituted 1,3- diaminoquinazoline compound has (i) an MIC < 16 µg/ml against a first fungus in the genus Candida and (ii) an MIC < 16 µg/ml against a second fungus, wherein the second fungus is not in the genus Candida.

In some embodiments, the substituted 1,3-diaminoquinazoline compound is described by formula (II)

wherein each of R ^AA , R ^BB , and R ^CC is, independently, H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted heteroalkenyl, optionally substituted heterocycloalkenyl, OH, SH, OR ^C , or SR ^D ; each of R ^C , R ^D is, independently, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted heteroalkenyl, or optionally substituted heterocycloalkenyl; or R ^AA , R ^BB , C ¹ , and C ² together form a fused ring comprising optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted heteroaryl, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted aryloxy, or optionally substituted heteroaryloxy; or a pharmaceutically acceptable salt thereof.

In some embodiments of this aspect, the second fungus is in the genus Aspergillus,

Cryptococcus, Fusarium, or Scedosporium, or in the order Mucorales.

In some embodiments of this aspect, the fungus in the genus Candida is Candida albicans. In some embodiments of this aspect, the fungus in the genus Aspergillus is Aspergillus fumigatus. In some embodiments of this aspect, the fungus in the genus Cryptococcus is Cryptococcus neoformans. In some embodiments of this aspect, the fungus in the genus Fusarium is Fusarium solani, F. verticillioides, or F. oxysporum. In some embodiments of this aspect, the fungus in the genus Scedosporium is

Scedosporium apiospermum. In some embodiments of this aspect, the fungus in the order Mucorales is Mucor circinelloides, Absidia corymbifera, Rhizopus oryzae, Cunninghamella bertholletiae, or Rhizomucor pusillus. In some embodiments of this aspect, the fungal infection in the subject is caused by one or more fungi, wherein the one or more fungi are in the genus Candida, Aspergillus, Cryptococcus, and/or Fusarium, and/or in the order Mucorales.

In some embodiments of this aspect, the one or more fungi that caused the fungal infection in the subject are selected from a group consisting of Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, Fusarium solani, Fusarium verticillioides, Fusarium oxysporum, Scedosporium

apiospermum, Mucor circinelloides, Absidia corymbifera, Rhizopus oryzae, Cunninghamella bertholletiae, and Rhizomucor pusillus.

In another aspect, the disclosure features a method of treating mucormycosis in a subject. The method includes administering to the subject a substituted 1,3-diaminoquinazoline compound having an MIC < 8 µg/ml against a fungus in the order Mucorales, or a pharmaceutically acceptable salt thereof. In some embodiments, the mucormycosis is caused by Mucor circinelloides, Absidia corymbifera, Rhizopus oryzae, Cunninghamella bertholletiae, or Rhizomucor pusillus. In a related aspect, the disclosure features a method of treating mucormycosis in a subject that includes administering to the subject a broad-spectrum substituted 1,3-diaminoquinazoline compound having (i) an MIC < 8 µg/ml against a first fungus in the order Mucorales and (ii) an MIC < 16 µg/ml against a second fungus, wherein the second fungus is not in the order Mucorales.

In some embodiments of the aforementioned aspects, the substituted 1,3-diaminoquinazoline compound is described by formula (II)

wherein each of R ^AA , R ^BB , and R ^CC is, independently, H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted heteroalkenyl, optionally substituted heterocycloalkenyl, OH, SH, OR ^C , or SR ^D ; each of R ^C , R ^D is, independently, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted heteroalkenyl, or optionally substituted heterocycloalkenyl; or R ^AA , R ^BB , C ¹ , and C ² together form a fused ring comprising optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted heteroaryl, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted aryloxy, or optionally substituted heteroaryloxy; or a pharmaceutically acceptable salt thereof.

In some embodiments of the methods described herein, the pharmaceutical composition or the compound is administered intramuscularly, intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, locally, by inhalation, by injection, or by infusion.

In some embodiments, the subject is immunocompromised. In some embodiments, the subject is being treated or is about to be treated with immunosuppresive drugs. In some embodiments, the subject has been diagnosed with a disease which causes immunosuppression.

In another aspect, the disclosure features a method of preventing, stabilizing, or inhibiting the growth of fungi, bacteria, and/or parasites, or killing fungi, bacteria, and/or parasites. The method includes contacting the fungi, bacteria, and/or parasites or a site susceptible to fungal, bacterial, and/or parasitic growth with a compound described herein or a pharmaceutically acceptable salt thereof and optionally a DHPS inhibitor and/or an ergosterol synthesis inhibitor.

In another aspect, the disclosure features a kit including: (i) a compound described herein; and (ii) instructions for administering (i) to a subject having a fungal, bacterial, and/or parasitic infection.

In another aspect, the disclosure features a kit including: (i) a compound described herein; (ii) a DHPS inhibitor and/or an ergosterol synthesis inhibitor; and (iii) instructions for administering (i) and (ii) to a subject having a fungal, bacterial, and/or parasitic infection.

In another aspect, the disclosure features a kit including: (i) a compound described herein; and (ii) instructions for administering (i) with a methotrexate rescue compound to a subject having a fungal, bacterial, and/or parasitic infection.

In another aspect, the disclosure features a kit including: (i) a compound described herein; (ii) a DHPS inhibitor and/or an ergosterol synthesis inhibitor; and (iii) instructions for administering (i) and (ii) with a methotrexate rescue compound to a subject having a fungal, bacterial, and/or parasitic infection. Definitions

As used herein, the term“alkyl,”“alkenyl,” and“alkynyl” include straight-chain, branched-chain and cyclic monovalent substituents, as well as combinations of these, containing only C and H when unsubstituted. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and the like. The term“cycloalkyl,” as used herein, represents a monovalent saturated or unsaturated non-aromatic cyclic alkyl group having between three to nine carbons (e.g., a C3-C9 cycloalkyl), unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1.]heptyl, and the like. When the cycloalkyl group includes at least one carbon-carbon double bond, the cycloalkyl group can be referred to as a“cycloalkenyl” group.

Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, and the like. When the cycloalkyl group includes at least one carbon-carbon triple bond, the cycloalkyl group can be referred to as a “cycloalkynyl” group. For the purposes herein, cycloalkenyl excludes aryl. When a list refers to what is otherwise the general term, e.g., alkyl, alkenyl, or alkynyl, and the cyclic form, e.g., cycloalkyl, cycloalkenyl, and cycloalkynyl, it will be understood that what is otherwise the general term refers only to acyclic radicals.

Typically, the alkyl, alkenyl, and alkynyl groups contain 1-12 carbons (e.g., C1-C12 alkyl) or 2-12 carbons (e.g., C2-C12 alkenyl or C2-C12 alkynyl). In some embodiments, the groups are C1-C8, C1-C6, C1-C4, C1-C3, or C1-C2 alkyl groups; or C2-C8, C2-C6, C2-C4, or C2-C3 alkenyl or alkynyl groups. Further, any hydrogen atom on one of these groups can be replaced with a substituent as described herein. For example, the term“aminoalkyl” refers to an alkyl group, as defined herein, comprising an optionally substituted amino group (e.g., NH2).

Heteroalkyl, heteroalkenyl, and heteroalkynyl are similarly defined and contain at least one carbon atom but also contain one or more heteroatoms independently selected from O, S, or N or combinations thereof within the backbone residue whereby each heteroatom in the heteroalkyl, heteroalkenyl, or heteroalkynyl group replaces one carbon atom of the alkyl, alkenyl, or alkynyl group to which the heteroform corresponds. In some embodiments, the heteroalkyl, heteroalkenyl, and heteroalkynyl groups have C at each terminus to which the group is attached to other groups, and the heteroatom(s) present are not located at a terminal position. As is understood in the art, these heteroforms do not contain more than three contiguous heteroatoms. In some embodiments, the heteroatom is O or N. The term“heterocyclyl,” as used herein, represents cyclic heteroalkyl or heteroalkenyl that is, e.g., a 3-, 4-, 5-, 6-, or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of N, O, and S. The 5- membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds. The term“heterocyclyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term“heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. When a list refers to what is otherwise the general term, e.g., heteroalkyl, heteroalkenyl, or heteroalkynyl, and the cyclic form, e.g., heterocyclyl, it will be understood that what is otherwise the general term refers only to acyclic radicals.

Heteroalkyl, heteroalkenyl, or heteroalkynyl substituents may also contain one or more carbonyl groups. Examples of heteroalkyl, heteroalkenyl and heteroalkynyl groups include CH2OCH3, CH2N(CH3)2, CH2OH, (CH2)nNR2, OR, COOR, CONR2, (CH2)nOR,(CH2)n COR, (CH2)nCOOR, (CH2)nSR, (CH2)nSOR, (CH2)nSO2R, (CH2)nCONR2, NRCOR, NRCOOR, OCONR2, OCOR, and the like where the R group in these examples of heteroalkyl, heteroalkenyl and heteroalkynyl groups contains at least one C and the size of the substituent is consistent with the definition of e.g., alkyl, alkenyl, and alkynyl, as described herein (e.g., n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12).

As used herein, the terms“alkylene,”“alkenylene,”“alkynylene,” and the prefix“alk” refer to divalent or trivalent groups having a specified size, typically C1-C2, C1-C3, C1-C4, C1-C6, or C1-C8 for the saturated groups (e.g., alkylene or alk) and C2-C3, C2-C4, C2-C6, or C2-C8 for the unsaturated groups (e.g., alkenylene or alkynylene). They include straight-chain, branched-chain, and cyclic forms as well as combinations of these, containing only C and H when unsubstituted. Because they are divalent, they can link together two parts of a molecule. Examples are methylene, ethylene, propylene, cyclopropan-1,1-diyl, ethylidene, 2-butene-1,4-diyl, and the like. These groups can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. Thus C=O is a C1 alkylene that is substituted by =O, for example. For example, the term“alkaryl,” as used herein, represents an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein, and the term“alkheteroaryl” refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. The alkylene and the aryl or heteroaryl group are each optionally substituted as described herein.

Heteroalkylene, heteroalkenylene, and heteroalkynylene are similarly defined as divalent groups having a specified size, typically C1-C3, C1-C4, C1-C6, or C1-C8 for the saturated groups and C2-C3, C2-C4, C2-C6, or C2-C8 for the unsaturated groups. They include straight chain, branched chain and cyclic groups as well as combinations of these, and they further contain at least one carbon atom but also contain one or more O, S, or N heteroatoms or combinations thereof within the backbone residue, whereby each heteroatom in the heteroalkylene, heteroalkenylene or heteroalkynylene group replaces one carbon atom of the alkylene, alkenylene, or alkynylene group to which the heteroform corresponds. As is understood in the art, these heteroforms do not contain more than three contiguous heteroatoms.

The term“alkoxy” represents a chemical substituent of formula–OR, where the R in–OR is an optionally substituted alkyl group (e.g., C1-C6 alkyl group), unless otherwise specified. In some embodiments, the alkyl group can be substituted, e.g., the alkoxy group can have 1, 2, 3, 4, 5, or 6 substituent groups as defined herein. The term“heteroalkoxy” contains one or more heteroatoms independently selected from O, S, or N or combinations thereof within the R in–OR. The heteroatoms in heteroalkoxy do not include the O in–OR.

The term“cycloalkoxy” represents a chemical substituent of formula -OR ^A , where the R ^A in–OR ^A is an optionally substituted cycloalkyl as defined herein. The term“heterocycloalkoxy” contains one or more heteroatoms independently selected from O, S, or N or combinations thereof within the R ^A in–OR ^A . The heteroatoms in heterocycloalkoxy do not include the O in–OR ^A .

The term“aryloxy” represents a chemical substituent of formula–OR ^B , where the R ^B in–OR ^B is an optionally substituted aryl as defined herein. The term“heteroaryloxy” contains one or more heteroatoms independently selected from O, S, or N or combinations thereof within the R ^B in–OR ^B . The heteroatoms in heteroaryloxy do not include the O in–OR ^B .

The term“amino,” as used herein, represents–N(R ^N1 )2, where each R ^N1 is, independently, H, OH, NO2, N(R ^N2 )2, SO2OR ^N2 , SO2R ^N2 , SOR ^N2 , an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkcycloalkyl, heterocyclyl (e.g., heteroaryl), alkheterocyclyl (e.g., alkheteroaryl), or two R ^N1 combine to form a heterocyclyl or an N-protecting group, and where each R ^N2 is, independently, H, alkyl, or aryl. In a preferred embodiment, amino is–NH2, or–NR ^N1 , where R ^N1 is, independently, OH, NO2, NH2, NR ^N2 2, SO2OR ^N2 , SO2R ^N2 , SOR ^N2 , alkyl, or aryl, and each R ^N2 can be H, alkyl, or aryl. The term“aminoalkyl,” as used herein, represents a heteroalkyl group, as defined herein, that is described as an alkyl group, as defined herein, substituted by an amino group, as defined herein. The alkyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group. For example, the alkyl moiety may comprise an oxo (=O) substituent. An“aromatic” moiety or“aryl” moiety refers to any monocyclic or fused ring bicyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system and includes a monocyclic or fused bicyclic moiety such as phenyl or naphthyl;“heteroaromatic” or “heteroaryl” also refers to such monocyclic or fused bicyclic ring systems containing one or more heteroatoms selected from O, S and N. The inclusion of a heteroatom permits inclusion of 5-membered rings to be considered aromatic as well as 6-membered rings. Thus, typical aromatic/heteroaromatic systems include pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, imidazolyl and the like. Because tautomers are theoretically possible, phthalimido is also considered aromatic. Typically, the ring systems contain 5-12 ring member atoms or 6-10 ring member atoms. In some embodiments, the aromatic or heteroaromatic moiety is a 6-membered aromatic rings system optionally containing 1-2 nitrogen atoms. More particularly, the moiety is an optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzothiazolyl, indolyl, or imidazopyridinyl. Even more particularly, such moiety is phenyl, pyridyl, thiazolyl, imidazopyridinyl, or pyrimidyl and even more particularly, it is phenyl.

The term“O-aryl” or“O-heteroaryl” refers to aromatic or heteroaromatic systems which are coupled to another residue through an oxygen atom. A typical example of an O-aryl is phenoxy.

Similarly,“arylalkyl” refers to aromatic and heteroaromatic systems which are coupled to another residue through a carbon chain, saturated or unsaturated, typically of C1-C8, C1-C6, or more particularly C1-C4 or C1-C3 when saturated or C2-C8, C2-C6, C2-C4, or C2-C3 when unsaturated, including the heteroforms thereof. For greater certainty, arylalkyl thus includes an aryl or heteroaryl group as defined above connected to an alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl moiety also as defined above. Typical arylalkyls would be an aryl(C6-C12)alkyl(C1-C8), aryl(C6-C12)alkenyl(C2-C8), or aryl(C6-C12)alkynyl(C2-C8), plus the heteroforms. A typical example is phenylmethyl, commonly referred to as benzyl.

The term“halo” or“halogen” may refer to any halogen atom, especially F, Cl, Br, or I, and more particularly it is fluoro or chloro.

The term“hydroxyl,” as used herein, represents an -OH group.

An“oxo” group is a substituent having the structure =O, where there is a double bond between a carbon and an oxygen atom.

Typical optional substituents on aromatic or heteroaromatic groups include independently halo, such as chloro or fluoro, CN, NO2, CF3, OCF3, COOR’, CONR’2, OR’, SR’, SOR’, SO2R’, NR’2,

NR’(CO)R’,NR’C(O)OR’, NR’C(O)NR’2, NR’SO2NR’2, or NR’SO2R’, where each R’ is independently H or an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and aryl (all as defined above); or the substituent may be an optionally substituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, O-aryl, O-heteroaryl and arylalkyl. I

Optional substituents on a non-aromatic group (e.g., alkyl, alkenyl, and alkynyl groups), are typically selected from the same list of substituents suitable for aromatic or heteroaromatic groups, except as noted otherwise herein. A non-aromatic group may also include an optional substituent selected from =O and =NOR’ where R’ is H or an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, heteroalkyl, heteroalkenyl, heteralkynyl, heteroaryl, and aryl (all as defined above).

In general, a substituent group (e.g., alkyl, alkenyl, alkynyl, or aryl, including all heteroforms defined above) may itself optionally be substituted by additional substituents. The nature of these substituents is similar to those recited with regard to the substituents on the basic structures above. Thus, where an embodiment of a substituent is alkyl, this alkyl may optionally be substituted by the remaining substituents listed as substituents where this makes chemical sense, and where this does not undermine the size limit of alkyl per se; e.g., alkyl substituted by alkyl or by alkenyl would simply extend the upper limit of carbon atoms for these embodiments, and is not included. However, alkyl substituted by aryl, amino, halo (preferably chloro or fluoro) and the like would be included. For example, where a group is substituted, the group may be substituted with 1, 2, 3, 4, 5, or 6 substituents. Optional substituents include, but are not limited to, C1-C6 alkyl or heteroaryl, C2-C6 alkenyl, or heteroalkenyl, C2- C6 alkynyl or heteroalkynyl, halogen; aryl, heteroaryl, azido(-N3), nitro (-NO2), cyano (-CN),

acyloxy(-OC(=O)R’), acyl (-C(=O)R’), alkoxy (-OR’), amido (-NR’C(=O)R”, or–C(=O)NRR’), amino (-NRR’), carboxylic acid (-CO2H), carboxylic ester (-CO2R’), carbamoyl (-OC(=O)NR’R” or -NRC(=O)OR’), hydroxy (-OH), isocyano (-NC), silyl (-SiRR’R”) sulfonate (-S(=O)2OR), sulfonamide (-S(=O)2NRR’ or– NRS(=O)2R’), or sulfonyl (-S(=O)2R), where each R, R’, or R” in the optional substituents is selected, independently, from H, C1-C6 alkyl, or heteroaryl, C2-C6 alkenyl, or heteroalkenyl, C2-C6alkynyl ,or heteroalkynyl, aryl, or heteroaryl. A substituted group may have, for example, 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents. Acyclic alkyl groups may not be substituted with aryl or heterocyclyl unless specifically stated.

The terms“dihydrofolate reductase inhibitor” and“DHFR inhibitor,” as used herein, refer to compounds that bind to DHFR and disrupt, inhibit, and/or prevent its natural function, thus, causing malfunction in cell division. DHFR is an enzyme that reduces dihydrofolate to tetrahydrofolate, which is an essential cofactor in the biosynthesis and metabolism of nucleic acids and amino acids. In some embodiments, DHFR inhibitors described herein are selective for fungal, bacterial, and/or parasitic DHFR over host DHFR (i.e., human DHFR). In some embodiments, DHFR inhibitors described herein inhibit the growth of fungi in the genus Candida, Aspergillus, Cryptococcus, Fusarium, Cunninghamella, and Scedosporium, and/or fungi in the order Mucorales.

The terms“dihydropteroate synthase inhibitor” and“DHPS inhibitor,” as used herein, refer to compounds that bind to the enzyme DHPS and disrupt, inhibit, or prevent its natural function. An example of a DHPS inhibitor is sulfamethoxazole.

The term“ergosterol synthesis inhibitor,” as used herein, refers to compounds that interfere with, inhibit, and/or prevent the synthesis of ergosterol. Ergosterol synthesis inhibitors may inhibit one or more enzymes in the biosynthetic pathway of ergosterol. Ergosterol synthesis inhibitors include, but are not limited to, compounds that inhibit fungal 14α-demethylase and squalene epoxidase.

The term“14α-demethylase inhibitor,” as used herein, refers to compounds that bind to the enzyme 14α-demethylase and disrupt, inhibit, and/or prevent its natural function. The enzyme 14α- demethylase is a cytochrome P450 enzyme that catalyzes the removal of the C-14 α-methyl group from lanosterol before lanosterol is converted to ergosterol. Therefore, by inhibiting 14α-demethylase, the synthesis of ergosterol is inhibited. Examples of 14α-demethylase inhibitors include, but are not limited to, azole compounds. Azole compounds refer to compounds that contain an azole group, which is a five- membered heterocyclic ring having at least one N and one or more heteroatoms selected from N, O, and S. Examples of 14α-demethylase inhibitors include, but are not limited to, VT-1161, fluconazole, albaconazole, bifonazole, butoconazole, clotrimazole, econazole, efinaconazole, fenticonazole, isavuconazole, isoconazole, itraconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, posaconazole, pramiconazole, ravuconazole, sertaconazole, sulconazole, terconazole, tioconazole, and voriconazole.

The term“squalene epoxidase inhibitor,” as used herein, refers to compounds that bind to the enzyme squalene epoxidase and disrupt, inhibit, and/or prevent its natural function. Squalene epoxidase is a mono-oxygenase that catalyzes the conversion of squalene to 2,3-oxidosqualene in the biosynthetic pathway of ergosterol. Therefore, by inhibiting squalene epoxidase, the synthesis of ergosterol is also inhibited. Examples of squalene epoxidase inhibitors include, but are not limited to, allylamine compounds. Allylamine compounds refer to compounds that contain an allylamine group, which is

described by the formula , wherein each of R ^U , R ^V , R ^W , R ^X , R ^Y is, independently, H or optionally substituted C1-C6 alkyl; or R ^U , R ^V , C ¹ , and C ² together form optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocycloalkenyl, or optionally substituted heteroaryl; or R ^X , R ^Y , and N together form optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl; and z is an integer from 0 to 6.

Examples of squalene epoxide inhibitors include, but are not limited to, terbinafine, butenafine, naftifine, and amorolfine.

The term“methotrexate rescue compound,” refers to a compound that is used to block or reverse the effects of methotrexate. Methotrexate, as conventionally known in the art, is a drug used in the treatments of cancers and autoimmune disorders. Methotrexate binds to DHFR to inhibit its function and thus, kills cells by blocking DNA synthesis. Methotrexate rescue is a technique used in cancer chemotherapy in which folic acid derivatives, such as leucovorin (a reduced folic acid), is administered in combination with methotrexate as an antidote to reverse the effects of methotrexate and to prevent methotrexate toxicity. As used herein, a methotrexate rescue compound blocks or reverses the effects of a DHFR inhibitor compound described herein. A methotrexate rescue compound may be used in combination with a DHFR inhibitor compound described herein. Examples of methotrexate rescue compounds include, but are not limited to, leucovorin, wellcovorin, and fusilev. In some embodiments, the methotrexate rescue compound used in combination with a DHFR inhibitor compound described herein is leucovorin.

The term“substituted 1,3-diaminoquinazoline compound,” as used herein, refers to a compound having a 1,3-diaminoquinazoline scaffold and at least one substituent moiety, preferably at position 5, 6 or 7 (using classical ring numbering, which corresponds to C ¹ , C ² , or C ³ , respectively, of the structure below). In preferred embodiments, the substituted 1,3-diaminoquinazoline compound can refer to a compound having a 1,3-diaminoquinazoline scaffold, which has the structure shown below: .

Each of R ^AA , R ^BB , and R ^CC is, independently, H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted heteroalkenyl, optionally substituted heterocycloalkenyl, OH, SH, OR ^C , or SR ^D , wherein each of R ^C , R ^D is, independently, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted heteroalkenyl, or optionally substituted heterocycloalkenyl. In some embodiments, R ^AA , R ^BB , C ¹ , and C ² together form a fused ring, wherein the fused ring may be, for example, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocycloalkenyl, an optionally substituted heteroaryl, an optionally substituted cycloalkoxy, an optionally substituted heterocycloalkoxy, an optionally substituted aryloxy, or an optionally substituted heteroaryloxy. Substituted 1,3-diaminoquinazoline compounds include, for example, compounds of formulas, (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), and (I-l). Examples of substituted 1,3-diaminoquinazoline compounds include, but are not limited to, compounds described in Examples 2- 165. In some embodiments, the substituted 1,3-diaminoquinazoline compound is a compound described by a formula or specifically disclosed in U.S. Patent No.8,835,445, incorporated herein by reference.

The term“broad-spectrum,” as used herein, describes a compound having antifungal activity against a wide range of fungi (i.e., fungi in, e.g., 2, 3, 4, 5, 6, or more genra or orders), such as fungi in the genus Candida, Aspergillus, Cryptococcus, Fusarium, Cunninghamella, and Scedosporium, and in the order Mucorales. For example, a broad-spectrum substituted 1,3-diaminoquinazoline compound exhibits at least an MIC < 16 µg/ml against a first fungus in the genus Candida (e.g., C. albicans) and (ii) an MIC < 16 µg/ml against a second fungus. The second fungus may be in the genus Aspergillus (e.g., A. fumigatus), Cryptococcus (e.g., Cryptococcus neoformans), Fusarium (e.g., Fusarium solani, F.

verticillioides, or F. oxysporum), or Scedosporium (e.g., Scedosporium apiospermum), or in the order Mucorales (e.g., Mucor circinelloides, Absidia corymbifera, Rhizopus oryzae, Cunninghamella bertholletiae, or Rhizomucor pusillus).

The term“mucormycosis,” as used herein, refers a fungal infection caused by a fungus in the order Mucorales. A fungus in the order Mucorales may be in the genus Mucor, Rhizopus, Rhizomucor, Absidia, Actinomucor, Apophysomyces, Backusella, Benjaminiella, Chaetocladium, Circinella, Cokeromyces, Dicranophora, Ellisomyces, Helicostylum, Hyphomucor, Kirkomyces, Parasitella, Pilaira, Pilophora, Pirella, Rhizopodopsis, Sporodiniella, Syzygites, Thamnidium, Thermomucor, Zygorhynchus, or Cunninghamella. Examples of a fungus in the order Mucorales include, but are not limited to, Mucor circinelloides, Absidia corymbifera, Rhizopus oryzae, Cunninghamella bertholletiae, and Rhizomucor pusillus.

The term“immunocompromised,” as used herein, refers to an immune response that has been weakened by a condition or an immunosuppressive agent.

The term“fungal infection,” as used herein, refers to the pathogenic growth of fungus in a host organism (e.g., a human subject). For example, the infection may include the excessive growth of fungi that are normally present in or on the body of a subject or growth of fungi that are not normally present in or on a subject. More generally, a fungal infection can be any situation in which the presence of a fungal population(s) is damaging to a host body. Thus, a subject has a fungal infection when an excessive amount of a fungal population is present in or on the subject’s body, or when the presence of a fungal population(s) is damaging the cells or other tissue of the subject.

The term“inhibiting the growth of fungi, bacteria, and/or parasites,” as used herein, refers to any slowing, stabilizing, interruption, suppression, delay, killing, or inhibition of growth of fungi, bacteria, and/or parasites. The compounds described herein that inhibit fungal, bacterial, and/or parasitic growth can display a minimal inhibitory concentration (MIC), e.g., less than 16 µg/mL. Inhibiting fungal, bacterial, and/or parasitic growth includes, for example, inhibiting the growth of resting fungal, bacterial, and/or parasitic cells. For example, resting fungal cells can include, e.g., spore germination, mycelia development, and/or the formation of fruiting structures on the fungus (e.g., sporangia/sporophores). Fungal growth can be produced by a fungus in the genus Aspergillus, Candida, Cryptococcus, Fusarium, Cunninghamella, or Scedosporium, and/or a fungus in the order Mucorales.

The term“pharmaceutically acceptable salt,” as used herein, refers to salt forms of the compounds described that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, and allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Pharmaceutical Salts:

Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2011. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.

The compounds may have ionizable groups so as to be capable of preparation as

pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds, may be prepared from inorganic or organic bases. Frequently, the compounds that are prepared or used as pharmaceutically acceptable salts are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulfuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, or various amines for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.

As used herein, the term“subject” can be a human, non-human primate, or other mammal, such as but not limited to, dog, cat, horse, cow, pig, turkey, goat, fish, monkey, chicken, rat, mouse, and sheep.

As used herein, and as understood in the art,“to treat” a condition or“treatment” of a fungal, bacterial, and/or parasitic infection is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition;

stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.“Palliating” a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.

The term“unit dosage form” refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with any suitable pharmaceutical excipient or excipients. Exemplary, non-limiting unit dosage forms include a tablet (e.g., a chewable tablet), caplet, capsule (e.g., a hard capsule or a soft capsule), lozenge, film, strip, gelcap, and syrup.

In some cases, the compounds may contain one or more chiral centers. The compounds include each of the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity, including racemic mixtures. It also encompasses the various diastereomers, enantiomers, and tautomers that can be formed.

Compounds useful may also be isotopically labeled compounds. Useful isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, (e.g., ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl). Isotopically labeled compounds can be prepared by synthesizing a compound using a readily available isotopically labeled reagent in place of a non-isotopically labeled reagent. In some embodiments, the compound, or a composition that includes the compound, has the natural abundance of each element present in the compound. Other features and advantages of the compounds described herein will be apparent from the following detailed description and the claims. DETAILED DESCRIPTION

Synthetic dihydrofolate reductase (DHFR) inhibitors are useful in the treatment of fungal, bacterial, and/or parasitic infections. The inventors have found that DHFR inhibitors described herein have antifungal, antibacterial, and/or antiparasitic activities due to their ability to efficiently bind to DHFR and inhibit its function, resulting in inhibition of DNA biosynthesis and reduced cell division. DHFR inhibitors described herein include, without limitation, compounds described in Examples 2-165. As is described herein, certain of the DHFR inhibitors exhibit broad spectrum activity, while certain of the DHFR inhibitors inhibit fungal DHFR to a greater extent than they inhibit human DHFR. I. DHFR inhibitors

DHFR catalyzes the reduction of dihydrofolate to tetrahydrofolate and at a slower rate, the conversion of folate to tetrahydrofolate. Tetrahydrofolate is an essential cofactor in the biosynthesis and metabolism of nucleic acids and amino acids. For example, methionine biosynthesis, a process necessary for the production of fungal sterols (e.g., ergosterols), is dependent on tetrahydrofolate. The only source of tetrahydrofolate for fungi, bacteria, and parasites is the tetrahydrofolate synthesized de novo by DHFR. Thus, inhibitors of DHFR inhibit nucleic acid/amino acid biosynthesis and cell division, resulting in cell death. This mechanism of action of DHFR inhibitors enables this class of antifungal, antibacterial, and/or antiparasitic compounds to overcome many limitations of other therapies against fungal, bacterial, and/or parasitic infections, such as toxicity, limited activity, and resistance. Furthermore, DHFR inhibitors described herein can be used either as monotherapies or in combination therapies with dihydropteroate synthase (DHPS) inhibitors and/or ergosterol synthesis inhibitors, both of which have synergistic effects when used in combination with DHFR inhibitors.

The inventors have identified DHFR inhibitors that can be used in the treatment of various human diseases, such as fungal, bacterial, and/or parasitic infections, psoriasis, autoimmune diseases, and neoplastic diseases. DHFR inhibitors described herein exhibit antifungal activities against fungi in the genus, e.g., Candida, Asperigllus, Cryptococcus, Fusarium, Cunninghamella, Scedosporium spp. and the order Mucorales. Fungi in the genus Asperigllus, Fusarium, and Mucor have been the predominant moulds isolated from cultures of wounds, such as wounds from combat-related trauma, burn, and blast injuries. DHFR inhibitors described herein also exhibit low Ki values and high selectivity for fungal, bacterial, and/or parasitic DHFR over human DHFR. The disclosure features DHFR inhibitors having a diaminoquinazoline scaffold. Exemplary DHFR inhibitors described herein include, without limitation, compounds having formula (I)

wherein X ¹ is–O-(R ^d )p-,–S-(R ^d )p-,–NR ^a -(R ^d )p-,–(R ^d )p-O-,–(R ^d )p-S-,–(R ^d )p-NR ^a -, optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene, or is absent; p is 0 or 1; X ² is O, S, or NR ^b ; R ¹ is H, hydroxyl, optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted C3- C6 heterocycloalkyl, optionally substituted heteroaryl, optionally substituted C1-C3 alkyl aryl, or -SR ^c ; R ² is H, hydroxyl, amino, aminoalkyl, CF3, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, or optionally substituted heteroalkoxy; or R ¹ , R ² , X ² , C ¹ , and C ² together form a fused ring including optionally substituted C3-C6 heterocycloalkyl (e.g., C5-C6 heterocycloalkyl) having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heterocycloalkenyl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C5-C6 cycloalkoxy, or optionally substituted C3-C6 heterocycloalkoxy (e.g., C5-C6 heterocycloalkoxy) having 1 or 2 heteroatoms independently selected from N, O, and S; R ³ is H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; each of R ^a , R ^b , and R ^c is, independently, H or optionally substituted C1-C3 alkyl; and R ^d is optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or C2-C4 optionally substituted alkynylene and R ^d , when present, joins to C ³ ; or a pharmaceutically acceptable salt thereof.

In some embodiments of this aspect, when R ¹ , R ² , X ² , C ¹ , and C ² do not form a fused ring and R ³ is H, X ¹ is not absent.

In some embodiments of the compounds having formula (I), R ¹ and X ² form an alkoxy and X ¹ is not absent. In some embodiments, X ² is S. In some embodiments, X ² is NR ^b , and R ^b is H or optionally substituted C1-C3 alkyl.

In some embodiments, the compounds have formula (I-a)

wherein X ¹ is–O-(R ^d )p-,–S-(R ^d )p-,–NR ^a -(R ^d )p-,–(R ^d )p-O-,–(R ^d )p-S-,–(R ^d )p-NR ^a -, optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene, or is absent; X ² is O, S, or NR ^b ; R ¹ is optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted C3-C6

heterocycloalkyl, optionally substituted heteroaryl, or optionally substituted C1-C3 alkyl aryl; R ² is H, hydroxyl, amino, aminoalkyl, CF3, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, or optionally substituted heteroalkoxy; R ³ is acyl, optionally substituted C1-C3 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted C1-C3 heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; and each of R ^a and R ^b is, independently, H or optionally substituted C1-C3 alkyl; and R ^d is optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene and R ^d , when present, joins to C ³ ; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds have formula (I-b)

wherein X ¹ is–O-(R ^d )p-,–S-(R ^d )p-,–NR ^a -(R ^d )p-,–(R ^d )p-O-,–(R ^d )p-S-,–(R ^d )p-NR ^a -, optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene, or is absent; X ² is O, S, or NR ^b ; R ³ is H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; R ¹ is optionally substituted C1-C3 alkyl; R ² is optionally substituted C1-C3 alkyl or optionally substituted C1-C3 alkoxy; R ¹ , R ² , X ² , C ¹ , and C ² together form a fused ring including optionally substituted C3-C6 heterocycloalkyl (e.g., C5-C6 heterocycloalkyl) having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heterocycloalkenyl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 cycloalkoxy, or optionally substituted C3-C6

heterocycloalkoxy (e.g., C5-C6 heterocycloalkoxy) having 1 or 2 heteroatoms independently selected from N, O, and S; and each of R ^a and R ^b is, independently, H or optionally substituted C1-C3 alkyl; and R ^d is optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene and R ^d , when present, joins to C ³ ; or a pharmaceutically acceptable salt thereof.

In some embodiments, DHFR inhibitors are described by formula (I-c) or (I-d)

wherein R ³ is H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; X ¹ is–O-(R ^d )p-,–S-(R ^d )p-,–NR ^a -(R ^d )p-,–(R ^d )p- O-,–(R ^d )p-S-,–(R ^d )p-NR ^a -, optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene, or is absent; R ⁴ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; R ⁵ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; R ⁶ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; R ⁷ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; each of R ⁸ and R ⁹ is, independently, H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; is a single bond or double bond; n is 0 or 1; when n is 0, R ⁸ and R ⁹ are absent; when is a double bond, R ⁴ and R ⁶ are absent; and R ^a is H or optionally substituted C1-C3 alkyl; and R ^d is optionally substituted C1-C4 alkylene, optionally substituted C2-C4 alkenylene, or optionally substituted C2-C4 alkynylene and R ^d , when present, joins to C ³ ; or a

pharmaceutically acceptable salt thereof. For compounds described by formula (I-d), R ⁴ and R ⁶ are not absent.

In some embodiments of the compounds described by formula (I-c) or formula (I-d), n is 1. In some embodiments, n is 0.

In some embodiments of the aforementioned compounds (i.e., compounds described by formula (I), (I-a), (I-b), (I-c), or (I-d)), R ³ is

hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5- C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy, -CONR ^f1 , -CN, -R ^f2 CN, or optionally substituted C1-C3 alkyl ester, and is not bonded to a heteroatom; q is an integer from 0 to 5; t is an integer from 0 to 4; u is an integer from 0 to 3; R ^f1 is H or optionally substituted C1-C3 alkyl; R ^f2 is optionally substituted C1- C4 alkylene; each of R ^g2 , R ^g3 , R ^g4 , R ^g5 , R ^g6 , and R ^g7 , R ^g8 , R ^g9 , R ^g10 , R ^g11 , and R ^g12 is independently CH or N; each of R ^h1 , R ^h2 , R ^h3 is, independently, S or O; each of ring A, ring A ¹ , ring A ² , and ring A ³ is, independently, optionally substituted C5-C6 cycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heterocycloalkyl (e.g., C5-C6

heterocycloalkyl) including 1-4 NR ⁱ , S, or O, optionally substituted C3-C6 heterocycloalkenyl (e.g., C5-C6 heterocycloalkenyl) including 1-4 NR ⁱ , S, or O, or optionally substituted C3-C6 heteroaryl (e.g., C5-C6 heteroaryl) including 1-4 heteroatoms independently selected from N and S; and R ⁱ is H, optionally substituted C1-C3 alkyl, or O.

In some particular embodiments of the aforementioned compounds (i.e., compounds described by formula (I), (I-a), (I-b), (I-c), or (I-d)), R ³ is

, In some particular embodiments, DHFR inhibitors are described by compounds having formula (I- e)

wherein R ³ is H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; and X ¹ is O or is absent; or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds described by formula (I-e), X ¹ is O and R ³ is , wherein each R ^f is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6

heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6

heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6

heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5-C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy, -CONR ^f1 , -CN, -R ^f2 CN, or optionally substituted C1-C3 alkyl ester; R ^f1 is H or optionally substituted C1-C3 alkyl; and R ^f2 is optionally substituted C1-C4 alkylene. In some particular embodiments, the compound has the structure

.

In some embodiments of the compounds described by formula (I-e), X ¹ is absent and R ³ is

, wherein each R ^f is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5- C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy, -CONR ^f1 , -CN, -R ^f2 CN, or optionally substituted C1-C3 alkyl ester; R ^f1 is H or optionally substituted C1-C3 alkyl; and R ^f2 is optionally substituted C1-C4 alkylene. In some particular embodiments, the compound has the structure

, , or .

In some particular embodiments, a DHFR inhibitor is described by compounds having formula (I- f)

wherein H, hydroxyl, amino, aminoalkyl, CF3, halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted

heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, or optionally substituted heteroaryloxy; each of R ⁴ , R ⁶ , and R ⁸ is, independently, H or optionally substituted C1-C3 alkyl; and X ¹ is O or is absent; or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds described by formula (I-f), X ¹ is absent and R ³ is

, wherein each R ^f is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6

heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6

heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6

heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5-C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy, -CONR ^f1 , -CN, -R ^f2 CN, or optionally substituted C1-C3 alkyl ester; R ^f1 is H or optionally substituted C1-C3 alkyl; and R ^f2 is optionally substituted C1-C4 alkylene. In some particular embodiments, the compound has the structure

In some embodiments, DHFR inhibitors are described by formula (I-g)

( g),

wherein X ² is O, S, or NR ^b ; R ¹ is H, hydroxyl, optionally substituted alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted heteroaryl, optionally substituted C1-C3 alkyl aryl, or -SR ^c ; R ² is H, hydroxyl, amino, aminoalkyl, CF3, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, or optionally substituted heteroalkoxy; or R ¹ , R ² , X ² , C ¹ , and C ² together form a fused ring comprising optionally substituted C3-C6 heterocycloalkyl (e.g., C5-C6 heterocycloalkyl) having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heterocycloalkenyl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C5-C6 cycloalkoxy, or optionally substituted C3-C6 heterocycloalkoxy ( e.g., C3-C6 heterocycloalkoxy) having 1 or 2 heteroatoms independently selected from N, O, and S; each of R ^b and R ^c is, independently, H or optionally substituted C1-C3 alkyl; and is optionally substituted heterocycloalkyl having 1-4 heteroatoms independently selected from N, O, and S, or optionally substituted heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; or a

pharmaceutically acceptable salt thereof.

In some embodiments, a DHFR inhibitor is described by formula (I-h)

wherein X ² and are defined as in formula (I-g); and R is optionally substituted alkyl, optionally

substituted C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted heteroaryl, or optionally substituted C1-C3 alkyl aryl; and R ² is H, hydroxyl, amino, aminoalkyl, CF3, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroalkyl, or optionally substituted heteroalkoxy;

or a pharmaceutically acceptable salt thereof.

In some embodiments, DHFR inhibitors are described by formula (I-i)

wherein X ² and are defined as in formula (I-g); R ¹ is optionally substituted C1-C3 alkyl; R ² is optionally substituted C1-C3 alkyl or optionally substituted C1-C3 alkoxy; and R ¹ , R ² , X ² , C ¹ , and C ² together form a fused ring including optionally substituted C3-C6 heterocycloalkyl (e.g., C3-C6 heterocycloalkyl) having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heterocycloalkenyl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C3-C6 heteroaryl having 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted C5-C6 cycloalkoxy, or optionally substituted C3-C6 heterocycloalkoxy (e.g., C5-C6 heterocycloalkoxy) having 1 or 2 heteroatoms independently selected from N, O, and S; or a pharmaceutically acceptable salt thereof.

In some embodiments, a DHFR inhibitor is described by formula (I-j) or (I-k)

wherein is defined as in formula (I-g); R ⁴ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; R ⁵ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; R ⁶ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; R ⁷ is H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl; each of R ⁸ and R ⁹ is, independently, H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, or is absent; is a single bond or double bond; n is 0 or 1; when n is 0, R ⁸ and R ⁹ are absent; and when is a double bond, R ⁴ and R ⁶ are absent; or a pharmaceutically acceptable salt thereof. For compounds described by formula (I-k), R ⁴ and R ⁶ are not absent

In some embodiments of the compounds described by formula (I-j) or formula (I-k), n is 1. In some embodiments, n is 0.

In some embodiments of the aforementioned compounds (i.e., compounds described by formula

( g) ( ) ( ) ( j) ( )) wherein each Z is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5-C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy; and wherein each Z is not bonded to N. In some particular embodiments of the aforementioned compounds (i.e., compounds described

by formula (I-g), (I-h), (I-i), (I-j), or (I-k)), is , ,

In some embodiments, a DHFR inhibitor is described by formula (I-l)

wherein is defined as in formula (I-g); and each of R ⁴ and R ⁶ is, independently, H or optionally substituted C1-C3 alkyl; or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds described by formula (I-l),

wherein each Z is, independently, H, hydroxyl, halo, carboxylic acid, ester, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 heteroalkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C4 heteroalkynyl, optionally substituted C5-C6 cycloalkyl, optionally substituted C3-C6 heterocycloalkyl, optionally substituted C5-C6 cycloalkenyl, optionally substituted C3-C6 heterocycloalkenyl, optionally substituted C5-C6 cycloalkynyl, optionally substituted C3-C6 heterocycloalkynyl, optionally substituted C5-C6 aryl, optionally substituted C3-C6 heteroaryl, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 heteroalkoxy, optionally substituted C5-C6 cycloalkoxy, optionally substituted C3-C6 heterocycloalkoxy, optionally substituted C5-C6 aryloxy, or optionally substituted C3-C6 heteroaryloxy; and wherein each Z is not bonded to N. In some embodim n h m n h h ructure

. II. Pharmaceutical Compositions and Preparations

The disclosure features pharmaceutical compositions that include the DHFR inhibitor compounds described herein. In some embodiments, the pharmaceutical composition includes a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further includes a DHPS inhibitor (e.g., sulfamethoxazole), an ergosterol synthesis inhibitor (e.g., a fungal 14α-demethylase inhibitor or a squalene epoxidase inhibitor), and/or a methotrexate rescue compound in addition to the DHFR inhibitor compounds described herein. In some embodiments, a DHFR inhibitor compound described herein is formulated alone in a single pharmaceutical composition. In some embodiments, a DHFR inhibitor compound described herein is formulated in combination with a DHPS inhibitor (e.g., sulfamethoxazole), an ergosterol synthesis inhibitor (e.g., a fungal 14α-demethylase inhibitor or a squalene epoxidase inhibitor), and/or a methotrexate rescue compound in the same pharmaceutical composition. Depending on the mode of administration and the dosage, the compounds described herein will be formulated into suitable compositions to permit facile delivery. Each compound of a combination therapy may be formulated in a variety of ways that are known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Examples of fungal 14α-demethylase inhibitors include, but are not limited to, azole compounds, such as VT-1161, fluconazole, albaconazole, bifonazole, butoconazole, clotrimazole, econazole, efinaconazole, fenticonazole, isavuconazole, isoconazole, itraconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, posaconazole, pramiconazole, ravuconazole, sertaconazole, sulconazole, terconazole, tioconazole, and voriconazole. Examples of squalene epoxidase inhibitors include, but are not limited to, allylamine compounds, such as terbinafine, butenafine, naftifine, and amorolfine. Examples of methotrexate rescue compounds include, but are not limited to, leucovorin, wellcovorin, and fusilev (levoleucovorin).

For use as treatment of human and animal subjects, the compounds can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy, the compounds are formulated in ways consonant with these parameters. A summary of such techniques is found in Remington: The Science and Practice of Pharmacy, 22 ^st Edition, Lippincott Williams & Wilkins, (2012); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 2006, Marcel Dekker, New York, each of which is incorporated herein by reference.

Acceptable carriers and excipients in the pharmaceutical compositions are nontoxic to recipients at the dosages and concentrations employed. Acceptable carriers and excipients may include buffers such as phosphate, citrate, HEPES, and TAE, antioxidants such as ascorbic acid and methionine, preservatives such as hexamethonium chloride, octadecyldimethylbenzyl ammonium chloride, resorcinol, and benzalkonium chloride, proteins such as human serum albumin, gelatin, dextran, and

immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, histidine, and lysine, and carbohydrates such as glucose, mannose, sucrose, and sorbitol.

The pharmaceutical compositions described herein can be administered parenterally in the form of an injectable formulation. Pharmaceutical compositions for injection can be formulated using a sterile solution or any pharmaceutically acceptable liquid as a vehicle. Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco’s Modified Eagle Medium (DMEM), α-Modified Eagles Medium (α-MEM), F-12 medium). Formulation methods are known in the art, see e.g., Banga (ed.) Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems (2nd ed.) Taylor & Francis Group, CRC Press (2006).

The pharmaceutical compositions can be prepared in the form of an oral formulation.

Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium,

methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like. Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

The pharmaceutical composition may be formed in a unit dose form as needed. The amounts of active components, e.g., the DHFR inhibitor compound described herein, included in the pharmaceutical preparations are such that a suitable dose within the designated range is provided (e.g., a dose within the range of 0.01-100 mg/kg of body weight). III. Routes, Dosage, and Administration

Pharmaceutical compositions that include the DHFR inhibitor compounds described herein may be formulated for, e.g., intravenous administration, parenteral administration, subcutaneous

administration, intramuscular administration, intra-arterial administration, intrathecal administration, or intraperitoneal administration. The pharmaceutical composition may also be formulated for, or administered via, oral, nasal, spray, aerosol, rectal, or vaginal administration. For injectable formulations, various effective pharmaceutical carriers are known in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 22 ^th ed., (2012) and ASHP Handbook on Injectable Drugs, 18th ed., (2014).

The dosage of the pharmaceutical compositions depends on factors including the route of administration, the disease to be treated, and physical characteristics, e.g., age, weight, general health, of the subject. Typically, the amount of the pharmaceutical composition contained within a single dose may be an amount that effectively prevents, delays, or treats the disease without inducing significant toxicity. A pharmaceutical composition may include a dosage of a DHFR inhibitor compound described herein ranging from 0.01 to 500 mg/kg (e.g., 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg/kg) and, in a more specific embodiment, about 0.1 to about 30 mg/kg and, in a more specific embodiment, about 1 to about 30 mg/kg. The dosage may be adapted by the physician in accordance with conventional factors such as the extent of the disease and different parameters of the subject.

The pharmaceutical compositions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective to result in an improvement or remediation of the symptoms. The pharmaceutical compositions are administered in a variety of dosage forms, e.g., intravenous dosage forms, subcutaneous dosage forms, and oral dosage forms (e.g., ingestible solutions, drug release capsules). The pharmaceutical composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemγas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice. Pharmaceutical compositions may be administered to a subject in need thereof, for example, one or more times (e.g., 1-10 times or more) daily, weekly, monthly, biannually, annually, or as medically necessary. Dosages may be provided in either a single or multiple dosage regimens. The timing between administrations may decrease as the medical condition improves or increase as the health of the patient declines. IV. Treatment of Fungal, Bacterial, and/or Parasitic Infections

The disclosure includes compositions and methods for treating or preventing a disease or condition associated with a fungal, bacterial, and/or parasitic infection in a subject by administering to the subject a DHFR inhibitor compound described herein. In some embodiments, the compounds described herein are used as monotherapies to treat fungal, bacterial, and/or parasitic infections. In some embodiments, the compounds described herein are used in combination with dihydropteroate synthase (DHPS) inhibitors (e.g., sulfamethoxazole), ergosterol synthesis inhibitors (e.g., fungal 14α-demethylase inhibitors and squalene epoxidase inhibitors), and/or methotrexate rescue compounds to treat fungal, bacterial, or parasitic infections. The disclosure also includes compositions and methods for treating or preventing a disease or condition associated with a fungal, bacterial, and/or parasitic infection in a subject by administering to the subject a pharmaceutical composition containing a DHFR inhibitor compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further includes a DHPS inhibitor, an ergosterol synthesis inhibitor (e.g., e.g., a fungal 14α-demethylase inhibitor or a squalene epoxidase inhibitor), and/or a methotrexate rescue compound. Examples of fungal 14α-demethylase inhibitors include, but are not limited to, azole compounds, such as VT-1161, fluconazole, albaconazole, bifonazole, butoconazole, clotrimazole, econazole, efinaconazole, fenticonazole, isavuconazole, isoconazole, itraconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, posaconazole, pramiconazole, ravuconazole, sertaconazole, sulconazole, terconazole, tioconazole, and voriconazole. Examples of squalene epoxidase inhibitors include, but are not limited to, allylamine compounds, such as terbinafine, butenafine, naftifine, and amorolfine. Examples of methotrexate rescue compounds include, but are not limited to, leucovorin, wellcovorin, and fusilev. In some embodiments, the methotrexate rescue compound is leucovorin.

In some embodiments, the fungal infection that can be treated using the compositions and methods described herein is an infection of Candida albicans, C. parapsilosis, C. glabrata, C.

guilliermondii, C. krusei, C. tropicalis, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus, or a fungus in the order Mucorales, or a fungus in the genus Cryptococcus, Fusarium, Cunninghamella, or Scedosporium. In some embodiments, the fungus in the order Mucorales is in the family Mucoraceae. In some embodiments, the fungus in the order Mucorales and the family Mucoraceae is in a genus selected from the group consisting of Mucor, Rhizopus, Rhizomucor, Absidia, Actinomucor, Apophysomyces, Backusella, Benjaminiella, Chaetocladium, Circinella, Cokeromyces, Dicranophora, Ellisomyces, Helicostylum, Hyphomucor, Kirkomyces,

Parasitella, Pilaira, Pilophora, Pirella, Rhizopodopsis, Sporodiniella, Syzygites, Thamnidium,

Thermomucor, and Zygorhynchus.

In some embodiments, the genus Mucor includes species M. amphibiorum, M. circinelloides, M. hiemalis, M. hiemalis f. silvaticus, M. indicus, M. mucedo, M. paronychius, M. piriformis, M. plumbeus, and M. racemosus. In some embodiments, the genus Rhizopus includes species Rhizopus azygosporus, R. caespitosus, R. delemar, R. homothallicus, R. microsporus, R. oryzae, R. reflexus, R. schipperae, and R. stolonifer. In some embodiments, the genus Rhizomucor includes species Rhizomucor pusillus. In some embodiments, the genus Absidia includes species Absidia coerulae, A. corymbifera, A.

cylindrospora, A. ginsan, A. glauca, and A. spinosa. In some embodiments, the fungus in the genus Cryptococcus is selected from the group consisting of Cryptococcus neoformans, C. gattii, C. albidus, and C. uniguttulatus. In some embodiments, the fungus in the genus Fusarium is selected from the group consisting of Fusarium solani, F. avenaceum, F. bubigeum, F. culmorum, F. graminearum, F. langsethiae, F. oxysporum, F. poae, F. sporotrichioides, F. tricinctum, F. verticillioides, and F. virguliforme. In some embodiments, the fungus in the genus Cunninghamella is selected from the group consisting of

Cunninghamella africana, C. bainieri, C. bertholletiae, C. binarieae, C. blakesleeana, C. clavata, C. echinulata, C. elegans, C. homothallica, C. intermedia, C. japonica, C. multiverticillata, C. phaeospora, C. polymorpha, C. septata, C. A18, C. CL023, and C. vesiculosa.

In some embodiments, the fungus in the genus Scedosporium is selected from the group consisting of Scedosporium apiospermum and S. prolificans.

In some embodiments, the bacterial infection that can be treated using the compositions and methods described herein is an infection of a bacterium in the genus Staphylococcus. In some embodiments, the bacterium in the genus Staphylococcus is selected from Staphylococcus aureus, S. arlettae, S. agnetis, S. auricularis, S. capitis, S. caprae, S. carnosus, S. caseolyticus, S. chromogenes, S. cohnii, S. condimenti, S. delphini, S. devriesei, S. epidermidis, S. equorum, S. felis, S. fleurettii, S.

gallinarum, S. haemolyticus, S. hominis, S. hyicus, S. intermedius, S. kloosii, S. leei, S. lentus, S.

lugdunensis, S. lutrae, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S. pettenkoferi, S. piscifermentans, S. pseudintermedius, S. pseudolugdunensis, S. pulvereri, S. rostri, S.

saccharolyticus, S. saprophyticus, S. schleiferi, S. sciuri, S. simiae, S. simulans, S. stepanovicii, S.

succinus, S. vitulinus, S. warneri, and S. xyloses. In some embodiments, the bacterium in the genus Staphylococcus is Staphylococcus aureus.

Compounds and/or pharmaceutical compositions described herein for treating or preventing a disease or condition associated with a fungal, bacterial, and/or parasitic infection in a subject may be administered by any appropriate route. The compounds may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient.

Administration may be intramuscular, intravenous, intradermal, intraarterial, intraperitoneal, intralesional, intracranial, intraarticular, intraprostatical, intrapleural, intratracheal, intranasal, intravitreal, intravaginal, intrarectal, topical, intratumoral, peritoneal, subcutaneous, subconjunctival, intravesicularl, mucosal, intrapericardial, intraumbilical, intraocularal, oral, local, by inhalation, by injection, or by infusion.

Compounds and/or pharmaceutical compositions described herein for treating or preventing a disease or condition associated with a fungal, bacterial, and/or parasitic infection in a subject may be administered to treat a blood stream infection, tissue infection (e.g., lung, kidney, or liver infection) in the subject, or any other type of fungal, bacterial, and/or parasitic infection in the subject. The fungal infection being treated can be an infection selected from, invasive aspergillosis, pulmonary aspergillosis, intra-abdominal abscess, peritonitis, a pleural cavity infection, esophagitis, candidemia, and invasive candidiasis.

The disclosure also includes methods for the prophylactic treatment of a fungal, bacterial, and/or parasitic infection in a subject. In some embodiments, the compound or pharmaceutical composition described herein is administered at least once over a period of 1-30 days (e.g., 1, 2, 3, 4, or 5 times over a period of 1-30 days). In some embodiments, the methods can be used for prophylatic treatment in subjects being prepared for an invasive medical procedure (e.g., preparing for surgery, such as receiving a transplant, stem cell therapy, a graft, a prosthesis, receiving long-term or frequent intravenous catheterization, or receiving treatment in an intensive care unit), in immunocompromised subjects (e.g., subjects with cancer, with HIV/AIDS, or taking immunosuppressive agents), or in subjects undergoing long term antibiotic therapy.

As is described herein, certain of the DHFR inhibitors exhibit broad spectrum activity.

Accordingly, the disclosure also includes methods of treating a fungal infection in a subject. The methods include administering to the subject a broad-spectrum substituted 1,3-diaminoquinazoline compound, or a pharmaceutically acceptable salt thereof, wherein the broad-spectrum substituted 1,3-diaminoquinazoline compound has (i) an MIC < 16 µg/ml against a first fungus in the genus Candida and (ii) an MIC < 16 µg/ml against a second fungus, wherein the second fungus is not in the genus Candida.

In some embodiments of these methods, the second fungus is in the genus Aspergillus,

Cryptococcus, Fusarium, or Scedosporium, or in the order Mucorales.

In some embodiments of these methods, the fungus in the genus Candida is Candida albicans. In some embodiments of this aspect, the fungus in the genus Aspergillus is Aspergillus fumigatus. In some embodiments of this aspect, the fungus in the genus Cryptococcus is Cryptococcus neoformans. In some embodiments of this aspect, the fungus in the genus Fusarium is Fusarium solani, F. verticillioides, or F. oxysporum. In some embodiments of this aspect, the fungus in the genus Scedosporium is Scedosporium apiospermum. In some embodiments of this aspect, the fungus in the order Mucorales is Mucor circinelloides, Absidia corymbifera, Rhizopus oryzae, Cunninghamella bertholletiae, or Rhizomucor pusillus.

In some embodiments of these methods, the broad-spectrum substituted 1,3-diaminoquinazoline compound is a compound described herein.

In some embodiments of these methods, the fungal infection in the subject is caused by one or more fungi, wherein the one or more fungi are in the genus Candida, Aspergillus, Cryptococcus, and/or Fusarium, and/or in the order Mucorales.

In some embodiments of these methods, the one or more fungi that caused the fungal infection in the subject are selected from a group consisting of Candida albicans, Aspergillus fumigatus,

Cryptococcus neoformans, Fusarium solani, Fusarium verticillioides, Fusarium oxysporum, Scedosporium apiospermum, Mucor circinelloides, Absidia corymbifera, Rhizopus oryzae, Cunninghamella bertholletiae, and Rhizomucor pusillus.

The disclosure also includes methods of treating mucormycosis in a subject. The methods include administering to the subject a substituted 1,3-diaminoquinazoline compound having an MIC < 8 µg/ml against a fungus in the order Mucorales, or a pharmaceutically acceptable salt thereof. The methods can also include treating mucormycosis in a subject that includes administering to the subject a broad-spectrum substituted 1,3-diaminoquinazoline compound having (i) an MIC < 8 µg/ml against a first fungus in the order Mucorales and (ii) an MIC < 16 µg/ml against a second fungus, wherein the second fungus is not in the order Mucorales. In some embodiments, the mucormycosis is caused by Mucor circinelloides, Absidia corymbifera, Rhizopus oryzae, Cunninghamella bertholletiae, or Rhizomucor pusillus. In some embodiments, the substituted 1,3-diaminoquinazoline compound is a compound described herein.

In some embodiments of the aforementioned methods, the substituted 1,3-diaminoquinazoline compound is described by formula (II)

wherein each of R ^AA , R ^BB , and R ^CC is, independently, H, hydroxyl, amino, aminoalkyl, CF ₃ , halo, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted heteroalkenyl, optionally substituted heterocycloalkenyl, OH, SH, OR ^C , or SR ^D ; each of R ^C , R ^D is, independently, acyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted aryloxy, optionally substituted heteroalkoxy, optionally substituted heterocycloalkoxy, optionally substituted heteroaryloxy, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted heteroalkenyl, or optionally substituted heterocycloalkenyl; or R ^AA , R ^BB , C ¹ , and C ² together form a fused ring comprising optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted heteroaryl, optionally substituted cycloalkoxy, optionally substituted heterocycloalkoxy, optionally substituted aryloxy, or optionally substituted heteroaryloxy; or a pharmaceutically acceptable salt thereof.

The disclosure also includes methods of preventing, stabilizing, or inhibiting the growth of fungi, bacteria, and/or parasites, or killing fungi, bacteria, and/or parasites. The methods include contacting said fungi, bacteria, and/or parasites or a site susceptible to fungal, bacterial, and/or parasitic growth with a DHFR inhibitor compound described herein or a pharmaceutically acceptable salt thereof and optionally a DHPS inhibitor and/or an ergosterol synthesis inhibitor. V. Kits

The individually or separately formulated compounds can be packaged together as a kit. The disclosure provides kits that include (i) a compound described herein, or a pharmaceutically acceptable salt thereof; and (ii) instructions for administering (i) to a subject having a fungal, bacterial, and/or parasitic infection. In some embodiments, the kits can also include (i) a compound described herein, or a pharmaceutically acceptable salt thereof; (ii) a DHPS inhibitor and/or an ergosterol synthesis inhibitor; and (iii) instructions for administering (i) and (ii) to a subject having a fungal, bacterial, and/or parasitic infection. In some embodiments, the kits can also include (i) a compound described herein, or a pharmaceutically acceptable salt thereof; and (ii) instructions for administering (i) with a methotrexate rescue compound to a subject having a fungal, bacterial, and/or parasitic infection. In some

embodiments, the kits can also include (i) a compound described herein, or a pharmaceutically acceptable salt thereof; (ii) a DHPS inhibitor and/or an ergosterol synthesis inhibitor; and (iii) instructions for administering (i) and (ii) with a methotrexate rescue compound to a subject having a fungal, bacterial, and/or parasitic infection.

Other non-limiting examples of kits include, but are not limited to, kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc.

Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions. The kit may be manufactured as a single use unit dose for one patient, multiple uses for another patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

The kits described herein may be used to treat or prevent a disease or condition associated with a fungal, bacterial, and/or parasitic infection in a subject. In some embodiments, the fungal infection that can be treated using the kits described herein is an infection of Candida albicans, C. parapsilosis, C. glabrata, C. guilliermondii, C. krusei, C. tropicalis, C. lusitaniae, Aspergillus fumigatus, A. flavus, A.

terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus, or a fungus in the order Mucorales, or a fungus in the genus Cryptococcus, Fusarium, Cunninghamella, or Scedosporium. Examples of species of fungus in the Mucorales, or in the genus Cryptococcus, Fusarium, Cunninghamella, or Scedosporium are described in detail herein.

The following Examples are intended to illustrate the synthesis of a representative number of compounds and antifungal activities of these compounds. Accordingly, the Examples are intended to illustrate but not to limit the disclosure herein. Additional compounds not specifically exemplified may be synthesized using conventional methods in combination with the methods described herein. EXAMPLES

General Methods

Preparative HPLC was performed using the following: Teledyne Isco HP C18, 50g column.

Eluent: CH3CN/H2O/ 0.1% formic acid or 0.1% trifluoroacetic acid; various linear gradients as necessary at 40 mL/min on the Isco Combiflash Rf LC unit. UV Detection at 220 and 254 nm or Luna 5 micron C18, 100 Å, AXIA 100 x 30 mm. Eluent: CH3CN/H2O/ 0.1% formic acid or 0.1% trifluoroacetic acid; various linear gradients as necessary at 25 mL/min on the Gilson System; 215 Liquid Handler, Gilson UV-VIS 155, Gilson 305 pump and Detector. UV detection at 220 and 254 nm.

Analytical LC/MS: High resolution liquid chromatography mass spectrometry (HRES-LC/MS) was performed using a Waters Q-TOF Premier mass spectrometer with an electrospray probe coupled with an Agilent 1100 HPLC system with a diode array detector set to collect from 190nm to 400 nm. A gradient of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B) was run from 15%B to 95% over 15min using a 100 x 3.02.6 µ Phenomenex Kinetex C18 column at 30°C.

Liquid chromatography mass spectrometry was performed using an Agilent 6120 mass spectrometer an electrospray probe coupled with an Agilent 1100 HPLC system with a variable wavelength detector set to either 220nm or 254nm. A gradient of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B) was run from 15%B to 99% over 3.5min using a 50x3.02.6µ Phenomenex Kinetex C18 column at 30°C.

1H-NMR (1H NMR) spectra were acquired on a Bruker 300 MHz system using a 5mm QNP probe and chemical shifts are reported as ppm (δ) downfield from tetramethylsilane.

Compounds herein may be made using synthetic methods known in the art, including procedures analogous to those disclosed below. General Schemes

Scheme 1

Scheme 5

Example 1. Preparation of Intermediates

Int-1. Preparation of 4,6-Difluoro-2,2-dimethyl-1-oxa-7-indancarbonitrile

Step a). Preparation of 4,6-Difluoro-2-(2-methyl-2-propenyloxy)benzonitrile

Sodium hydride (560 mg, 14 mmol, 60% in mineral oil) was added to a stirring solution of the 2,4,6-trifluorocyanobenzene (2g, 13.7 mmol) and 2-methyl-2-propen-1-ol (1.2 mL, 14 mmol) in a 1/1 mixture of dioxane/THF (25 mL) cooled to 0°C. The reaction was stirred for 2 hours at 0°C then water was added and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to afford the product as a waxy brown solid. ¹ H NMR (300 MHz, CDCl3) δ 6.03-6.49 (m, 2H), 5.15 (d, 2H, J=20.1 Hz), 4.56 (s, 2H), 1.87 (s, 3H). LC/MS [M+H] ⁺ 210.2. Step b). Preparation of Int-1

4,6-Difluoro-2-(2-methyl-2-propenyloxy)benzonitrile (1.7g, 8.1 mmol) was dissolved in NMP (10 mL) and irradiated in the microwave at 215°C for 15 minutes. The reaction mixture was cooled and purified by reversed phase HPLC (30-95% acetonitrile in DI water containing 0.1% TFA: 20 min gradient; the fractions were monitored at 220 nM on the UV detector). The pure fractions were pooled and concentrated to afford the product as a light amber solid. Yield 0.79g, 46%. ¹ H NMR (300 MHz, CDCl3) δ 6.45 (dd, 1H, J=9.6, 8.7 Hz), 3.06 (s, 2H), 1.58 (s, 6H). LC/MS [M+H] ⁺ 196.0.LC/MS [M+H] ⁺ 210.0. Int-2. Preparation of 4,6-Difluoro-2-methyl-1-oxa-7-indancarbonitrile

Step a). Preparation of 2-(Allyloxy)-4,6-difluorobenzonitrile

The title compound was prepared by a procedure similar to that described in Int-1 step a). ¹ H NMR (300 MHz, CDCl3) δ 6.59-6.51 (m, 2H), 6.08 (m, 1H), 5.15 (d, 1H, J=17.4 Hz), 5.39 (d, 1H, J=11.1 Hz), 4.68 (d, 2H, J=4.8 Hz). LC/MS [M+H] ⁺ 196.0. Step b). Preparation of Int-2

The title compound was prepared by a method similar to that described for Int-1 Step b). ¹ H NMR (300 MHz, CDCl3) δ 6.46 (dd, 1H, J=9.6, 8.4 Hz), 5.28 (m, 1H, J=7.2 Hz), 3.44 (dd, 1H, J=15.9, 9 Hz), 2.90 (dd, 1H, J=15.6, 7.2 Hz), 1.58(d, 3H, J=6.3 Hz). LC/MS [M+H] ⁺ 196.0. LC/MS [M+H] ⁺ 196.0. Int-3. Preparation of 3-Allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile

2-(Allyloxy)-4-bromo-6-fluorobenzonitrile (4g, 15.6 mmol) was stirred in 1,2-dicholorbenzene (150 mL) at 175°C for approximately 36 hours. The resulting mixture was cooled, concentrated, and purified by silica gel chromatography (5% ethyl acetate in hexanes) to afford 3-Allyl-4-bromo-6-fluoro-2- hydroxybenzonitrile as a bright yellow solid. Yield 73%. ¹ H NMR (300 MHz, CDCl3) δ 7.10 (d, 1H, J=8.1 Hz), 5.98-5.85 (m, 1H), 5.22-5.13 (m, 2H), 3.63 (d, 2H, J=6 Hz). Int-4. Preparation of 5,7-Difluoro-8-chromancarbonitrile

Step a). Borane-methyl sulfide complex (4.06 mL, 2.02 mmol, 0.5M in THF) was added to 3-allyl- 4,6-difluoro-2-hydroxybenzonitrile (0.40g, 2.03 mmol, see Int-7) in THF (20 mL) cooled to 0°C. The mixture was stirred at 0°C for 45 minutes at which point 5 mL of a 1/1 mixture of 30% H2O2/3M aqueous NaOH was added and the mixture was stirred for 30 minutes at 0°C.1N Aqueous HCl was added and the mixture was extracted into ethyl acetate, dried over sodium sulfate and concentrated. The crude was taken directly to the next step. Step b). To a mixture of the alcohol from above and triphenyl phosphine (0.53g, 2.03 mmol) in dry THF (5 mL) was added DIAD (0.40 mL, 2.03 mmol), dropwise and the mixture was stirred for 30 minutes at ambient temperature. Half of the THF was removed on the rotovap and the mixture was purified by silica gel chromatography (5 to 100% ethyl acetate in hexanes) to afford the product as a white solid. Yield 45%, 2 steps. ¹ H-NMR (300 MHz, CDCl3) δ 6.47 (t, 1H, J = 9 Hz), 4.36 (t, 2H, J = 4.5 Hz), 2.701.45 (t, 2H, J = 5.7 Hz), 2.05 (m, 2H); LC/MS [M+H] ⁺ 196.0 Int-5. Preparation of 5-Bromo-7-fluoro-8-chromancarbonitrile

Step a). Preparation of 4-Bromo-6-fluoro-2-hydroxy-3-(3-hydroxypropyl)benzonitrile

2-Cyano-3-fluoro-5-bromo-6-allyl phenol (2.8g, 10.9 mmol) was dissolved in THF (70 mL) and cooled to 0°C. Borane-dimethyl sulfide complex (12 mL, 12 mmol, 1M in THF) was added dropwise over 10 minutes. The reaction was stirred for 1 hour at which time a 1/1 mixture of 30% peroxide and saturated, aqueous sodium hydrogen carbonate (~5 mL) was added dropwise while maintaining the reaction temperature below 10°C. The reaction was monitored by TLC until complete, then quenched with saturated aqueous sodium thiosulfate (~50 mL). The reaction was acidified with conc. HCL (to pH ~2), extracted into ethyl acetate, dried over sodium sulfate, concentrated, and purified on silica gel (5-90% ethyl acetate in hexanes) to afford 4-bromo-6-fluoro-2-hydroxy-3-(3-hydroxypropyl)benzonitrile as a yellow oil. Yield 44%. ¹ H-NMR (300 MHz, CDCl3) δ 7.044 (d, 1H, J=8.1 Hz), 3.70 (t, 2H, J=5.7), 2.98 (t, 2H, J=6.3 Hz), 1.97 (m, 2H, J=5.7 Hz). Step b). Preparation of 5-Bromo-7-fluoro-8-chromancarbonitrile

4-Bromo-6-fluoro-2-hydroxy-3-(3-hydroxypropyl)benzonitrile (1.25g, 4.56 mmol) and

triphenylphosphine (1.2g, 4.56 mol) were dissolved in THF (30 mL) and cooled to 0°C. DIAD (0.71 mL, 4.56 mmol) was added dropwise and the reaction was stirred for 30 minutes at 0°C then concentrated and purified by reversed phase HPLC (20-95% acetonitrile/water containing 0.1% TFA: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a white solid. Yield 73%. ¹ H-NMR (300 MHz, CDCl3) δ 8.11 (d, 1H, J=8.4 Hz), 7.61 (dt, 1H, J=6.3,1.5 Hz), 7.56-7.33 (m, 3H), 7.20 (d, 1H, J=7.2 Hz), 6.72 (d, 1H, J=9.3 Hz), 4.35 (t, 2H, J=4.2 Hz), 2.77 (s, 3H), 2.37-2.18 (m, 2H), 1.90 (m, 2H, J=6.3 Hz). LC/MS [M+H] ⁺ 318.0. Int-6. Preparation of 3-(2-Cyclopropyl-2-hydroxyethyl)-4,6-difluoro-2-dimethyl-ter t- butylsilyloxybenzonitrile

Step a). Preparation of 3-allyl-4,6-difluoro-2-dimethyl-tert-butylsilyloxybenzonitri le

3-Allyl-4,6-difluoro-2-hydroxybenzonitrile (600 mg, 3.07 mmol) was dissolved in THF (20 mL). Imidazole (230 mg, 3.38 mmol) followed by TBS chloride (275 mg, 3.38 mmol) were added and the reaction was stirred for 1 hour. DI water (100 mL) was added and the mixture was extracted into ethyl acetate (3x, 25 mL). The combined organic extracts were dried over sodium sulfate, concentrated and purified by silica gel chromatography (ethyl acetate/hexanes) to afford the product as a clear viscous oil. Yield 87%. LC/MS [M+H]+ 310.2. Step b). Preparation of 3-(2-Cyclopropyl-2-hydroxyethyl)-4,6-difluoro-2-dimethyl-ter t- butylsilyloxybenzonitrile

3-allyl-4,6-difluoro-2-dimethyl-tert-butylsilyloxybenzonitri le (280 mg, 0.90 mmol) was taken up in a 1/1 mixture of DCM/methanol (20 mL) and cooled to -78˚C. Ozone was bubbled through the cooled, stirring solution for 1 hour at which point LC/MS analysis showed complete conversion of starting material. Dimethyl sulfide (1.5 mL) was added to the stirring reaction and the cooling bath removed. The reaction was stirred for 1 hour while warming to ambient temperature, LC/MS analysis showed clean conversion to the aldehyde; [M+H]+ 312.0. The solvent was removed by rotovap and the crude aldehyde product was dried under high vacuum then dissolved in THF and cooled to 0C. Cyclopropylmagnesium chloride (2 mL, 2 mmol, 1M in THF) was added dropwise to the cooled, stirring solution and then stirred for an additional 30 minutes. The mixture was quenched with aqueous 1N HCl, extracted into ethyl acetate, dried over sodium sulfate and concentrated to afford 3-(2-Cyclopropyl-2-hydroxyethyl)-4,6- difluoro-2-dimethyl-tert-butylsilyloxybenzonitrile as a clear oil . Yield 65%, 3 steps. LC/MS [M+H]+ 353.2. Step c). Preparation of 3-(2-Cyclopropyl-2-hydroxyethyl)-4,6-difluoro-2-dimethyl-ter t- butylsilyloxybenzonitrile

Int-6

3-(2-Cyclopropyl-2-hydroxyethyl)-4,6-difluoro-2-dimethyl-ter t-butylsilyloxybenzonitrile (200 mg, 0.57 mmol) was taken up in THF (15 mL) and treated with TBAF (2 mL, 2 mmol, 1M in THF). Upon removal of the silyl protecting group, as judged by LC/MS, the mixture was diluted with DI water (50 mL) and extracted into ethyl acetate, dried over sodium sulfate and concentrated. The crude product was taken up in THF and triphenylphosphine (148 mg, 0.57 mmol) followed by DIAD (114 mg, 0.57 mmol) were added and the reaction was stirred for 30 minutes at ambient temperature. The mixture was concentrated and purified by silica gel chromatography (hexanes/ethyl acetate) to afford 3-(2-cyclopropyl- 2-hydroxyethyl)-4,6-difluoro-2-dimethyl-tert-butylsilyloxybe nzonitrile as a clear oil. Yield 95%. LC/MS [M+H] ⁺ 222.0. Int-7. Preparation of 3-Allyl-4,6-difluoro-2-hydroxybenzonitrile

The title compound was prepared by a method similar to that described for Int-3. ¹ H-NMR (300 MHz, CDCl3) δ 6.54 (t, 1H, J=17.4 Hz), 5.92 (m, 1H), 5.18 (d, 1H, J=1.2 Hz), 5.13 (d, 1H, J = 0.9 Hz), 3.43 (dd, 2H, J = 1.2 Hz, 6 Hz). LC/MS [M+H] ⁺ 196.0 Int-8. Preparation of 4,6-Difluoro-2-vinyl-1-oxa-7-indancarbonitrile

Step a). Preparation of 4,6-Difluoro-2-dimethyl-tertbutylsilyloxy-3-(2-hydroxy-3- butenyl)benzonitrile

The title compound was prepared by a method similar to that described for Int-6 Step b). LC/MS [M+H] ⁺ 340.2. Step b). Preparation of 4,6-Difluoro-2-vinyl-1-oxa-7-indancarbonitrile

The title compound was prepared by a method similar to that described for Int-6 Step c). LC/MS [M+H] ⁺ 208.0 Int-9. Preparation of 2-(Allyloxy)- - - - benzonitrile

Sodium hydride (1.1 g, 27.5 mmol, 60% in mineral oil) was added, in 4 portions over 10 minutes, to a stirring mixture of allyl alcohol (1.71 mL, 25.2 mmol) and 2,4-di-fluoro-4-bromo cyano benzene (5g, 22.9 mmol) in 9/1 Dioxane/THF (40 mL) cooled to 0C. The mixture was stirred for 12 hours while gradually warming to ambient temperature. The reaction mixture was quenched with 1N aqueous HCl (100 mL) and extracted into ethyl acetate (3x, 50 mL). The combined organic reactions were dried over sodium sulfate and concentrated to afford 2-(allyloxy)-4-bromo-6-fluorobenzonitrile as a light orange, viscous oil. The product was used without further purification. Yield 95%.1H-NMR (300 MHz, CDCl3) d 7.03 (dd, 1H, J=8.1, 1.5 Hz), 6.94 (s, 1H), 6.10-5.98 (m, 1H), 5.53 (dd, 1H, J=17.4, 1.2 Hz), 5.42 (dd, 1H, J=10.5, 1.2 Hz), 4.69 (d, 2H, J=4.8, 1.5 Hz). LC/MS [M+H] ⁺ 256.0 Int-10. Synthesis of 4-bromo-6-fluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitri le

Step a). Synthesis of 2-((E)-but-2-en l x -4- r m -6-fluorobenzonitrile

Sodium hydride (60% in mineral oil, 1.21g, 30.3 mmol) was added in 5 portions over a 30 minute period to a solution of 4-bromo-2,6-difluorobenzonitrile (6.00g, 27.5 mmol) and (E)-2-Buten-1-ol (2.57 mL, 30.3 mmol) in dioxane (30mL) at room temperature, with cooling from a room temperature water bath (reaction foams). After 2h LCMS shows a small amount of unreacted starting material and a large product peak at 220 nm. Work-up: quenched with 1N HCl until just acidic by pH paper, diluted with ethyl acetate, washed with NaHCO3, brine, and dried with Na2SO4. Chromatographed on silica gel (0-25% ethyl acetate/hexanes). Upon concentration a tan solid was obtained (4.91g, 66% yield). ¹ H NMR (300 MHz, CDCl3) δ 7.03 (dd, 1H, J =1.54, 8.11Hz), 6.94 (s, 1H), 5.93 (m, 1H), 5.70 (m, 1H), 4.60 (d, 2H, J = 5.98Hz), 1.78 (d, 3H, J = 6.48Hz); LC/MS, 271.0 [M+H]+ calculated 271.1. Step b). Synthesis of 4-bromo-3-(but-3-en-2-yl)-6-fluoro-2-hydroxybenzonitrile

A solution of 2-((E)-but-2-enyloxy)-bromo-6-fluorobenzonitrile (4.91g, 18.2mmol), dissolved in ortho-dichlorobenzene (20ml), was equipped with an air condenser and heated in a 180˚C oil bath for 4h. The solution was cooled to room temperature, where the product crystalized. The solid was collected by filtration (0.81g). The mother liquor was concentrated under high vacuum in a 60˚C water bath and purified by flash chromatography (0 to 40% ethyl acetate/hexanes). Combined yield 3.13g, 64%. ¹ H NMR (300 MHz, CDCl3) δ 7.08 (d, 1H, J =8.15Hz), 6.31 (m, 1H), 5.55 (m, 1H), 4.26 (m, 1H), 1.41 (d, 3H, J = 7.15Hz); LC/MS, 271.0 [M+H]+ calculated 271.1. Step c). Synthesis of 4-bromo-6-fluoro-2-hydroxy-3-(1-hydroxypropan-2-yl)benzonitr ile

4-bromo-3-(but-3-en-2-yl)-6-fluoro-2-hydroxybenzonitrile (3.13g, 11.6mmol), was dissolved in 1:1 DCM/MeOH (20mL), cooled to -78˚C and treated with O ₃ until a pale blue color persists. O ₂ was bubbled through the mixture for 5 min, then NaBH4 was added slowly (bubbles vigorously) and the mixture was warmed to room temperature slowly over 15 min. Work-up: diluted with ethyl acetate, washed with 1N HCl, 1N NaHCO3, brine, dried over Na2SO4. This material was used without further purification. Mass recovery = 3.15g, 99%. ¹ H NMR (300 MHz, MeOD) δ 7.11 (d, 1H, J =8.64Hz), 3.97 (dd, 1H, J = 4.15, 11.16Hz), 3.87 (dd, 1H, J = 2.55, 10.53Hz), 3.76 (m, 1H), 1.32 (d, 3H, J = 7.26Hz); LC/MS, 275.1 [M+H]+ calculated 275.0. Step d). Synthesis of 4-bromo-6-fluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitri le DIAD(2.5 mL, 12.6 mmol) was added dropwise to a 0˚C solution of 4-bromo-6-fluoro-2-hydroxy-3- (1-hydroxypropan-2-yl)benzonitrile (3.15g, 11.5mmol), and triphenylphosphine (3.32g, 12.6 mmol) in THF (36mL). LCMS after 10 min. shows complete conversion. The solution was concentrated and purified by normal phase chromatography (0 to 25% ethyl acetate/hexanes). Yield 1.36g (46%). ¹ H NMR (300 MHz, CDCl3) δ 6.87 (d, 1H, J =8.97Hz), 4.86 (t, 1H, J = 8.80 Hz), 4.48 (dd, 1H, J = 3.91, 9.00Hz), 3.57 (m, 1H), 1.41 (d, 3H, J = 6.95Hz); LC/MS, 257.2 [M+H]+ calculated 257.1. Int-11. Synthesis of 4, 6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile

Step a). Synthesis of 2-((E)-but-2-enyloxy)-4,6-di-fluorobenzonitrile

NaH (60% in mineral oil, 1.21g, 30.3 mmol) was added in one portion to (E)-2-Buten-1-ol (1.62g, 20 mmol) in 20 ml THF with cooling from an ice water bath. The mixture was stirred for 10 min, then added dropwise to 2,4,6-trifluorobenzonitrile (3.2 g, 20 mmol) in 20ml THF, with cooling from an ice bath. The solution was stirred at room temperature for 4 hours, then quenched with acetic acid. This solution was dried onto silica gel and purified by normal phase chromatography using an ISCO Combiflash, eluted with ethyl acetate and hexane. Yield (3.2g, 80% yield). ¹ H NMR (300 MHz, CDCl3) δ 6.53(m, 2H) 5.93(m, 1H) 5.73(m, 1H) 4.60(m, 2H) 1.81(d, J=6Hz, 3H). LC/MS, 210.2 [M+H]+ calculated 210.2 Step b). Synthesis of 3-(but-3-en-2-yl)-4,6-difluoro-2-hydroxybenzonitrile

A solution of 2-((E)-but-2-enyloxy)-4,6-difluorobenzonitrile (2.4g, 11.4mmol), dissolved in ortho- dichlorobenzene (20ml), was equipped with an air condenser and heated in a 180⁰C oil bath overnight. The reaction mixture was cooled down and was dried onto silica gel under high vacuum. The resulting material was purified on an ISCO Combiflash eluted with ethyl acetate and hexane to provide desired product (1.6g, 67% yield) ¹ H NMR (300 MHz, CDCl3) δ 7.07(br, 1H) 6.54(t, J=9Hz) 6.17(m, 1H) 5.32(m, 2H) 4.00(m, 1H) 1.42((d, J=7.2Hz, 3H) LC/MS, 210.1 [M+H]+ calculated 210.2 Step c). Synthesis of 4,6-difluoro-2-hydroxy-3-(1-hydroxypropan-2-yl)benzonitrile

3-(But-3-en-2-yl)-4,6-fluoro-2-hydroxybenzonitrile (420mg, 2mmol), was dissolved in 1:1 DCM/MeOH (10mL), cooled to -78 ^o C and treated with O3 until a pale blue color persists. O2 was bubbled through the mixture for 5 min, then NaBH4 was added slowly (bubbles vigorously) and the mixture was warmed to room temperature slowly over 15 min. Work-up: diluted with EtOAc, washed with 1N HCl, 1N NaHCO3, brine, and dried over Na2SO4. This material was used without further purification. Mass recovery = 3.15g, 99%. ¹ H NMR (300 MHz, CDCl3) δ 6.47(t, J=9Hz, 1H) 4.09(m, 2H) 3.55 (m, 2H) 1.41(d, J=9Hz, 3H); LC/MS, 211.1 [M+H]+ calculated 211.2. Step d). Synthesis of 4, 6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile

DIAD (1.3 mL, 6.2 mmol) was added dropwise to a 0 ^o C solution of 4,6-difluoro-2-hydroxy-3-(1- hydroxypropan-2-yl)benzonitrile (1.2, 5.6 mmol), and triphenylphosphine (1.62g, 6.2 mmol) in THF (20mL). LCMS after 10 min. shows complete conversion. The solution was concentrated and purified by normal phase chromatography (0 to 25% ethyl acetate/hexanes). Yield 1.36g (46%) of white solid. ¹ H NMR (300 MHz, CDCl3) δ 6.44(t, J=9Hz, 1H) 4.93(t, J=9Hz, 1H) 4.40(dd, J1=6Hz, J2=9Hz, 1H) 3.75(m, 1H) 1.42(d, J=6Hz, 3H); LC/MS, 195.2 [M+H]+ calculated 195.1.

Int-12 Step a). Synthesis of 2-((E)-pent-2- n l x -4 - i-fl orobenzonitrile

The title compound was prepared analogously to 2-((E)-but-2-enyloxy)-4,6-di-fluorobenzonitrile (Int-11, Step a). ¹ H NMR (300 MHz, CDCl3) δ 6.50(m, 2H), 5.90(m, 1H) 5.67(m, 1H) 4.61(d, J=0.9Hz, 2H) 2.13(m, 2H) 1.03(t, J=7.2Hz). Step b). Synthesis of 3-(pent-3-en-2-yl)-4,6-difluoro-2-hydroxybenzonitrile

The title compound was prepared analogously to 3-(but-3-en-2-yl)-4,6-difluoro-2- hydroxybenzonitrile (Int-11, Step b). ¹ H NMR (300 MHz, CDCl3) δ 7.07(bs, 1H) 6.54(t, J=9Hz) 5.87(m, 1H) 5.26(m, 2H) 3.76(m, 1H) 1.82(m, 2H) 1.28((t, J=7.2Hz, 3H) Step c). Synthesis of 4,6-difluoro-2-hydroxy-3-(1-hydroxybutan-2-yl)benzonitrile

The title compound was prepared analogously to 4,6-difluoro-2-hydroxy-3-(1-hydroxypropan-2- yl)benzonitrile (Int-11, Step c). ¹ H NMR (300 MHz, CDCl3) δ 6.66(m, 1H) 4.00(m, 2H), 3.52(m, 1H) 1.83(m, 2H) 0.89(t, J= 7.2Hz, 3H) Step d). Synthesis of 4, 6-difluoro-2,3-dihydro-3-ethylbenzofuran-7-carbonitrile

The title compound was prepared analogously to 4, 6-difluoro-2,3-dihydro-3-methylbenzofuran-7- carbonitrile (Int-11, Step d). ¹ H NMR (300 MHz, CDCl3) δ 6.45(d, J=9.6Hz, 1H) 4.78(t, J=8.7Hz, 1H) 4.47(m, 1H) 3.63(m, 1H) 1.87(m, 2H), 0.96(t, J=7.5Hz, 3H). Int-13. Synthesis of 4-(bromo-methylenyl)-6-difluoro-2,3-dihydro-3-methylbenzofur an-7- carbonitrile

Step a). Synthesis of 4-hydroxymeth l-26-difluorobenzonitrile Sodium borohydride (1.0g, 25mmol) was slowly added to a solution of 4-formyl-2,6- difluorobenzonitrile(3.4g, 20mmol) in 100ml methanol (bubbles vigorously). The resulting solution was stirred for 1 hour, then methanol was removed and the residue was partitioned between 100ml ethyl acetate and 50ml 1N HCl. The organic layer was separated and washed with 1N sodium bicarbonate, brine, dried over sodium sulfate, and concentrated to provide the desired product, which was used without further purification. ¹ H NMR (300 MHz, CDCl3) δ 7.08(d, J=8.4Hz, 2H) 4.81(s, 2H). Step b). Synthesis of 4-tertbutyldimeth lsil lox l-meth lenyl-2,6-difluorobenzonitrile

Imidazole (1.4g, 20mmol) was added to a solution of 4-hydroxymethyl-2,6-difluorobenzonitrile (1.7g, 10mmol) in 30ml DMF, followed by TBS-Cl(1.80g, 11mmol). The resulting solution was stirred overnight, then concentrated to remove DMF. The residue was dissolved in 100ml ethyl acetate then extracted with 50ml 1N HCl. The organic layer was separated and washed with 1N sodium bicarbonate and brine, then dried over sodium sulfate, and concentrated to remove all solvents. The resulting residue was purified by normal phase chromatography, eluting with ethyl acetate and hexane to provide the desired product (2.8g, 99% yield). ¹ H NMR (300 MHz, CDCl3) δ 7.05(d, J=8.4Hz, 2H) 4.77(s, 2H) 0.97(s, 9H) 0.14(s, 6H). Step c). Synthesis of 2-((E)-but-2-enyloxy)-4-(tertbutyldimethylsilyloxyl-methylen yl)-6- fluorobenzonitrile

The title compound was prepared analogously to 2-((E)-but-2-enyloxy)-4,6-di-fluorobenzonitrile (Int-11, Step a). ¹ H NMR (300 MHz, CDCl3) δ 6.77(s, 1H), 6.73(d, J=9.3Hz, 1H), 5.72(m, 2H), 4.73(s, 2H) 4.60(d, J=6Hz, 2H), 1.77(d, J=6.6Hz, 3H), 0.96(s, 9H), 0.1(s, 6H). Step d). Synthesis of 3-(but-3-en-2-yl)-4-(tertbutyldimethylsilyloxyl-methylenyl)- 6-difluoro-2- hydroxybenzonitrile

The title compound was prepared analogously to 3-(but-3-en-2-yl)-4,6-difluoro-2- hydroxybenzonitrile (Int-11, Step b). ¹ H NMR (300 MHz, CDCl3) δ 6.96(d, J=10Hz, 1H) 6.53(s, 1H) 6.24(m, 1H) 5.48(m, 2H) 4.72(dd, J1=18.6Hz, J2=4.5Hz, 2H) 3.2(m, 1H) 1.42(d, J=7.2Hz, 3H) 0.96(s, 9H) 0.14(s, 6H). Step e). Synthesis of 4-(tertbutyldimethylsilyloxyl-methylenyl)-6-fluoro-2-hydroxy -3-(1- hydroxypropan-2-yl)benzonitrile

The title compound was prepared analogously to 4,6-difluoro-2-hydroxy-3-(1-hydroxypropan-2- yl)benzonitrile (Int-11, Step c). ¹ H NMR (300 MHz, CDCl3) δ 6.80(d, J=9.6Hz, 1H), 4.65(q, t=10.8Hz, 2H), 4.08(m, 2H), 3.26(m, 1H), 1.41(d, J=7.5Hz), 0.94(s, 9H), 0.11(s, 6H). Step f). Synthesis of 4-(tertbutyldimethylsilyloxyl-methylenyl)-6-difluoro-2,3-dih ydro-3- methylbenzofuran-7-carbonitrile

The title compound was prepared analogously to of 4, 6-difluoro-2,3-dihydro-3-methylbenzofuran- 7-carbonitrile (Int-11, Step d). ¹ H NMR (300 MHz, CDCl3) δ 6.80(d, J=9Hz, 1H), 4.81(t, J=9Hz, 1H), 4.71(s, 2H), 4.39(dd, J1=6Hz, J2=9Hz), 3.57(m, 1H), 1.31(d, J=9Hz, 3H), 0.96(s, 9H), 0.14(s, 6H). Step g). Synthesis of 4-(hydroxyl-methylenyl)-6-difluoro-2,3-dihydro-3-methylbenzo furan-7- carbonitrile

4-(tertbutyldimethylsilyloxyl-methelenyl)-6-difluoro-2,3-dih ydro-3-methylbenzofuran-7- carbonitrile(330mg, 1mmol) was dissolved into 5ml 20% TFA/DCM at room temperature. The resulting solution was stirred for 30 minute then stripped of solvents. The residue was purified by a flash chromatography to provide the desired product 180mg, 85% yield. ¹ H NMR (300 MHz, CDCl3) δ 6.80(d, J=10.2Hz, 1H) 4.80(t, J=9Hz, 1H) 4.71(s, 2H) 4.38(dd, J1=4.2Hz, J2=9Hz, 1H) 3.60(m, 1H), 2.90(br, 1H) 1.31(d, J=7.5Hz, 3H) Step h). Synthesis of 4-(bromo-methylenyl)-6-difluoro-2,3-dihydro-3-methylbenzofur an-7- carbonitrile

Triphenylphosphine (290mg, 1.1 mmol), tetrabromomethane (330mg, 1mmol) was added to a solution of 4-(hydroxyl-methenyl)-6-difluoro-2,3-dihydro-3-methylbenzofu ran-7-carbonitrile(180mg, 0.87mmol) in DCM (10mL). The reaction was complete in 3 hour by TLC. The resulting solution was purified by normal phase chromatography. Yield (150mg, 64% yield). ¹ H NMR (300 MHz, CDCl3) δ 6.68 (d, J=9.9Hz, 1H) 4.83(t, J=9Hz, 1H) 4.40(m, H) 4.31(dd, J1=10.5, J2=44.4Hz, 2H) 3.65(m, 1H), 1.39(d, J=76.9 Hz, 3H). Int-14. Synthesis of 4,6-Difluoro-2-(3-oxetanyloxy)benzonitrile

The title compound was prepared analogously to Int-1, step a. ¹ H NMR (300 MHz, CDCl3) d 6.65 (td, 1H, J=8.7, 2.4 Hz), 6.11 (dt, 1H, J=9.6, 1.5 Hz), 5.30 (m, 1H, J=5.7 Hz), 5.03-4.99 (m, 2H), 4.87-4.82 (m, 2H). Int-15. Synthesis of 5-(3-chloro-5-hydroxyphenyl)-7-fluoro-3,4-dihydro-2H-1-benzo pyran-8- carbonitrile.

The title compound was prepared by a method similar to that described for Example 65 using int- 5 as the starting material. 1H-NMR (300 MHz, MeOD d4) δ 6.86 (d, 1H, J=2.1 Hz), 6.80 (s, 1H), 6.72- 6.66 (m, 2H), 4.39 (t, 2H, J=5.1 Hz), 2.63 (t, 2H, J=6.3 Hz), 2.00 (m, 2H, J=5.4 Hz). LC/MS [M+H]+ 304.0. Example 2. Preparation of 2,3-dihydro-2-meth l-4- hen lthio)furo[2,3-f]quinazoline-7,9-diamine

4,6-difluoro-2,3-dihydro-2-methylbenzofuran-7-carbonitrile (97 mg, 0.50 mmol, Int2, step b), thiophenol (54 mg, 0.50 mmol), and potassium carbonate (69 mg, 0.50 mmol) were stirred in NMP (3 mL) at 80°C for 12 hours at which point LCMS indicated that the reaction was complete. Guanidine carbonate (273 mg, 2.49 mmol) was added and the reaction temperature was raised to 150°C for 3 hours. The mixture was cooled and purified directly by reversed phase chromatography (15 to 95% ACN/water containing 0.1% TFA, 15 minute gradient). The pure fractions were pooled and concentrated to afford desired product as a light yellow solid.93 mg, 58% yield, 2 steps. ¹ H-NMR (300 MHz, DMSO d6) δ 12.59 (s, 1H), 8.92 (s, 1H), 8.81 (bs, 2H), 7.68-7.55 (m, 5H), 6.23 (s, 1H), 5.33 (m, 1H), 3.33 (m, 1H), 2.76 (m, 1H), 1.53 (d, 3H, J=6.3 Hz). LC/MS [M+H], 325.2. Example 3. Preparation of 2,3-dih r -2-m h l-4- h n x f r [2,3-f]quinazoline-7,9-diamine

4,6-difluoro-2,3-dihydro-2-methylbenzofuran-7-carbonitrile (Int-2, step b) (70 mg, 0.36 mmol), phenol (37 mg, 0.39 mmol) and potassium carbonate (49 mg, 0.36 mmol) were dissolved in NMP (3 mL) and irradiated in a microwave at 140°C for 10 minutes, at which point LC/MS analysis indicated that the reaction was complete. Guanidine carbonate (217 mg, 1.79 mmol) was added and the reaction was irradiated in the microwave at 150°C for 15 minutes. The mixture was cooled and purified directly by RP HPLC (15 to 95% ACN in DI water containing 0.1% TFA: 15 minute gradient). The pure fractions were pooled and concentrated to afford the product as a light yellow solid. Yield: 53 mg, 48%, 2 steps. ¹ H-NMR (300 MHz, DMSO d6) δ 12.21 (s, 1H), 8.87 (s, 1H), 7.71 (bs, 2H), 7.54-7.45 (m, 2H), 7.34-7.29 (m, 1H), 7.22 (d, 2H, J=7.8 Hz), 6.18 (s, 1H), 5.34 (m, 1H), 3.35 (m, 1H), 2.83 (m, 1H), 1.54 (d, 3H, J=6.3 Hz). LC/MS [M+H], 309.0. Example 4. Preparation of 5,7-Diphenox -24- uinazolinediamine

2,4,6-trifluorobenzonitrile (100 mg, 64 mmol), phenol (120 mg, 1.2 mmol) and potassium carbonate (87 mg, 64 mmol) were irradiated in the microwave in NMP (3 mL) at 120°C for 10 minutes at which point LCMS indicated that the reaction was complete. Guanidine carbonate (231 mg, 1.91 mmol) was added and the reaction irradiated in the microwave at 150°C for 15 minutes. The mixture was cooled and purified directly by reversed phase HPLC (15 to 95% ACN in DI water containing 0.1% TFA: 15 minute gradient). The pure fractions were pooled and concentrated to afford the product as an off white solid.135 mg, 61% yield, 2 steps. ¹ H-NMR (300 MHz, DMSO d6) δ 12.68 (s, 1H), 8.93 (s, 1H), 8.40 (bs, 2H), 7.54-7.43 (m, 6H), 7.37-7.28 (m, 2H), 7.15 (d, 2H, J=7.2 Hz), 6.42 (s, 1H), 6.01 (s, 1H). LC/MS [M+H] ⁺ 345.4. Example 5. Preparation of 5-(3-(trifluoromethyl)-5-(isoxazol-4-yl)phenoxy)-3,4-dihydro -4-methyl- 2H-pyrano[2,3-f]quinazoline-8,10-diamine

5-(3-bromo-5-(trifluoromethyl)phenoxy)-3,4-dihydro-4-methyl- 2H-pyrano[2,3-f]quinazoline-8,10- diamine (60 mg, 0.13 mmol) and isoxazole-4-boronic acid (22 mg, 0.19 mmol) were dissolved in dioxane (3 mL). Sodium potassium carbonate (53 mg, 0.38 mmol) dissolved in DI water (1 mL) was then added followed by tetrakis(triphenylphosphine)palladium (4 mg, 0.0077 mmol) and the flask was flushed with nitrogen and refluxed under an atmosphere of nitrogen for 1 hour. The reaction mixture was cooled, concentrated and purified by reversed phase HPLC (20-95% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the title compound as a white solid. Yield 46%. Example 6. Preparation of 2,3-dihydro-2-methyl-4-(1H-pyrrolo[2,3-b]pyridin-1-yl)furo[2 ,3- f]quinazoline-7,9-diamine

1H-pyrrolo[2,3-b]pyridine (109 mg, 0.92 mmol), 4,6-difluoro-2-methyl-1-oxa-7-indancarbonitrile (Int-2) (180 mg, 0.92 mmol) and potassium carbonate(127 mg, 0.92 mmol) were stirred in NMP (2 mL) at 100°C for 1 hour. Guanidine carbonate was added and the reaction was stirred at 150°C for 3 hours. The reaction was cooled to RT and purified directly by RP HPLC (10-95% acetonitrile in DI water, 0.1% TFA: 20 min gradient). The pure fractions were pooled and lyophilized to afford the title compound as a white solid. Yield 56%. ¹ H-NMR (300 MHz, MeOD d4) δ 8.32 (d, 1H, J=3.9 Hz), 8.14 (d,1H, J=7.5 Hz), 7.67 (d, 1H, J=2.7 Hz), 7.28 (t, 1H, J=4.8 Hz), 7.09 (s, 1H), 6.79 (d, 1H, J=2.7 Hz), 5.37 (m ,1H), 3.49 (dd, 1H, J=15, 8.7 Hz), 2.98 (dd, 1H, J= 15.3, 7.5 Hz), 1.60 (d, 3H, J=6 Hz). LC/MS[M+H]+ = 333.2. Example 7. Preparation of 4-(6-(trifluoromethyl)pyridin-2-yloxy)-2,3-dihydro-2-methylf uro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described in Example 2. ¹ H-NMR (300 MHz, DMSO d6) δ 12.38 (s, 1H), 8.99 (s, 1H), 8.27 (t, 1H, J=7.5 Hz), 7.79 (m, 3H), 7.55 (d, 1H, J=8.4 Hz), 6.65 (s, 1H), 5.32 (m, 1H, J=6.9 Hz), 3.20 (dd, 1H, J=15.6, 9.3 Hz), 2.61 (dd, 1H, J=15.6, 7.2 Hz),1.47 (d, 3H, J=6.3 Hz). LC/MS [M+H] ⁺ 378.2. Example 8. Preparation of (2,4-Diamino-5-phenoxy-7-quinazolinyl)phenylmethanol and (2,4- diamino-5-phenoxyquinazolin-7- l hen l methanone

Step a). Preparation of 2,6-Difluoro-4-(hydroxyphenylmethyl)benzonitrile

2,6-Difluoro-4-formylbenzonitrile (1.3g, 7.78 mmol) was dissolved in THF (20 mL) and cooled to 0°C, under nitrogen. Phenyl magnesium chloride (3.9 mL, 7.8 mmol, 2 M in THF) was added, slowly via syringe and the mixture was stirred for 10 minutes then quenched with 1N aqueous HCl (75 mL). The aqueous phase was extracted into ethyl acetate (3x30 mL). The combined organics were dried over sodium sulfate, concentrated and purified by silica gel chromatography (ethyl acetate/hexanes) to afford 2,6-difluoro-4-(hydroxyphenylmethyl)benzonitrile. Yield 73%. ¹ H-NMR (300 MHz, CDCl3) δ 7.43-7.28 (m, 5H), 7.15 (d, 2H, J=8.4 Hz), 5.83 (d, 1H, J=3 Hz). LC/MS [M+H] ⁺ 246.2. Step b). Preparation of (2,4-Diamino-5-phenoxy-7-quinazolinyl)phenylmethanol and (2,4- diamino-5-phenoxyquinazolin-7-yl)(phenyl)methanone

Phenol (200 mg, 0.82 mmol) was added to a stirring mixture of 2,6-difluoro-4- (hydroxyphenylmethyl)benzonitrile (92 mg, 0.97 mmol) and potassium carbonate (112 mg, 0.82 mmol) in NMP (3 mL) and the mixture stirred at 80°C for 2 hours at which point guanidine carbonate (303 mg, 2.44 mmol) was added and the mixture was stirred at 150°C for 30 minutes. The reaction was cooled to ambient temperature and purified by RP HPLC (20-95% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient) to afford a mixture (~1/1) of the title compounds. Yield 27%. LC/MS [M+H] ⁺ (a) 359.2 and (b) 357.2. Example 9. Preparation of 3,4-dihydro-4-methyl-5-phenoxy-2H-pyrano[2,3-f]quinazoline-8 ,10- diamine

Step a). Preparation of 2-[(E)-2-Butenyloxy]-4,6-difluorobenzonitrile

The title compound was prepared by a method similar to that described for Int-1 step a. LC/MS [M+H] ⁺ 210.0. Step b). 4,6-Difluoro-2-hydroxy-3-(1-methyl-2-propenyl)benzonitrile

The title compound was prepared by a method similar to that described for Int-3. LC/MS [M+H]+ 210.0. Step c). 5,7-Difluoro-4-methyl-8-chromancarbonitrile

The title compound was prepared by a method similar to that described for Int-4 but utilizing 4,6- Difluoro-2-hydroxy-3-(1-methyl-2-propenyl)benzonitrile as the starting material. ¹ H-NMR (300 MHz, CDCl3) δ 6.48 (t, 1H J = 9.3 Hz), 4.54-4.46 (m, 1H) 4.31 (dt, 1H J = 12, 2.4 Hz), 3.17 (t, 1H, J = 5.7 Hz), 2.17-2.05 (m, 1H), 1.83-1.73 (m, 1H), 1.33 (d, 3H, J=7.2 Hz). LC/MS [M+H] ⁺ 210.0. Step d). Preparation of 8-methyl-9-phenoxy-5-oxa-1,3-diaza-7,8-dihydro-6H-phenanthre ne-2,4- diamine

The title compound was prepared by a method similar to that described for Example 3 except utilizing 5,7-Difluoro-4-methyl-8-chromancarbonitrile as the starting material. ¹ H-NMR (300 MHz, DMSO) δ 12.05 (s, 1H), 8.73 (s,1H), 8.45 (s, 1H), 7.55-7.33 (m, 4H), 7.35 (t, 1H, J = 7.4 Hz), 7.19 (d, 2H, J = 7.5 Hz), 6.15 (s, 1H), 4.62 (d, 1H J = 10.5 Hz), 4.33 (t, 1H J = 11.1 Hz), 3.22 (t, 1H, J = 6.6 Hz), 2.09-2.01 (m, 1H),1.85 (d, 1H, J = 13.8 Hz), 1.35 (s, 3H), 1.33 (s, 3H). LC/MS [M+H] ⁺ 323.2. Example 10. Preparation of methyl 1-(3-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin- 4- yloxy)phenyl)cyclopropanecarboxylate

The title compound was prepared by a method similar to that described for Example 3. ¹ H-NMR (300 MHz, MeOD) δ 7.47(t,1H, J=7.8 Hz), 7.31 (d, 1H, J=7.5 Hz), 7.18 (d, 1H, J=1.5 Hz), 7.10 (dd, 1H, J=8.1, 1.5 Hz), 6.14 (s, 1H), 5.06 (t, 1H, J=9.3 Hz), 4.59 (dd, 1H, J=9, 5.4 Hz), 3.84 (m, 1H), 3.65 (s, 3H),1.62 (d, 2H, J=3 Hz), 1.45 (d, 3H, J=6.6 Hz), 1.27 (d, 2H, J=3.6 Hz). LC/MS [M+H]+ 407.2. Example 11. Preparation of 1-(3-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin- 4- yloxy)phenyl)cyclopropanecarboxylic acid

Methyl 1-(3-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin- 4- yloxy)phenyl)cyclopropanecarboxylate (Example 10) was stirred in a 1/1/2 mixture of THF/MeOH/1N NaOH aqueous (3 mL) at ambient temperature for 1 hour. The mixture was purified directly by reversed phase HPLC (10-95% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the desired product as a white solid. LC/MS [M+H] ⁺ 393.4 Example 12. Preparation of 4-(3-(trifluoromethyl)-5-(pyridin-3-yl)phenoxy)-2,3-dihydro- 3- methylfuro[2,3-f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 5. ¹ H-NMR (300 MHz, MeOD) δ 8.90(d, 1H, J = 1.8 Hz),8.63 (d, 1H, J=4.8 Hz), 8.42 (s, 1H), 8.22 (d, 1H, J = 7.8 Hz), 7.95 (s, 1H), 7.83 (s, 1H), 7.59 (s, 1H), 6.26 (s, 1H), 5.09 (t, 1H, J = 9.1 Hz), 3.85 (m, 1H), 3.82 (m, 1H), 1.49 (d, 3H, J=6.9). LC/MS [M+H] ⁺ 454.2. Example 13. Preparation of 4-(3-(trifluoromethyl)-5-(pyridin-3-yl-N-oxide)phenoxy)-2,3- dihydro-3- methylfuro[2,3-f]quinazoline-7,9-diamine

mCPBA (18 mg, 0.072 mmol) was added to a stirring solution of 4-(3-(trifluoromethyl)-5-(pyridin- 3-yl)phenoxy)-2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9 -diamine (Example 12) (30 mg, 0.066 mmol) in DCM (3 mL) for 30 minutes. The mixture was concentrated and purified by reversed phase HPLC (20- 95% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a light yellow solid. Yield 35%. ¹ H-NMR (300 MHz, MeOD d4) δ 8.72 (s, 1H),8.43 (d, 1H, J=6.3 Hz), 7.99-7.97 (m, 2H), 7.85 (s, 1H), 7.69-7.66 (m, 2H), 6.28 (s, 1H), 5.10 (t, 1H, J = 19 Hz), 4.60 (dd, 1H, J=8.7, 5.7 Hz), 3.84 (m, 1H), 1.47 (d, 3H, J=6.9).LC/MS [M+H]+ 470.2 Example 14. Preparation of 4-(3-((azetidin-1-yl)methyl)-5-bromophenoxy)-2,3-dihydro-3- methylfuro[2,3-f]quinazoline-7,9-diamine

Step a). Preparation of 3-[(1-Azetidinyl)methyl]-5-bromophenol

Sodium triacetoxy borohydride (1.6 g, 7.5 mmol) was added to a stirring mixture of 3-bromo-5- hydroxy benzaldehyde (1 g, 5 mmol) and azetidine hydrochloride (0.58 g, 9.9 mmol) in ethanol 30 mL) at ambient temperature for 12 hours. The mixture was diluted with DI water, concentrated and purified by reversed phase HPLC (5-95% acetonitrile in DI water containing 0.1% formic acid: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a clear viscous oil. Yield 78 %. ¹ H- NMR (300 MHz, MeOD d4) δ 8.55 (s, 1H), 7.10, s, 1H), 7.03 (s, 1H), 6.88 (s, 1H), 4.24 (s, 2H), 4.12 (t, 4H, J=8.1 Hz), 2.54 (m, 2H, J=8.1 Hz). Step b). 4-(3-((azetidin-1-yl)methyl)-5-bromophenoxy)-2,3-dihydro-3-m ethylfuro[2,3-f]quinazoline- 7,9-diamine

The title compound was prepared by a method similar to that described for Example 3. ¹ H-NMR (300 MHz, MeOD d4) δ 7.61 (s, 1H), 7.52 (s, 1H), 7.32 (s, 1H), 6.26 (s, 1H), 5.07 (t, 1H, J=9 Hz), 4.59 (dd, 1H, J=9, 5.4 Hz), 4.40 (s, 2H), 4.21-4.15 (m, 4H), 3.78 (m, 1H), 2.57-2.51 (m, 2H), 1.43 (d, 3H, J=6.9 Hz). LC/MS [M+H]+ 456.0. Example 15. Preparation of 4-(3-bromo-5-(trifluoromethyl)phenoxy)-2,3-dihydro-2-methylf uro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 3. ¹ H-NMR (300 MHz, MeOD d4) δ 7.81 (s, 1H), 7.70 (s, 1H), 7.53 (s, 1H), 6.26 (s, 1H), 5.42 (m, 1H, J=6.9 Hz), 3.43 (dd, 1H, J=15.6, 9.3 Hz), 2.91 (dd, 1H, 15.6, 7.2 Hz), 1.62 (d, 3H, J= 6.3 Hz).LC/MS [M+H] ⁺ 455.0. Example 16. Preparation of 5-Cyclobutox -7- henox -24- uinazolinediamine

Step a). Preparation of 2-Cyclobutoxy-4,6-difluorobenzonitrile

The title compound was prepared by a method similar to that described in Int-1 step a). ¹ H-NMR (300 MHz, MeOD d4) δ 6.51 (t, 1H, J=9 Hz), 6.37 (1H, J=10.2 Hz), 4.67 (m, 1H, J=6.9 Hz), 2.51-2.46 (m, 2H), 2.31-2.25 (m, 2H), 1.99-1.89 (m, 1H), 1.82-1.66 (m, 1H). LC/MS [M+H] ⁺ 210.0. Step b). Preparation of 5-Cycl x -7- h n x -24- in zolinediamine

The title compound was prepared by a method similar to that described for Example 50, where cyclobutanol was substituted for methanol in step a, and phenol was substituted for 2-hydroxy-6- trifluoromethylpyridine in step b. ¹ H-NMR (300 MHz, MeOD d4) δ 7.53-7.47 (m, 2H), 7.33 (t, 1H, J=7.5 H), 7.18 (d, 2H, J=7.5 Hz), 6.32 (d, 1H, J=2.4 Hz), 6.16 (d, 1H, J=2.1 Hz), 5.48 (m, 1H, J=5.7 Hz), 5.03 (t, 2H,J=7.2 Hz), 4.91-4.83 (m, 2H). LC/MS [M+H] ⁺ 325.2. Example 17. Preparation of 7-(5-Br m -2- hl r h n x - - lobutoxy-2,4-quinazolinediamine

The title compound was prepared by a method similar to that described in Example 16. ¹ H-NMR (300 MHz, MeOD d4) δ 7.55 (bs, 3H), 6.48 (d,1H, J=2.4 Hz),6.27(d,1H, J=2.1 Hz), 4.97 (m, 1H, J=7.2 Hz), 2.61-2.51 (m, 2H), 2.40-2.27 (m, 2H), 2.02-1.92 (m, 1H), 1.89-1.77 (m, 1H). LC/MS [M+H] ⁺ 435.0 Example 18. Preparation of (7,9-diamino-4-bromo-2,3-dihydrofuro[2,3-f]quinazolin-2-yl)m ethanol

Step a). Preparation of 4-bromo-6-fluoro-2,3-dihydro-2-(hydroxymethyl)benzofuran-7-c arbonitrile

mCPBA (7.7 g, 31.4 mmol) was dissolved in DCM (30 mL) and sodium sulfate (~2g) was added and the mixture was allowed to stand for 1 hour. The solution was filtered to remove sodium sulfate and 3-allyl-4-bromo-6-fluoro-2-hydroxybenzonitrile (2.7 g, 10.5 mmol, Int-3) was added. The reaction was stirred at ambient temperature for 2 hours at which point saturated aqueous sodium carbonate was added and the mixture was extracted into DCM (3 x 25 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexanes/ether) to afford the product as a white solid. ¹ H-NMR (300 MHz, CDCl3) δ 6.89(d, 1H, J=9 Hz), 5.23 (m, 1H), 4.05 (dd, 1H, J=12.6, 3 Hz), 3.84 (dd, 1H, J=12.6, 4.8 Hz), 3.30 (dt, 2H, J=16.2, 9.3 Hz). LC/MS [M+H] ⁺ 272.0. Step b). Preparation of (7,9-diamin -4- r m -2 - ih rofuro[2,3-f]quinazolin-2-yl)methanol

4-bromo-6-fluoro-2,3-dihydro-2-(hydroxymethyl)benzofuran-7-c arbonitrile (425 mg, 1.56 mmol) and guanidine carbonate(284 mg, 2.34 mmol) were stirred together in NMP (3 mL) at 150°C for 1 hour. The reaction was cooled and purified by reversed phase HPLC (5-95% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a light pink colored solid. ¹ H-NMR (300 MHz, MeOD d4) δ 7.04 (s, 1H), 5.32 (m, 1H), 3.97 (dd, 1H, 12.6, 2.7 Hz), 3.83 (dd, 1H, J=12.6, 5.7 Hz), 3.42-3.10 (m, 1H), 3.16 (dd, 1H, J=15.9, 9.9 Hz). LC/MS [M+H] ⁺ 311.0 Example 19. Preparation of (7,9-diamino-2,3-dihydro-4-(1-methylnaphthalen-4-yl)furo[2,3 - f]quinazolin-2-yl)methanol

The title compound was prepared starting with the compound from (7,9-diamino-4-bromo-2,3- dihydrofuro[2,3-f]quinazolin-2-yl)methanol (Example 18) by a method similar to that described for Example 65. ¹ H-NMR (300 MHz, MeOD) δ 8.17 (d, 1H, J=8.4 Hz), 7.67-7.43 (m, 4H), 7.34 (m, 1H), 6.85 (s, 1H),5.20 (m, 1H), 3.87-3.83 (m, 1H), 3,76-3,71 (m, 1H), 3.05-2.94 (m, 1H), 2.85-2.69 (m, 1H), 2.77 (s, 3H). LC/MS [M+H] ⁺ 373.2 Example 20. Preparation of 4-(3-chlorophenoxy)-2,3-dihydro-2-methylfuro[2,3-f]quinazoli ne-7,9- diamine

Cl

The title compound was prepared by a method similar to that described for Example 3. ¹ H-NMR (300 MHz, DMSO d6) δ 12.21 (s, 1H), 8.91 (s, 1H), 7.91 (bs, 2H), 7.55 (t, 1H, J=8.1 Hz), 7.38-7.30 (m, 2H), 7.20 (dd, 1H, J=8.4, 1.8 Hz), 6.24 (s, 1H), 5.36 (m, 1H), 3.35 (m, 1H), 2.80 (m, 1H), 1.53 (d, 3H, J=6 Hz). LC/MS [M+H] ⁺ 343.0. Example 21. Preparation of (p-{11,13-Diamino-4-methyl-3-oxa-10.12-diazatricyclo[7.4.0.0 ^2,6 ]trideca- 1(9),2(6),7,10,12-pentaen-7-ylox hen l methanol

The title compound was prepared by a method similar to that described for Example 3. ¹ H-NMR (300 MHz, DMSO d6) δ 12.22 (s, 1H), 8.86 (s, 1H), 7.79 (bs, 2H), 7.45 (d, 2H, J=8.7 Hz), 7.17 (d, 2H, J=8.7 Hz), 6.15 (s, 1H), 5.36 (m, 1H), 4.49 (s, 2H) 3.39 (m, 1H), 2.83 (m, 1H), 1.54 (d, 3H, J=6.4 Hz). LC/MS [M+H] ⁺ 339.2. Example 22. Preparation of 4-(5-(trifluoromethyl)pyridin-2-yloxy)-2,3-dihydro-2-methylf uro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 3. ¹ H-NMR (300 MHz, DMSO d6) δ 12.60(s, 1H), 9.15 (s, 1H), 8.34 (s, 1H), 8.08 (bs, 2H), 7.85 (dd, 1H, J=9.6, 2.7 Hz), 6.94 (s, 1H), 6.72 (d, 1H, J=9.9 Hz), 6.22 (s, 1H), 5.35 (m, 1H), 3.33 (m, 1H), 2.78 (m, 1H), 1.52 (d, 3H, J=6.3 Hz). LC/MS [M+H] ⁺ 378.2. Example 23. Preparation of 2,3-dihydro-2,2-dimethyl-4-(phenylthio)furo[2,3-f]quinazolin e-7,9- diamine

The title compound was prepared by a method similar to that described for Example 3 but utilizing Int-1 as the starting material. ¹ H-NMR (300 MHz, DMSO d6) ^ ^12.33 (s, 1H), 9.91 (s, 1H), 7.83 (bs, 2H), 7.58-7.55 (m, 5H), 6.22 (s, 1H), 2.96 (s, 2H), 1.56 (s, 6H). LC/MS [M+H] ⁺ 339.0. Example 24. Preparation of 2,3-dih r -22- im h l-4- h n x furo[2,3-f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 3 but utilizing Int-1 as the starting material. ¹ H-NMR (300 MHz, DMSO d6) δ 12.36 (s, 1H), 8.87 (s, 1H), 7.84 (bs, 2H), 7.53-7.46 (m, 2H), 7.34 (t, 1H, J=9.9 Hz), 7.22 (d, 2H, J=9 Hz), 6.18 (s, 1H), 3.01 (s, 2H), 1.57 (s, 6H). LC/MS [M+H] ⁺ 324.2. Example 25. Preparation of 5,7-bis( h n l hi in z lin -24-diamine

The title compound was prepared by a method similar to that described in Example 4. ¹ H-NMR (300 MHz, DMSO d6) δ 12.76 (s, 1H), 8.74 (s, 1H), 7.94 (bs, 2H), 7.53-7.47 (m, 6H), 7.41-7.37 (m, 2H), 7.31-7.28 (m, 2H), 6.98 (s, 1H), 6.95 (s, 1H). LC/MS [M+H] ⁺ 377.2. Example 26. Preparation of 1-(2,4-diamino-5-(phenylthio)quinazolin-7-yl)-2-methyl-1- phenylpropan-1-ol

Step a. Preparation of (2,4-diamino-5-(phenylthio)quinazolin-7-yl)(phenyl)methanone

Thiophenol (89 mg, 0.82 mmol) was added to a stirring mixture of 2,6-difluoro-4- (hydroxyphenylmethyl)benzonitrile (200 mg, 0.82 mmol, Example 8, step a) and potassium carbonate (112 mg, 0.82 mmol) in NMP (3 mL) and the mixture stirred at ambient temperature for 2 hours at which point guanidine carbonate was added and the mixture was stirred at 150°C for 30 minutes. The reaction was cooled to ambient temperature and purified by RP HPLC (20-95% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient) to afford the product as a light yellow solid. Yield 79mg, 26%. LC/MS [M+H]+ 373.2 Step b. Preparation of 1-(2,4-diamino-5-(phenylthio)quinazolin-7-yl)-2-methyl-1-phe nylpropan-1- ol

[2,4-Diamino-5-(phenylthio)-7-quinazolinyl]phenylformaldehyd e (40 mg, 0.11 mmol) was dissolved in THF (1.5 mL) and isopropyl magnesium chloride (0.27 mL, 0.54 mmol, 2M in diethyl ether) was added and the mixture was stirred for 15 minutes. Methanol (1 mL) was added and the mixture was applied directly to reversed phase HPLC (20-90% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a white solid. ¹ H-NMR (300 MHz, DMSO d6) δ 12.68 (s, 1H), 9.11 (s, 1H), 8.99 (s, 1H), 7.71 (s, 1H), 7.49 (d, 2H, J=7.8 Hz), 7.35-7.27 (m, 6H), 7.21-7.14 (m, 3H), 6.75 (s, 1H), 5.68 (s, 1H), 2.88 (m, 1H), 0.82 (dd, 6H, J=13.5, 6.3 Hz). LC/MS [M+H] ⁺ 417.2. Example 27. Preparation of 1-(2,4-diamino-5-phenoxyquinazolin-7-yl)-2-methyl-1-phenylpr opan-1- ol

(2,4-Diamino-5-phenoxy-7-quinazolinyl)phenylformaldehyde (Compound b from Example 8) (19 mg, 0.053 mmol) was dissolved in THF (1.5 mL) and isopropyl magnesium chloride (0.13 mL, 0.27 mmol, 2M in diethylether) was added and the mixture was stirred for 15 minutes. Methanol (1 mL) was added and the mixture was applied directly to reversed phase HPLC (20 - 90% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a white solid. Yield 79%. ¹ H-NMR (300 MHz, DMSO d6) δ 12.35 (s, 1H), 8.93 (s, 1H), 8.33 (s, 1H), 7.81 (s, 1H), 7.53 (t, 2H, J=6.9 Hz), 7.39 (t, 2H, J=7.8Hz), 7.29-7.19 (m, 4H), 7.53 (d, 2H, J=7.8 Hz), 6.75 (s, 1H), 5.45 (s, 1H), 2.69 (m, 1H), 0.77 (dd, 6H, J=13.5, 5.7 Hz). LC/MS [M+H] ⁺ 401.2. Example 28. Preparation of 1-(2,4-diamino-5-methoxyquinazolin-7-yl)-1-phenylethanol

Step a). Preparation of 4-Benzoyl-2,6-difluorobenzonitrile

Dess-Martin periodinane (2.3 g, 5.5 mmol) was added to a stirring solution of 2,6-difluoro-4- (hydroxyphenylmethyl)benzonitrile (0.90g, 3.76 mmol, described in step a of example 8) in DCM (25 mL) and the mixture was stirred at ambient temperature for 2 hours. Aqueous saturated sodium hydrogen carbonate (30 mL) was added and the mixture was stirred vigorously for 30 minutes then filtered through celite. The celite was rinsed with additional DCM (2 x 10 mL) and then the combined washings were washed with brine, dried over sodium sulfate and concentrated to afford the 4-benzoyl-2,6- difluorobenzonitrile as a waxy white solid. Yield 95%. LC/MS [M+H] ⁺ 244.0. Step b). Preparation of 4-Benzoyl- - - - ile

Sodium methoxide (7 mL, 3.49 mmol) was added to a stirring mixture of 4-benzoyl-2,6- difluorobenzonitrile in THF(15 mL) cooled to 0°C. The mixture was stirred for 3 hours at which point the reaction was complete as judged by LC/MS analysis. Aqueous 1N HCl (30 mL) was added to the reaction mixture and it was stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (3x, 25 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The crude residue was purified by silica gel chromatography (hexanes/ethyl acetate) to afford the product as a viscous clear oil. Yield 84%. LC/MS [M+H] ⁺ 256.0 Step c). Preparation of 2-fluoro-4-(1-hydroxy-1-phenylethyl)-6-methoxybenzonitrile

Methylmagnesium chloride(1.01 mL,3.02 mmol, 3M in THF) was added, dropwise to a cooled (0°C), stirring solution of 4-benzoyl-2-fluoro-6-anisonitrile (0.7 g, 2.74 mmol) in THF (30 mL) and the reaction was stirred at 0°C for 30 minutes. Aqueous 1N HCl (70 mL) was added to the reaction mixture and it was stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (3x, 35 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The crude was purified by silica gel chromatography (hexanes/ethyl acetate) to afford 2-Fluoro-4-(1-hydroxy-1-phenylethyl)-6- anisonitrile as a white solid. Yield 65%. LC/MS [M+H] ⁺ 272.4. Step d). Preparation of 1-(2,4-diamino-5-methoxyquinazolin-7-yl)-1-phenylethanol

2-Fluoro-4-(1-hydroxy-1-phenylethyl)-6-anisonitrile (25 mg, 0.092 mmol) and guanidine carbonate (12 mg, 0.13 mmol) were stirred in NMP (5 mL) at 150°C for 4 hours. The mixture was cooled to ambient temperature and purified by reversed phase HPLC (10-95% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a white solid. Yield 15mg, 52%. ¹ H-NMR (300 MHz, MeOD d4) δ 7.52(d, 2H, J = 8.7 Hz), 7.34 (t, 2H, J = 7.2 Hz), 7.28- 7.22 (m, 1H), 7.06 (s, 1H), 7.04 (s, 1H), 4.02 (s, 3H), 1.97 (s, 3H).LC/MS [M+H] ⁺ 311.2 Example 29. Preparation of 3,4-dihydro-5-phenoxy-2H-pyrano[2,3-f]quinazoline-8,10-diami ne

The title compound was prepared by a method similar to that described for Example 9. LC/MS [M+H] ⁺ =309.2 Example 30. Preparation of 4-Cyclopropyl-7-phenoxy-3-oxa-10.12-diazatricyclo[7.4.0.0 ^2,6 ]trideca- 1,6,8,10,12-pentaene-11,13-diamine

Step a). Preparation of 3-allyl-4,6-difluoro-2-dimethyl-tert-butylsilyloxybenzonitri le

3-Allyl-4,6-difluoro-2-hydroxybenzonitrile (600 mg, 3.07 mmol) was dissolved in THF (20 mL). Imidazole (230 mg, 3.38 mmol) followed by TBS chloride (275 mg, 3.38 mmol) were added and the reaction was stirred for 1 hour. DI water (100 mL) was added and the mixture was extracted into ethyl acetate (3x, 25 mL). The combined organic extracts were dried over sodium sulfate, concentrated and purified by silica gel chromatography (ethyl acetate/hexanes) to afford the product as a clear viscous oil. Yield 87%. LC/MS [M+H]+ 310.2. Step b). Preparation of 3-(2-Cyclopropyl-2-hydroxyethyl)-4,6-difluoro-2-dimethyl-ter t- butylsilyloxybenzonitrile

3-allyl-4,6-difluoro-2-dimethyl-tert-butylsilyloxybenzonitri le (280 mg, 0.90 mmol) was taken up in a 1/1 mixture of DCM/methanol (20 mL) and cooled to -78C. Ozone was bubbled through the cooled, stirring solution for 1 hour at which point LC/MS analysis showed complete conversion of starting material. Dimethyl sulfide (1.5 mL) was added to the stirring reaction and the cooling bath removed. The reaction was stirred for 1 hour while warming to ambient temperature, LC/MS analysis showed conversion to the aldehyde was complete; [M+H]+ 312.0. The solvent was removed on the rotovap and the crude aldehyde product was dried under high vacuum then dissolved in THF and cooled to 0C.

Cyclopropylmagnesium chloride (2 mL, 2 mmol, 1M in THF) was added dropwise to the cooled, stirring solution and then stirred for an additional 30 minutes. The mixture was quenched with aqueous 1N HCl, extracted into ethyl acetate, dried over sodium sulfate and concentrated to afford 3-(2-Cyclopropyl-2- hydroxyethyl)-4,6-difluoro-2-dimethyl-tert-butylsilyloxybenz onitrile as a clear oil . Yield 65%, 3 steps. LC/MS [M+H]+ 353.2. Step c). Preparation of 3-(2-Cyclopropyl-2-hydroxyethyl)-4,6-difluoro-2-dimethyl-ter t- butylsilyloxybenzonitrile

3-(2-Cyclopropyl-2-hydroxyethyl)-4,6-difluoro-2-dimethyl-ter t-butylsilyloxybenzonitrile (200 mg, 0.57 mmol) was taken up in THF (15 mL) and treated with TBAF (2 mL, 2 mmol, 1M in THF). Upon removal of the silyl protecting group, as judged by LC/MS, the mixture was diluted with DI water (50 mL) and extracted into ethyl acetate, dried over sodium sulfate and concentrated. The crude product was taken up in THF and triphenyl phosphine (148 mg, 0.57 mmol) followed by DIAD (114 mg, 0.57 mmol) were added and the reaction was stirred for 30 minutes at ambient temperature. The mixture was concentrated and purified by silica gel chromatography (hexanes/ethyl acetate) to afford 3-(2- Cyclopropyl-2-hydroxyethyl)-4,6-difluoro-2-dimethyl-tert-but ylsilyloxybenzonitrile as a clear oil. Yield 95%. LC/MS [M+H] ⁺ 222.0. Step d). Preparation of 2-cyclopropyl-2,3-dihydro-4-phenoxyfuro[2,3-f]quinazoline-7, 9-diamine

The title compound was prepared by a method similar to that described for Example 3, where int- 6 was used as the starting material.1H-NMR (300 MHz, MeOD) δ 7.53-7.47 (m, 2H), 7.32 (t,1H, J = 7.5 Hz), 7.17 (d, 2H, J = 7.8 Hz), 6.15 (s, 1H), 4.69 (m, 1H J = 8.4 Hz), 3.42 (m, 1H, J = 9.6 Hz), 3.10 (m, 1H, J = 7.8 Hz), 1.35 (m, 1H), 0.75-0.72 (m, 2H), 0.67 (m, 1H), 0.63 (m, 1H). LC/MS [M+H] ⁺ 335.2. Example 31. Preparation of 2,3-dih dro-4- henox -2-vin lfuro 2,3-f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 3, where Int- 8 was used as the starting material. ¹ H-NMR (300 MHz, MeOD) δ 8.55 (s, 1H),7.48 (t, 2H, J=7.5 Hz), 7.29 (t,1H, J = 7.2 Hz), 7.17 (d, 2H, J = 7.8 Hz), 6.19 (m, 1H, J=6.6 Hz), 6.15 (s, 1H), 5.62 (q, 1H, J=7.8 Hz), 5.51 (d, 1H, J=17.4 Hz), 5.36 (d, 1H, J=10.2 Hz), 3.45 (dd, 1H, J = 15.6, 6 Hz), 3.07 (m, 1H, J = 15.6, 7.5 Hz). LC/MS [M+H] ⁺ 321.2. Example 32. Preparation of 5-(3-bromo-5-(trifluoromethyl)phenoxy)-3,4-dihydro-4-methyl- 2H- pyrano[2,3-f]quinazoline-8,10-diamine

The title compound was prepared by a method similar to that described in Example 9. LC/MS [M+H] ⁺ 469.0. Example 33. Preparation of 4-(3-bromo-5-(trifluoromethyl)phenoxy)-2,3-dihydro-3-methylf uro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described Example 3. ¹ H-NMR (300 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.93 (s,1H), 7.93 (s, 1H), 7.84 (s, 2H), 7.74 (s, 1H), 7.69 (s, 1H), 6.27 (s, 1H), 5.03 (m, 1H), 4.52 (m, 1H), 3.72 (m, 1H), 1.33 (d, 3H, J=6.6 Hz). LC/MS [M+H] ⁺ 455.0. Example 34. Preparation of 4-(3-(trifluoromethyl)-5-(isoxazol-4-yl)phenoxy)-2,3-dihydro -3- methylfuro[2,3-f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 5. ¹ H-NMR (300 MHz, MeOD) δ 8.18 (s,1H), 7.97 (s, 1H), 7.77 (s, 2H), 7.37 (s, 1H), 6.19 (s, 1H), 5.08 (t, 1H, J=9 Hz), 4.61 (dd, 1H, J=9, 5.7 Hz), 3.82 (m, 1H), 1.47 (d, 3H, J=6.9 Hz). LC/MS [M+H] ⁺ 444.0. Example 35. Preparation of (4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yloxy)phenyl)methanol

The title compound was prepared by a method similar to that described for Example 2, using int- 10 as the starting material. ¹ H-NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.22 (s,1H), 7.39 (d, 2H, J=8.1 Hz), 7.09 (d, 2H, J=8.4 Hz), 6.43 (s, 2H), 5.96 (s, 1H), 4.91 (t, 1H, J=9 Hz), 4.509 (s, 2H), 4.41 (dd, 1H, J=9, 5.7 Hz), 3.61 (m, 1H), 1.30 (d, 3H, J=6.6 Hz). LC/MS [M+H] ⁺ 339.4. Example 36. Preparation of 4-(3-((azetidin-1-yl)methyl)-5-(isoxazol-4-yl)phenoxy)-2,3-d ihydro-3- methylfuro[2,3-f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 5 but using the product of Example 14 as the starting material. LC/MS [M+H] ⁺ 445.2 Example 37. Preparation of 4-(3-(trifluoromethyl)-5-(isoxazol-4-yl)phenoxy)-2,3-dihydro -2- methylfuro[2,3-f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 5 but using the product of Example 15 as the starting material. LC/MS [M+H]+ 444.0 Example 38. Preparation of 4-(5-bromo-2-chlorophenoxy)-2,3-dihydro-2-methylfuro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 3. ¹ H-NMR (300 MHz, MeOD d4) δ 7.52 (bs, 3H), 6.08 (s,1H),5.41(m,1H, J=6.9 Hz), 3.49-3.33 (dd, 1H, J=15.6, 9.3 Hz), 2.94-2.86 (dd, 1H, J=15.6, 7.2 Hz), 1.62 (d, 3H, J=6 Hz). LC/MS [M+H] ⁺ 421.0. Example 39. Preparation of 2-methyl-4-{[5-(trifluoromethyl)[1,1'-biphenyl]-3-yl]oxy}-2, 3- dihydrofuro[2,3-f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 3. ¹ H-NMR (300 MHz, MeOD d4) δ 7.83 (s, 1H), 7.70-7.67 (m, 2H), 7.53-7.44 (m, 5H), 6.25 (s, 1H), 5.41 (m, 1H, J=6.9 Hz), 3.48 (dd, 1H, J=9.3, 6.9 Hz), 2.93 (dd, 1H, J=15.3, 7.2 Hz), 1.61 (d, 3H, J=6.3 Hz). LC/MS [M+H] ⁺ 453.0. Example 40. Preparation of 4-[(4-chloro[1,1'-biphenyl]-3-yl)oxy]-2-methyl-2,3-dihydrofu ro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described for Example 3. ¹ H-NMR (300 MHz, MeOD d4) δ 7.67-7.62 (m, 5H), 7.50-7.40 (m, 3H), 6.08 (s, 1H), 5.417 (m, 1H, J=7.2 Hz), 3.57 (dd, 1H, J=15.6, 9.3 Hz), 3.02 (dd, 1H, J=15.6, 9.3 Hz), 1.64 (d, 3H, J=6.3 Hz). LC/MS [M+H] ⁺ 419.2 Example 41. Preparation of 5-(oxetan-3- lox -7- henox uinazoline-2,4-diamine

The title compound was prepared by a method similar to that described for Example 16 employing Int-14 as the starting material. ¹ H-NMR (300 MHz, MeOD d4) δ 7.53-7.47 (m, 2H), 7.33 (t, 1H, J=7.5 H), 7.18 (d, 2H, J=7.5 Hz), 6.32 (d, 1H, J=2.4 Hz), 6.16 (d, 1H, J=2.1 Hz), 5.48 (m, 1H, J=5.7 Hz), 5.03 (t, 2H,J=7.2 Hz), 4.91-4.83 (m, 2H). LC/MS [M+H] ⁺ 325.2. Example 42. Preparation of 7-(3-bromo-5-(trifluoromethyl)phenoxy)-5-(oxetan-3-yloxy)qui nazoline- 2,4-diamine

The title compound was prepared by a method similar to that described for Example 16 employing Int-14 as the starting material. ¹ H-NMR (300 MHz, MeOD d4) δ 7.78 (s, 1H), 7.68 (s, 1H), 7.45 (s, 1H), 6.43 (d, 1H, J=2.1 Hz), 6.16 (d, 1H, J=1.8 Hz), 5.53 (m, 1H, J=4.8 Hz), 5.07 (t, 2H,J=6.9 Hz), 4.83-4.79 (m, 2H). LC/MS [M+H] ⁺ 471.0 Example 43. Preparation of 5-[(oxetan-3-yl)oxy]-7-{[5-(trifluoromethyl)[1,1'-biphenyl]- 3- yl]oxy}quinazoline-2,4-diamine

The title compound was prepared by a method similar to that described for Example 16 employing Int-14 as the starting material. ¹ H-NMR (300 MHz, MeOD d4) δ 7.88 (s, 1H), 7.73-7.68 (m, 3H), 7.54-7.45 (m, 4H), 6.44 (d, 1H, J=1.8 Hz), 6.35 (d, 1H, J=2.1 Hz), 5.55 (m, 1H), 5.07 (t, 1H, J=7.2 Hz), 4.88-4.84 (m.1H). LC/MS [M+H] ⁺ 469.2 Example 44. Preparation of 2,3-dihydro-2-methyl-4-(1H-pyrrolo[2,3-c]pyridin-1-yl)furo[2 ,3- f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described in Example 6. ¹ H-NMR (300 MHz, MeOD d4) δ 8.81(s, 1H), 8.28 (d, 1H, J=5.7 Hz), 7.89 (d, 1H, J=3Hz), 7.80 (d, 1H, J=5.7 Hz), 7.06 (s, 1H), 6.92 (d, 1H, J=3.3 Hz), 5.45 (m,1H), 3.48 (dd, 1H, J=15.6, 9 Hz), 2.97 (dd, 1H, J= 15.6, 7.5 Hz), 1.63 (d, 3H, J=6.3 Hz). LC/MS[M+H] ⁺ 333.2. Example 45. Preparation of 2,3-dihydro-2-methyl-4-(1H-pyrrolo[3,2-c]pyridin-1-yl)furo[2 ,3- f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described in Example 6. ¹ H-NMR (300 MHz, MeOD d4) δ 8.98 (s, 1H), 8.33 (d, 1H, J=6.3 Hz), 7.74 (s, 1H), 7.57(d, 1H, J=5.1 Hz), 7.00 (s, 2H), 5.44 (m,1H, J=6.9 Hz), 3.48 (dd, 1H, J=13.8, 6.9 Hz), 2.93 (dd, 1H, J= 15.6, 7.5 Hz), 1.62 (d, 3H, J=6.3 Hz). LC/MS [M+H] ⁺ 333.2. Example 46. Preparation of 2,3-dihydro-2-methyl-4-(1H-pyrrolo[3,2-b]pyridin-1-yl)furo[2 ,3- f]quinazoline-7,9-diamine

The title compound was prepared by a method similar to that described in Example 6. ¹ H-NMR (300 MHz, DMSO d6) δ 8.45 (d, 1H, J=4.2 Hz), 8.24 (s, 1H), 7.97 (d, 1H, J=3.3 Hz), 7.83 (d, 1H, J=8.4 Hz), 7.579bs, 1H), 7.33 (s, 1H), 7.24 (dd, 1H, J=8.1, 4.5 Hz), 6.84 (d, 1H, J=3.3 Hz), 6.74 (s, 1H), 6.38 (s, 1H), 5.25 (m,1H, J=6.3 Hz), 3.30 (m, 1H), 2.81 (dd, 1H, J= 14.7, 7.5 Hz), 1.51 (d, 3H, J=6 Hz). LC/MS [M+H] ⁺ 333.2. Example 47. Preparation of 3,4-dihydro-5-(1-methylnaphthalen-4-yl)-2H-pyrano[2,3-f]quin azoline- 8,10-diamine

The title compound was prepared by a method similar to that described for Example 65 using int- 5 as the starting material. ¹ H-NMR (300 MHz, MeOD d4) δ 8.15 (d, 1H, J=8.4 Hz), 7.59 (m, 1H), 7.44 (m 3H), 7.25 (d, 1H, J=7.2 Hz), 6.85 (s, 1H), 4.44 (m, 2H), 2.76 (s, 3H), 2.41-2.22 (m, 2H), 1.94-1.90 (m, 2H). LC/MS [M+H] ⁺ 357.2 Example 48. Preparation of 5-(benzofuran-3-yl)-3,4-dihydro-2H-pyrano[2,3-f]quinazoline- 8,10- diamine

The title compound was prepared by a method similar to that described for Example 65 using int- 5 as the starting material. ¹ H-NMR (300 MHz, MeOD d4) δ 8.54 (s, 1H), 7.62 (d, 1H, J=7.5 Hz), 7.54 (d, 1H, J=7.8 Hz), 7.41-7.30 (m, 2H), 7.02 (s, 1H), 4.51 (m, 2H), 2.78 (m, 2H), 2.03 (m, 2H). LC/MS [M+H] ⁺ 333.2. Example 49. Synthesis of 4-(phenylthio)furo[2,3-f]quinazoline-7,9-diamine

Step a). Synthesis of 1-(2,2-dimethox ethox -2-bromo-3,5-difluorobenzene

A mixture of 2-bromo-3,5-difluorophenol(3.135g, 15.0 mmol), 2-bromo-1,1- dimethoxyethane(2.30mL, 19.50 mmol), potassium carbonate(4.14g, 30.0 mmol), sodium iodide(0.224g, 1.50mmol), and DMF(10mL), were heated in a 100˚C oil bath for 24hr. The reaction was monitored by LCMS. Work-up: The crude reaction was filtered, concentrated to an oil, and purified by flash chromatography (0 to 50% ethylacetate/hexanes). Yield 3.91g, 88%. ¹ H NMR (300 MHz, CDCl3) δ 6.55 (m, 2H), 4.59 (t, 1H, J = 5.1 Hz), 4.05 (d, 2H), 3.81 (s, 6H); LC/MS 319.0 [M+H]+. Step b). Synthesis of 7-bromo-4,6-difl an

1-(2,2-dimethoxyethoxy)-2-bromo-3,5-difluorobenzene (3.91g, 13.16mmol) was added to a stirring solution of polyphosphoric acid (4.7mL) and toluene (16mL), then placed in a 120˚C oil bath for 2hr. Work-up: The solution was diluted with ice, then extracted with ethyl acetate. The organic layer was washed with 1N NaHCO3, dried with Na2SO4, and purified by flash chromatography (0 to 50% ethylacetate/hexanes). Yield 1.58g, 52%. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.69 (d, 1H, J = 2.3 Hz), 6.94 (d, 1H, J = 2.3 Hz), 6.99 (t, 1H, J = 9.1 Hz); LC/MS 277.0 [M+COOH-]-. Step c). Synthesis of 4,6-difluoroben - - onitrile

A mixture of 7-bromo-4,6-difluorobenzofuran(0.233, 1.00 mmol), zinc cyanide(0.070g,

0.600mmol), tris(dibenzylideneacetone)dipalladium(0)(0.037g, 0.040mmol), xantphos(0.046g,

0.080mmol), TMEDA(0.030mL, 0.200mmol), and DMF(4.3mL) were heated in a microwave at 160˚C for 6 minutes. Work-up: The mixture was concentrated and purified by flash chromatography (0 to 50% ethylacetate/hexanes). Yield 0.055g, 31%. ¹ H NMR (300 MHz, CDCl3) δ 7.77 (d, 1H, J = 2.3 Hz), 6.96 (d, 1H, J = 2.3 Hz), 6.93 (t, 1H, J = 9.5 Hz). Step d). Synthesis of 6-fluoro-4-(phenylthio)benzofuran-7-carbonitrile

A mixture of 4,6-difluorobenzofuran-7-carbonitrile(0.055g, 0.307mmol), thiophenol(0.032mL, 0.307mmol), and K2CO3 (0.051g, 0.368mmol), in NMP(1.0mL), was heated in a microwave for 10 minutes at 140˚C. The crude reaction mixture was used without isolation in the final step. Step e). Synthesis of 4-(phenyl hi f r 2 -f in z lin -7,9-diamine

A solution of crude 6-fluoro-4-(phenylthio)benzofuran-7-carbonitrile in NMP was treated with guanidine carbonate(0.042g, 0.462mmol) and heated in a microwave for 15 minutes at 150˚C. The product was isolated by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. ¹ H NMR (300 MHz, DMSO d6) δ 8.16 (s, 1H), 8.02 (d, 1H, J = 2.1 Hz), 7.51 (m, 5H), 6.87 (d, 1H, J = 2.08 Hz), 6.66 (s, 1H), 6.19 (s, 2H); LC/MS 309.0 [M+H]+. Example 50. Synthesis of 7-(6-(trifl r m h l ri in-2- l x -5-methoxyquinazoline-2,4-diamine

Step a). Synthesis of 2,4-difluoro-6-methoxybenzonitrile

NaH (60% in mineral oil, 1.32g, 33.0 mmol) was added in 4 portions over a 30 minute period to a solution of 2,4,6-trifluorobenzonitrile (4.72g, 30.0 mmol) and methanol (1.46 mL, 36.0 mmol) in dioxane(30 mL) at room temperature, with cooling from a room temperature water bath (reaction foams). After 12h LCMS shows a small amount of unreacted starting material and a large product peak at 220 nm. Work-up: quenched with 1N HCl until just acidic by pH paper, diluted with ethyl acetate, washed with NaHCO3, brine, and dried with Na2SO4. Yield 5.56g, 109% (Note the product contains mineral oil). This material was used in the next step without further purification. ¹ H NMR (300 MHz, MeOD) δ 6.55 (m, 2H), 3.95 (s, 3H); LC/MS 170.0 [M+H]+. Step b). Synthesis of 4-(6-(trifluorometh l ridin-2- lox -2-fluoro-6-methoxybenzonitrile A mixture of 2,4-difluoro-6-methoxybenzonitrile(0.200g, 1.183mmol), 2-hydroxy-6- trifluoromethylpyridine(0.231g, 1.419mmol), potassium carbonate(0.196g, 1.419mmol), and NMP(2mL), were heated via microwave for 10minutes at 130˚C. LCMS shows the desired product. The crude reaction was used in the next step without purification. Step c). Synthesis of 7-(6-(trifluoromethyl)pyridin-2-yloxy)-5-methoxyquinazoline- 2,4-diamine

Crude 4-(6-(trifluoromethyl)pyridin-2-yloxy)-2-fluoro-6-methoxyben zonitrile from the previous step was treated with guanidine carbonate(0.279g, 1.550mmol) and heated in a microwave at 150˚C for 10 minutes. The mixture was purified directly by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield 0.047g, 13%. ¹ H NMR (300 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.73 (m, 2H), 7.50 (s, 1H), 7.40 (d, 1H, J = 8.5Hz), 6.80 (d, 1H, J = 1.6Hz), 6.61 (d, 1H, J = 1.5Hz), 6.50 (s, 2H), 3.89 (s, 3H); LC/MS 352.0 [M+H]+. Example 51. Synthesis of 7-(3-(trifluoromethyl)phenoxy)-5-methoxyquinazoline-2,4-diam ine

Prepared analogously to 7-(6-(trifluoromethyl)pyridin-2-yloxy)-5-methoxyquinazoline- 2,4- diamine(Example 50). ¹ H NMR (300 MHz, MeOD) δ 8.48 (s, 1H), 7.66 (m, 2H), 7.47 (m, 2H), 6.71 (d, 1H, J = 2.1Hz), 6.37 (d, 1H, J = 2.1Hz), 4.05 (s, 3H); LC/MS 351.1 [M+H]+. Example 52. Synthesis of (4-(2,4-diamino-5-methoxyquinazolin-7-yloxy)phenyl)methanol

Prepared analogously to 7-(6-(trifluoromethyl)pyridin-2-yloxy)-5-methoxyquinazoline- 2,4- diamine(Example 50). ¹ H NMR (300 MHz, MeOD) δ 8.48 (s, 1H), 7.49 (d, 2H, J = 8.6Hz), 7.16 (d, 2H, J = 8.5Hz), 6.64 (d, 1H, J = 2.1Hz), 6.32 (d, 1H, J = 2.2Hz), 4.66 (s, 2H), 4.03 (s, 3H); LC/MS 313.1 [M+H]+. Example 53. Synthesis of 7-(2,5-dichlorophenoxy)-5-methoxyquinazoline-2,4-diamine

Prepared analogously to 7-(6-(trifluoromethyl)pyridin-2-yloxy)-5-methoxyquinazoline- 2,4- diamine(Example 50). ¹ H NMR (300 MHz, MeOD) δ 8.47 (s, 1H), 7.61 (m, 1H), 7.40 (m, 2H), 6.72 (d, 1H, J = 2.3Hz), 6.23 (d, 1H, J = 2.3Hz), 4.07 (s, 3H); LC/MS 351.0 [M+H]+. Example 54. Synthesis of (3-(2,4-diamino-5-methoxyquinazolin-7-yloxy)phenyl)methanol

Prepared analogously to 7-(6-(trifluoromethyl)pyridin-2-yloxy)-5-methoxyquinazoline- 2,4- diamine(Example 50). ¹ H NMR (300 MHz, MeOD) δ 8.52 (s, 1H), 7.47 (t, 1H, J = 8.0Hz), 7.30 (d, 1H, J = 7.4Hz), 7.20 (s, 1H), 7.08 (d, 1H, J = 8.4Hz), 6.65 (d, 1H, J = 2.0Hz), 6.31 (d, 1H, J = 2.0Hz), 4.66 (s, 2H), 4.03 (s, 3H); LC/MS 313.1 [M+H]+. Example 55. Synthesis of 7-(2-(triflu r m h l ri in-4- l x )-5-methoxyquinazoline-2,4-diamine

Prepared analogously to 7-(6-(trifluoromethyl)pyridin-2-yloxy)-5-methoxyquinazoline- 2,4- diamine(Example 50). ¹ H NMR (300 MHz, MeOD) δ 8.69 (d, 1H, J = 5.6Hz), 8.43 (s, 1H), 7.58 (d, 1H, J = 2.3Hz), 7.35 (dd, 1H, J = 2.3, 5.6Hz), 6.84 (d, 1H, J = 2.0Hz), 6.68 (d, 1H, J = 2.1Hz), 4.07 (s, 3H); LC/MS 352.2 [M+H]+. Example 56. Synthesis of 7-(6-meth l ridin-2- lox -5-methoxyquinazoline-2,4-diamine

Prepared analogously to 7-(6-(trifluoromethyl)pyridin-2-yloxy)-5-methoxyquinazoline- 2,4- diamine(Example 50). ¹ H NMR (300 MHz, MeOD) δ 8.51 (s, 1H), 7.84 (t, 1H, J = 7.9Hz), 7.17 (d, 1H, J = 7.5Hz), 6.95 (d, 1H, J = 8.1Hz), 6.75 (d, 1H, J = 2.1Hz), 6.57 (d, 1H, J = 2.1Hz), 4.05 (s, 3H), 2.48 (s, 3H); LC/MS 298.1 [M+H]+. Example 57. Synthesis of 5-methoxy-7-phenoxyquinazoline-2,4-diamine

Prepared to analogously to 7-(6-(trifluoromethyl)pyridin-2-yloxy)-5-methoxyquinazoline- 2,4- diamine(Example 50). ¹ H NMR (300 MHz, MeOD) δ 8.52 (s, 1H), 7.51 (m, 2H), 7.32 (m, 1H), 7.19 (m, 2H), 6.65 (d, 1H, J = 2.1Hz), 6.30 (d, 1H, J = 2.1Hz), 4.03 (s, 3H); LC/MS 283.1 [M+H]+. Example 58. Synthesis of 2,3-dihydro-4-phenoxyfuro[2,3-f]quinazoline-7,9-diamine

Step a). Synthesis of 3-allyl-4,6-difluoro-2-h drox benzonitrile

A solution of 2-(allyloxy)-4,6-difluorobenzonitrile(0.700g, 3.59mmol, Int-2), in ortho- dichlorobenzene(4.0mL), was heated in a 180˚C oil bath overnight. The product was only identified in the negative ion trace. The reaction was concentrated by rotary evaporation with a bath temperature of 60C. The resulting dark brown oil was purified by flash chromatography (0 to 40% ethyl acetate/hexanes). Yield 0.148g, 21%. ¹ H NMR (300 MHz, CDCl3) δ 6.58 (t, 1H, J = 6.5Hz), 5.93 (m, 1H), 5.17 (m, 2H), 3.43 (d, 2H, J = 6.2Hz); LC/MS 196.2 [M+H]+. Step b). Synthesis of 4,6-difluoro-2-h drox -3- 2-h droxyethyl)benzonitrile

3-allyl-4,6-difluoro-2-hydroxybenzonitrile (0.148g, 0.758mmol), was dissolved in 1:1 DCM/MeOH (5mL), cooled to -78˚C and treated with O3 until a pale blue color persists. O2 was bubbled through the mixture for 5 min, then NaBH4 was added slowly (bubbles vigorously) and the mixture was warmed to room temperature slowly over 15 min. Work-up: diluted with ethyl acetate, washed with 1N HCl, 1N NaHCO3, brine, dried over Na2SO4. Yield 0.102g, 67%. This material was used without further purification. ¹ H NMR (300 MHz, CDCl3) δ 6.51 (t, 1H, J = 9.6Hz), 4.04 (d, 2H, J = 5.3Hz), 2.96 (d, 2H, J = 4.9Hz); LC/MS 200.0 [M+H]+. Step c). Synthesis of 4,6-difluoro-2,3- ih r nz furan-7-carbonitrile

Diisopropyl azodicarboxylate (0.109 mL, 0.552 mmol) was added dropwise to a 0˚C solution of 4,6-difluoro-2-hydroxy-3-(2-hydroxyethyl)benzonitrile (0.100g, 0.502mmol), and triphenylphosphine (0.145g, 0.552 mmol) in THF (2.0 mL). LCMS after 10 min. shows complete conversion. The solution was concentrated and purified by normal phase chromatography (0 to 25% ethyl acetate/hexanes). Yield 0.075g, 82%. ¹ H NMR (300 MHz, CDCl3) δ 6.46 (t, 1H, J = 9.0Hz), 4.87 (t, 2H, J = 8.9Hz), 3.30 (t, 2H, J = 8.8Hz); LC/MS 182.0 [M+H]+. Step d). Synthesis of 2,3-dihydro-4-phenoxyfuro[2,3-f]quinazoline-7,9-diamine

A mixture of 4,6-difluoro-2,3-dihydrobenzofuran-7-carbonitrile(0.075g, 0.414 mmol), phenol(0.043g, 0.455 mmol), and potassium carbonate (0.069g, 0.497 mmol), dissolved in NMP(2.0mL), were heated in a microwave at 130˚C for 10minutes. To this solution was added guanidine carbonate (0.097g, 0.538 mmol), and the resulting solution was heated via microwave for an additional 10 minutes at 150C. The crude reaction was purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield of light brown powder, 0.028g, 23%. ¹ H NMR (300 MHz, MeOD) δ 8.53 (s, 1H), 7.48 (m, 2H), 7.31 (m, 1H), 7.17 (m, 2H), 6.16 (s, 1H), 4.96 (t, 2H, J = 8.7Hz), 3.28 (m, 2H); LC/MS 295.1 [M+H]+ . Example 59. Synthesis of 2,3-dihydro-4-(isoquinolin-7-yloxy)-3-methylfuro[2,3-f]quina zoline-7,9- diamine

The title compound was prepared analogously to 2,3-dihydro-4-phenoxyfuro[2,3-f]quinazoline- 7,9-diamine (Example 58). ¹ H NMR (300 MHz, MeOD) 9.24 (s, 1H), 8.46 (m, 2H), 8.11 (d, 1H, J = 8.6Hz), 7.88 (m, 3H), 7.68 (dd, 1H, J = 2.5, 9.0Hz), 6.25 (s, 1H), 5.06 (t, 1H, J = 9.1Hz), 4.58 (dd, 1H, J = 5.6, 9.0Hz), 3.80 (m, 1H), 1.46 (d, 3H, J = 6.8Hz); LC/MS 360.2 [M+H]+ . Example 60. Synthesis of 2,3-dihydro-3-methyl-4-(pyridin-3-yloxy)furo[2,3-f]quinazoli ne-7,9- diamine

The title compound was prepared analogously to 2,3-dihydro-4-phenoxyfuro[2,3-f]quinazoline- 7,9-diamine (Example 58). ¹ H NMR (300 MHz, MeOD) δ 8.50 (m, 3H), 7.71 (m, 1H), 7.58 (m, 1H), 6.19 (s, 1H), 5.05 (t, 1H, J = 9.1Hz), 4.57 (dd, 1H, J = 5.6, 9.1Hz), 3.79 (m, 1H), 1.44 (d, 3H, J = 6.8Hz);

LC/MS 310.2[M+H]+ . Example 61. Synthesis of 4-(benzo[d]isoxazol-6-yloxy)-2,3-dihydro-3-methylfuro[2,3-f] quinazoline- 7,9-diamine The title compound was prepared analogously to 2,3-dihydro-4-phenoxyfuro[2,3-f]quinazoline- 7,9-diamine (Example 58). ¹ H NMR (300 MHz, MeOD) δ 8.19 (s, 1H), 7.71 (d, 1H, J = 8.5Hz), 6.71 (m, 1H), 6.36 (s, 2H), 6.16 (m, 1H), 4.90 (t, 1H, J = 9.2Hz), 4.38 (m, 1H), 3.54(m, 1H), 1.27 (d, 3H, J = 6.8Hz); LC/MS 350.2[M+H]+ . Example 62. Synthesis of 4-(3-chloro-5-fluorophenoxy)-2,3-dihydro-3-methylfuro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared analogously to 2,3-dihydro-4-phenoxyfuro[2,3-f]quinazoline- 7,9-diamine (Example 58). ¹ H NMR (300 MHz, MeOD) δ 8.47 (s, 1H), 7.17 (dt, 1H, J = 1.9, 8.5Hz), 7.09 (s, 1H), 7.00 (dt, 1H, J = 2.1, 9.5Hz), 6.29 (s, 1H), 5.04 (t, 1H, J = 9.0Hz), 4.56 (dd, 1H, J = 5.8, 9.0Hz), 3.75 (m, 1H), 1.41 (d, 3H, J = 6.9Hz); LC/MS 361.0 [M+H]+ . Example 63. Synthesis of 2,3-dihydro-3-methyl-4-(naphthalen-1-yloxy)furo[2,3-f]quinaz oline-7,9- diamine

The title compound was prepared analogously to 2,3-dihydro-4-phenoxyfuro[2,3-f]quinazoline- 7,9-diamine (Example 58). ¹ H NMR (300 MHz, MeOD) δ 8.52 (s, 1H), 7.93 (m, 3H), 7.56 (m, 3H), 7.29 (d, 1H, J = 7.6Hz), 5.93 (s, 1H), 5.10 (t, 1H, J = 9.2Hz), 4.62 (dd, 1H, J = 5.5, 9.0Hz), 3.96 (m, 1H), 1.58 (d, 3H, J = 6.8Hz); LC/MS 359.1 [M+H]+. Example 64. Synthesis of 4-bromo-2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diami ne

A mixture of 4-bromo-6-fluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitri le (Int-10) (1.36g, 5.31 mmol), guanidine carbonate (1.24g, 6.90 mmol), and NMP (5mL), were heated via microwave at 150˚C for 10 min. LCMS shows complete conversion. The crude reaction was purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield of light brown powder, 1.57g, 82%. ¹ H NMR (300 MHz, MeOD) δ 8.48 (s, 1H), 7.06 (s, 1H), 4.96 (t, 1H, J = 8.90Hz), 4.62 (dd, 1H, J=3.81, 9.02Hz), 3.65 (m, 1H), 1.41 (d, 3H, J = 6.73Hz); LC/MS, 296.0 [M+H]+ calculated 296.1. Example 65. General procedure for the synthesis of 4-Aryl-2,3-dihydro-3-methylfuro[2,3- f]quinazoline-7,9-diamines

A mixture of 4-bromo-2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diami ne (0.05g, 0.169 mmol, 1.0 eq, Example 64), aryl-boronic acid (0.2033mmol, 1.2eq), bis(triphenylphosphine)palladium(II) dichloride (2.6mg, 0.0085mmol, 0.05eq), 2N K2CO3 (0.25 mL), and NMP (0.5 mL), were heated in a microwave at 140˚C for 10 min, with stirring. The resulting black/brown colored solution was purified directly by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Example 66. Synthesis of 2-(3-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin- 4-yl)phenyl)- 2-methylpropanenitrile

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.50 (s, 1H), 7.74 (s, 1H), 6.88 (s, 1H), 5.05 (t, 1H, J = 8.7Hz), 4.54 (dd, 1H, J = 4.8, 9.0Hz), 4.00 (m, 1H), 1.80 (s, 6H), 0.90 (d, 3H, J = 6.8Hz); LC/MS 360.2 [M+H]+. Example 67. Synthesis of 2-(3-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin- 4- yl)phenyl)acetonitrile S ^{ee Example 65. 1H NMR (300 MHz, MeOD)} δ ^{8.49 (s, 1H), 7.55 (m, 4H), 6.86 (s, 1H), 5.04 (t,} 1H, J = 9.0Hz), 4.53 (dd, 1H, J = 4.7, 9.0Hz), 4.03 (s, 3H), 0.90 (d, 3H, J = 6.8Hz); LC/MS 343.2 [M+H]+. Example 68. Synthesis of 2,3-dihydro-3-methyl-4-(naphthalen-3-yl)furo[2,3-f]quinazoli ne-7,9- diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.36 (bs, 1H), 8.00 (m, 4H), 7.63 (m, 3H), 6.96 (s, 1H), 5.07 (t, 1H, J = 8.6Hz), 4.55 (dd, 1H, J = 4.6, 8.9Hz), 4.11 (m, 1H), 0.88 (d, 3H, J = 6.9Hz); LC/MS 343.2 [M+H]+. Example 69. Synthesis of 2,3-dihydro-3-methyl-4-(1-methylnaphthalen-4-yl)furo[2,3-f]q uinazoline- 7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.50 (s, 1H), 8.16 (m, 1H), 7.74-7.33 (m, 5H), 6.83 (d, 1H, J = 18.7Hz), 5.00 (m, 1H), 4.45 (m, 1H), 3.73 (m, 1H), 2.79 (s, 3H), 0.66 (d, 3H, J = 6.8Hz); LC/MS 357.2 [M+H]+. Example 70. Synthesis of 2,3-dihydro-4-(isoquinolin-5-yl)-3-methylfuro[2,3-f]quinazol ine-7,9- diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 9.38 (s, 1H), 8.45 (m, 2H), 8.28 (d, 1H, J = 7.4Hz), 7.86 (m, 2H), 7.60 (m, 1H), 6.87 (d, 1H, J = 16.9Hz), 5.04 (m, 1H), 4.49 (m, 1H), 3.77 (m, 1H), 0.67 (t, 3H, J = 7.0Hz); LC/MS 344.1 [M+H]+. Example 71. Synthesis of 2,3-dihydro-3-methyl-4-(naphthalen-1-yl)furo[2,3-f]quinazoli ne-7,9- diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.51 (s, 1H), 8.00 (m, 2H), 7.57 (m, 5H), 6.86 (d, 1H, J = 17.8Hz), 5.00(m, 1H), 4.45 (m, 1H), 3.74 (m, 1H), 0.66 (dd, 3H, J = 1.9, 6.8Hz); LC/MS 343.2 [M+H]+. Example 72. Synthesis of 4-(benzo[b]thiophen-7-yl)-2,3-dihydro-3-methylfuro[2,3-f]qui nazoline- 7,9-diamine

S ^{ee Example 65. 1H NMR (300 MHz, MeOD)} δ ^{8.48 (s, 1H), 7.97 (d, 1H, J = 7.8Hz), 7.65 (d, 1H,} J = 5.5Hz), 7.53 (m, 2H), 7.41 (d, 1H, J = 7.4Hz), 7.00 (s, 1H), 5.03 (t, 1H, J = 9.4Hz), 4.50 (dd, 1H, J = 5.1, 8.9Hz), 3.83 (m, 1H), 0.75 (d, 3H, J = 6.9Hz); LC/MS 349.2 [M+H]+. Example 73. Synthesis of 2,3-dihydro-3-methyl-4-(1-methyl-1H-indazol-4-yl)furo[2,3-f] quinazoline- 7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 7.93 (s, 1H), 7.68 (d, 1H, J = 8.8Hz), 7.57 (m, 1H), 7.44 (m, 1H), 7.28 (d, 1H, J =7.0Hz), 6.95 (s, 1H), 5.05 (t, 1H, J = 8.8Hz), 4.50 (dd, 1H, J = 4.8, 8.9Hz), 4.15 (s, 3H), 3.85 (m, 1H), 0.73(d, 3H, J = 6.8Hz); LC/MS 347.2 [M+H]+. Example 74. Synthesis of 4-(benzo[b]thiophen-3-yl)-2,3-dihydro-3-methylfuro[2,3-f]qui nazoline- 7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.65 (bs, 1H), 8.03 (m, 1H), 7.79 (s, 1H), 7.68 (m, 1H), 6.94 (s, 1H), 5.04 (t, 1H, J = 9.3Hz), 4.52 (m, 1H), 3.79 (m, 1H), 0.83 (d, 3H, J = 7.3Hz); LC/MS 349.1 [M+H]+. Example 75. Synthesis of 3'-(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin-4- yl)[1,1'- biphenyl]-3-carbonitrile

Step a). Synthesis of 3'-Bromo-3-biphenylcarbonitrile

A mixture of 1,3-dibromobenzene(2g, 8.48mmol), 3-cyano-phenylboronic acid(0.623g,

4.24mmol), bis(triphenylphosphine)palladium(II) dichloride(0.298g, 0.424 mmol), 2N K2CO3(8.0 mL, 16 mmol), and NMP(16 mL), were heated in a microwave at 140C, for 10 minutes. The crude mixture was purified directly by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield 0.46g, 21%. ¹ H NMR (300 MHz, CDCl3) δ 7.34-7.87 (m, 8H); LC/MS 258.0 [M+H]+. Step b). Synthesis of 3'-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-biphenylc arbonitrile

A flask was charged with 3'-Bromo-3-biphenylcarbonitrile(0.200g, 0.775mmol),

bis(pinacolato)diboron(0.216g, 0.852mmol), potassium acetate(0.228g, 2.32mmol),1,1'- bis(diphenylphosphino)ferrocene dichlorpalladium (II) (0.056g, 0.077mmol), DMSO(1.5mL), flushed with nitrogen for 5 minutes, then heated in an 80˚C oil bath. LCMS after 2h shows complete conversion. Work-up: diluted with ethyl acetate, washed with water (3x), dried over Na2SO4, concentrated, and purified by flash chromatography (0 to 30% ethyl acetate/hexanes). Yield 0.213g, 90%. ¹ H NMR (300 MHz, CDCl3) δ 8.03 (s, 1H), 7.9 (m, 3H), 7.66 (m, 2H), 7.53 (m, 2H), 1.39 (s, 12H); LC/MS 306.0 [M+H]+. Step c). Synthesis of 3'-(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin-4- yl)[1,1'- biphenyl]-3-carbonitrile

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.51 (s, 1H), 8.04 (m, 2H), 7.87-7.60 (m, 6H), 6.91 (s, 1H), 5.05(t, 1H, J = 8.4Hz), 4.54 (dd, 1H, J = 4.6, 8.9Hz), 4.05 (m, 1H), 0.94 (d, 3H, J = 6.8Hz); LC/MS 394.2 [M+H]+. Example 76. Synthesis of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalene-1-carboxamide

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.50 (bs, 1H), 8.42 (m, 1H), 7.83-7.51 (m, 5H), 6.84 (d, 1H, J = 22.4Hz), 5.00 (m, 1H), 4.47 (m, 1H), 3.74 (m, 1H), 0.69 (dd, 3H, J = 6.9, 8.9Hz); LC/MS 386.2 [M+H]+. Example 77. Synthesis of 2,3-dihydro-3-methyl-4-(quinolin-4-yl)furo[2,3-f]quinazoline -7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.99 (t, 1H, J = 4.8Hz), 8.43 (s, 2H), 8.18 (m, 1H), 7.85 (m, 1H), 7.63 (m, 2H), 6.88 (d, 1H, J = 15.4Hz), 5.04 (m, 1H), 4.50 (m, 1H), 3.78 (m, 1H), 0.71 (dd, 3H, J = 6.9, 11.9Hz); LC/MS 344.1 [M+H]+. Example 78. Synthesis of 2,3-dihydro-3-methyl-4-(quinolin-5-yl)furo[2,3-f]quinazoline -7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.95 (m, 1H), 8.51 (s, 1H), 8.17 (m, 2H), 7.92 (m, 1H), 7.67 (dd, 1H, J = 7.1, 13.6Hz), 7.58 (pentet, 1H, J = 4.2Hz), 6.86 (d, 1H, J = 28.2Hz), 5.02 (m, 1H), 4.48 (m, 1H), 3.77 (m, 1H), 0.67 (dd, 3H, J = 6.9, 10.3Hz); LC/MS 344.2 [M+H]+. Example 79. Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalen-5-yl)methanol

Step a). Synthesis of (1-bromonaphthalen-5-yl)methanol

A flask was charged with methyl 5-bromo-1-naphthoate(1.00g, 3.77mmol), and dry THF(12mL), cooled to 0C, then treated with 2M lithium aluminum hydride in THF(2.07mL, 4.15mmol). LCMS after 10min showed clean conversion to the desired product. Work-up: the reaction was quenched with ethyl acetate, then treated with 3N NaOH (2mL), stirred for 10 minutes, mixed with Celite and filtered. Yield 0.864g, 97%. The crude material was used in the next step without further purification. ¹ H NMR (300 MHz, CDCl3) δ 8.28 (m, 1H), 8.13 (d, 1H, J = 8.2Hz), 7.84 (d, 1H, J = 7.7 Hz), 7.60 (m, 2H), 7.40 (t, 1H, J = 7.7Hz), 5.17 (s, 2H); LC/MS 237.0 [M+H]+. Step b). Synthesis of (1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-5 -yl)methanol

A flask was charged with (1-bromonaphthalen-5-yl)methanol(0.400g, 1.687mmol),

bis(pinacolato)diboron(0.471g, 1.856mmol), potassium acetate(0.497g, 5.061mmol), 1,1'- bis(diphenylphosphino)ferrocene dichloropalladium (II)(0.123g, 0.169mmol), DMSO(1.5mL), flushed with nitrogen(3x), and heated in an 80˚C oil bath. LCMS after 2h shows complete conversion. Work-up: diluted with ethyl acetate, washed with water (3x), dried over Na2SO4, concentrated, and purified by flash chromatography (0 to 60% ethyl acetate/hexanes). Yield 0.447g, 93%. ¹ H NMR (300 MHz, CDCl3) δ 8.79 (m, 1H), 8.28 (d, 1H, J = 8.8Hz), 8.13 (d, 1H, J = 6.8 Hz), 7.54 (m, 3H), 1.45 (s, 12H); LC/MS 285.2 [M+H]+. Step c). Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalen- 5-yl)methanol

S ^{ee Example 65. 1H NMR (300 MHz, MeOD)} δ ^{8.41 (s, 1H), 8.29 (dd, 1H, J = 3.4, 8.5Hz), 7.77-} 7.43 (m, 5H), 6.84 (d, 1H, J = 22.3 Hz), 5.16 (s, 2H), 5.00 (m, 1H), 4.45 (m, 1H), 3.73 (m, 1H), 0.66 (dd, 3H, J = 1.9, 6.8Hz); LC/MS 373.2 [M+H]+. Example 80. Synthesis of 2,3-dihydro-4-(2-methoxynaphthalen-6-yl)-3-methylfuro[2,3- f]quinazoline-7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.54 (s, 1H), 7.98 (s, 1H), 7.89 (m, sH), 7.64 (d, 1H, J = 9.3Hz), 7.33 (s, 1H), 7.22 (dd, 1H, J = 2.5, 9.0Hz), 6.92 (s, 1H), 5.06 (t, 1H, J = 8.6Hz), 4.54 (dd, 1H, J = 4.5, 8.9 Hz), 4.11 (m, 1H), 3.97 (s, 3H), 0.88 (d, 3H, J = 6.8Hz); LC/MS 373.2 [M+H]+. Example 81. Synthesis of 2,3-dihydro-3-methyl-4-(quinolin-7-yl)furo[2,3-f]quinazoline -7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.97 (dd, 1H, J = 1.7, 4.4 Hz), 8.49 (d, 1H, J = 8.2 Hz), 8.39 (s, 1H), 8.21 (s, 1H), 8.14 (d, 1H, J = 1.8, 8.5Hz), 7.85 (dd, 1H, J = 1.8, 8.5Hz), 7.65 (dd, 1H, J = 4.3, 8.2Hz), 6.98 (s, 1H), 5.09 (t, 1H, J = 8.8 Hz), 4.56 (dd, 1H, J = 4.7, 8.8Hz), 4.11 (m, 1H), 0.89 (d, 3H, J = 6.9Hz); LC/MS 344.2 [M+H]+. Example 82. Synthesis of 4-(benzo[b]thiophen-2-yl)-2,3-dihydro-3-methylfuro[2,3-f]qui nazoline- 7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.51 (s, 1H), 7.91 (t, 2H, J = 7.4 Hz), 7.77 (s, 1H), 7.43 (m, 2H), 7.11 (s, 1H), 4.99 (t, 1H, J = 8.2 Hz), 4.64 (d, 1H, J = 8.2Hz), 4.16 (t, 1H, J = 6.0Hz), 1.17 (d, 3H, J = 6.8Hz); LC/MS 349.2 [M+H]+. Example 83. Synthesis of 2,3-dihydro-4-(1-methoxynaphthalen-4-yl)-3-methylfuro[2,3- f]quinazoline-7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.49 (s, 1H), 8.36 (m, 1H), 7.53 (m, 4H), 7.04 (d, 1H, J = 7.8 Hz), 6.83 (d, 1H, J = 17.2Hz), 5.00 (m, 1H), 4.45 (m, 1H), 4.10 (s, 3H), 3.76 (m, 1H), 0.68 (m, 3H); LC/MS 373.2 [M+H]+. Example 84. Synthesis of 2,3-dihydro-4-(isoquinolin-4-yl)-3-methylfuro[2,3-f]quinazol ine-7,9- diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 9.39 (s, 1H), 8.37 (m, 3H), 7.78 (m, 3H), 6.90 (d, 1H, J = 11.4 Hz), 5.04 (m, 1H), 4.50 (m, 1H), 3.78 (m, 1H), 0.70 (dd, 3H, J = 7.1, 9.5Hz); LC/MS 344.2 [M+H]+. Example 85. Synthesis of 4-(7-chloroquinolin-4-yl)-2,3-dihydro-3-methylfuro[2,3-f]qui nazoline-7,9- diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 9.01 (t, 1H, J = 4.9 Hz), 8.45 (s, 1H), 8.18 (s, 1H), 7.65 (m, 3H), 6.86 (d, 1H, J = 16.6Hz), 5.04 (dd, 1H, J = 8.8, 19.5Hz), 4.50 (m, 1H), 3.78 (m, 1H), 0.72 (dd, 3H, J = 6.8, 12.5Hz); LC/MS 378.0 [M+H]+. Example 86. Synthesis of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-3-methylf uro[2,3- f]quinazoline-7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 9.13 (s, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 7.96 (s, 2H), 6.96 (s, 1H), 5.07 (t, 1H, J = 9.5Hz), 4.58 (dd, 1H, J = 4.5, 8.9Hz), 4.06 (m, 1H), 4.06 (m, 1H), 0.98 (d, 3H, J = 6.8Hz); LC/MS 334.2 [M+H]+. Example 87. Synthesis of 2,3-dihydro-3-methyl-4-(1,5-naphthyridin-3-yl)furo[2,3-f]qui nazoline-7,9- diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 9.22 (d, 1H, J = 2.0Hz), 9.10 (dd, 1H, J = 1.5, 4.4Hz), 8.64 (s, 1H), 8.58 (d, 1H, J = 8.5Hz), 8.41(s, 1H), 7.90 (dd, 1H, J = 4.3, 8.7Hz), 7.03 (s, 1H), 5.11(t, 1H, J = 9.0Hz), 4.59 (dd, 1H, J = 4.5, 9.0Hz), 0.92 (d, 3H, J = 6.8Hz); LC/MS 345.1 [M+H]+. Example 88. Synthesis of 2,3-dihydro-4-phenylfuro[2,3-f]quinazoline-7,9-diamine

Prepared as described in Example 65 where 4-bromo-2,3-dihydrofuro[2,3-f]quinazoline-7,9- diamine was substituted for 4-bromo-2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diami ne. 4-bromo- 2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine was prepared analogously to 4-bromo-2,3-dihydro-3- methylfuro[2,3-f]quinazoline-7,9-diamine, where allyl alcohol was substituted for (E)-2-Buten-1-ol in the first step of that sequence of reactions. ¹ H NMR (300 MHz, MeOD) δ 8.56 (s, 1H), 7.52 (m, 5H), 6.89 (s, 1H), 4.92 (t, 2H, J = 8.8Hz), 3.39 (t, 2H, J = 8.8Hz); LC/MS 279.1 [M+H]+. Example 89. Synthesis of 2,3-dihydro-4-(naphthalen-1-yl)furo[2,3-f]quinazoline-7,9-di amine

Prepared as described in the Example 65 where 4-bromo-2,3-dihydrofuro[2,3-f]quinazoline-7,9- diamine was substituted for 4-bromo-2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diami ne. 4-bromo- 2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine was prepared analogously to 4-bromo-2,3-dihydro-3- methylfuro[2,3-f]quinazoline-7,9-diamine, where allyl alcohol was substituted for (E)-2-Buten-1-ol in the first step of that sequence of reactions. ¹ H NMR (300 MHz, MeOD) δ 8.50 (s, 1H), 8.00 (m, 2H), 7.54 (m, 5H), 6.91 (s, 1H), 4.90 (m, 2H), 3.0 (m, 2H); LC/MS 329.2 [M+H]+. Example 90. General procedure for synthesis of 5-methoxy-7-(2-arylethynyl)quinazoline-2,4- diamines

A mixture of 7-bromo-5-methoxyquinazoline-2,4-diamine(0.100g, 0.372mmol, see below), arylethyne(0.0695g, 0.409mmol), copper iodide(0.0028g, 0.01486mmol),

bis(triphenylphosphine)palladium(II)dichloride(0.00522g, 0.0074mmol), and 1:1

DMF/diisopropylamine(1.0 mL), were heated at 120˚C in a microwave for 5 minutes. The product was isolated by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Example 91. Synthesis of 7-bromo-5-methoxyquinazoline-2,4-diamine

Step a). Synthesis of 4-bromo-2-fluoro-6-methoxybenzonitrile

Sodium hydride (60% in mineral oil, 0.44g, 11.0 mmol) was added in 3 portions, 15 minutes apart to a solution of 4-bromo-2,6-difluorobenzonitrile(0.440g, 11.0 mmol), MeOH(0.49 mL, 12.0 mmol), and dioxane(30mL) at room temperature, in a room temperature water bath. The mixture was stirred overnight. Work-up: diluted with ethyl acetate, washed with 1N HCl, 1N NaHCO3, and brine, then dried with Na2SO4, and concentrated to a solid. (Product contains mineral oil.) Mass = 2.52g, 109%. This material was without further purification. Step b). Synthesis of 7-bromo-5-methoxyquinazoline-2,4-diamine

A solution of 4-bromo-2-fluoro-6-methoxybenzonitrile (1.0g, 4.35 mmol) and guanidine carbonate (0.509g, 1.3 mmol) in DMF (10 mL) were heat at 140˚C by microwave for 10min. Product solidified out of the reaction after cooling. Water was added to dissolve unreacted guanidine, and the resulting mixture was filtered. The collected dark brown solid (0.473g, 40% yield) was used without further purification. ¹ H- NMR (300 MHz, DMSO d6) ^ ^ ^7.31 (s, 2H), 6.92 (d, 1H, J = 1.78 Hz), 6.65 (d, 1H, J = 1.78 Hz), 6.10 (s, 2H), 3.92 (s, 3H), 2.69 (m, 1H), 1.45 (d, 1H, J = 6.2 Hz); LC/MS 269.0 [M+H]+. Example 92. Synthesis of 5-methoxy-7-(2-phenylethynyl)quinazoline-2,4-diamine

Prepared as described in Example 90. ¹ H-NMR (300 MHz, DMSO d6) δ 8.20 (s, 1H), 7.61 (m, 2H), 7.47 (m, 5H), 6.95 (d, 1H, J = 1.37 Hz), 6.67 (d, 1H, J = 1.37 Hz), 6.42 (s, 2H), 3.97 (s, 3H); LC/MS 291.1 [M+H]+. Example 93. Synthesis of 5-methoxy-7-2- ri in-4- l h n l)quinazoline-2,4-diamine

Prepared as described in Example 90. ¹ H-NMR (300 MHz, DMSO d6) δ 8.70 (bs, 2H), 7.60 (bs, 2H), 7.53 (bs, 2H), 7.02 (s, 1H), 6.72 (s, 1H), 6.43 (s, 2H), 3.97 (s, 3H); LC/MS 292.2 [M+H]+. Example 94. Synthesis of 5-methox -7-2-4-m h x h n l hynyl)quinazoline-2,4-diamine

Prepared as described in Example 90. ¹ H-NMR (300 MHz, DMSO d6) δ 8.20 (s, 1H), 7.54 (d, 2H, J = 8.7 Hz), 7.47 (bs, 2H), 7.01 (d, 2H, J = 9.1 Hz), 6.92 (s, 1H), 6.65 (s, 1H), 6.36 (bs, 2H), 3.96 (s, 3H), 3.81 (s, 3H); LC/MS 321.2 [M+H]+. Example 95. Synthesis of 5-methoxy-7-2-2-m h x h n lethynyl)quinazoline-2,4-diamine

Prepared as described in Example 90. ¹ H-NMR (300 MHz, DMSO d6) δ 8.18 (s, 1H), 7.45 (m, 4H), 7.12 (d, 1H, J = 8.3 Hz), 6.99 (t, 1H, J = 7.7), 6.90 (d, 1H, J = 1.43 Hz), 6.60 (d, 1H, J = 1.43 Hz), 6.28 (bs, 2H), 3.96 (s, 3H), 3.88 (s, 3H); LC/MS 321.2 [M+H]+. Example 96. Synthesis of 5-methoxy-7-(2-o-tolylethynyl)quinazoline-2,4-diamine

Prepared as described in Example 90. ¹ H-NMR (300 MHz, DMSO d6 δ 8.17 (s, 1H), 7.54 (d, 1H, J = 7.7 Hz), 7.44 (m, 2H), 7.35 (d, 2H, J = 4.7), 7.26 (m, 1H), 6.96 (s, 1H), 6.65 (s, 1H), 6.25 (bs, 1H), 3.97 (s, 3H), 2.49 (s, 3H); LC/MS 305.1 [M+H]+. Example 97. Synthesis of 7-(2-(2-chloro hen l eth n l -5-methoxyquinazoline-2,4-diamine

Prepared as described in Example 90. ¹ H-NMR (300 MHz, DMSO d6 δ 8.18 (s, 1H), 7.73 (m, 1H), 7.62 (m, 1H), 7.45 (m, 4H), 6.97 (s, 1H), 6.64 (s, 1H), 6.26 (s, 1H), 3.97 (s, 3H); LC/MS 325.0 [M+H]+. Example 98. Synthesis of 7-(2-(3-chloro hen l eth n l -5-methoxyquinazoline-2,4-diamine

Prepared as described in Example 90. ¹ H-NMR (300 MHz, DMSO d6) δ 8.18 (s, 1H), 7.63 (d, 1H, J = 7.3 Hz), 7.42 (m, 2H), 7.35 (d, 2H, J = 4.4), 7.24 (m, 1H), 6.96 (s, 1H), 6.59 (s, 1H), 6.22 (s, 1H), 3.97 (s, 3H); LC/MS 325.1 [M+H]+. Example 99. Synthesis of 5-methoxy-7- 2- ri in-2- l h n l)quinazoline-2,4-diamine

Prepared as described in Example 90. ¹ H-NMR (300 MHz, DMSO d6) δ 8.64 (d, 1H, J = 4.3 Hz), 8.21 (bs, 1H), 7.89 (m, 1H), 7.70 (d, 1H, J = 7.2 Hz), 7.53 (s, 2H), 7.45 (m, 1H), 7.00 (s, 1H), 6.72 (s, 1H), 6.44 (s, 2H), 3.97 (s, 3H); LC/MS 292.2 [M+H]+. Example 100. Synthesis of 7-(2-(4-(trifluoromethyl)phenyl)ethynyl)-5-methoxyquinazolin e-2,4- diamine

P ^{repared as described in Example 90. 1H-NMR (300 MHz, DMSO d6)} δ ^{8.19 (s, 1H), 7.83 (s, 4H),} 7.51 (s, 2H), 7.00 (d, 1H, J = 1.4Hz), 6.72 (d, 1H, J = 1.4), 6.38 (s, 2H), 3.97 (s, 3H); LC/MS 359.0

[M+H]+. Example 101. Synthesis of 5-methoxy-7-phenethylquinazoline-2,4-diamine

A mixture of 5-methoxy-7-(2-phenylethynyl)quinazoline-2,4-diamine (0.025g, 0.0861 mmol, Example 92), 5% Pd/C (50mg) and methanol (5mL) were flushed with hydrogen and stirred under a hydrogen atmosphere for 60 minutes. The mixture was filtered and concentrated to give an off white solid (0.023g, 91%). ¹ H-NMR (300 MHz, MeOH d4) δ 8.58 (s, 1H), 7.23 (m, 5H), 6.72 (d, 1H, J = 1.37 Hz), 6.64 (d, 1H, J = 1.37 Hz), 3.97 (s, 3H), 3.00(s, 4H); LC/MS 291.1 [M+H]+. Example 102. Synthesis of 5-(4-tert-but l henox -7-bromo uinazoline-2,4-diamine

Prepared as described for the preparation of 7-bromo-5-methoxyquinazoline-2,4- diamine(Example 91), where 4-tert-butylphenol was substituted for methanol. ¹ H-NMR (300 MHz, DMSO d6) δ 8.19 (d, 1H, J = 8.2 Hz), 7.41 (s, 1H), 7.03 (s, 1H), 6.28 (s, 1H), 1.32 (s, 9H); LC/MS 387.0 [M+H]+. Example 103. Synthesis of 5-(4-tert-but l henox -7- 2- hen lethynyl)quinazoline-2,4-diamine

Prepared as described in Example 90, where 5-(4-tert-butylphenoxy)-7-bromoquinazoline-2,4- diamine(Example 102) was substituted for 7-bromo-5-methoxyquinazoline-2,4-diamine. ¹ H-NMR (300 MHz, DMSO d6) δ 8.17 (s, 1H), 7.53 (m, 4H), 7.42 (m, 3H), 7.16 (d, 2H, J = 8.8 Hz), 7.06 (s, 1H), 6.41 (s, 2H), 6.23 (s, 1H), 1.32 (s, 9H); LC/MS 409.2 [M+H]+. Example 104. Synthesis of 5-(4-tert-butylphenoxy)-7-(2-(trimethylsilyl)ethynyl)quinazo line-2,4- diamine

Prepared as described in Example 90, where 5-(4-tert-butylphenoxy)-7-bromoquinazoline-2,4- diamine was substituted for 7-bromo-5-methoxyquinazoline-2,4-diamine. ¹ H-NMR (300 MHz, DMSO d6) δ 7.50 (d, 2H, J = 8.6 Hz), 7.43 (bs, 2H), 7.13 (d, 2H, J = 8.6 Hz), 6.36 (s, 2H), 6.08 (s, 1H), 1.31 (s, 9H), 0.19 (s, 9H); LC/MS 405.2 [M+H]+. Example 105. Synthesis of 5-(4-tert- l h n x -7- h n l inazoline-2,4-diamine

Formed as a side product in the preparation of 5-(4-tert-butylphenoxy)-7-(2- (trimethylsilyl)ethynyl)quinazoline-2,4-diamine (Example 104). ¹ H-NMR (300 MHz, DMSO d6) δ 7.50 (d, 2H, J = 8.6 Hz), 7.40 (bs, 2H), 7.12 (d, 2H, J = 8.6 Hz), 6.05 (s, 1H), 4.31 (s, 1H), 1.31 (s, 9H); LC/MS 333.2 [M+H]+. Example 106. Synthesis of 5-(4-tert- l h n x -7-vin l in zoline-2,4-diamine

A mixture of 5-(4-tert-butylphenoxy)-7-bromoquinazoline-2,4-diamine (75 mg, 0.194 mmol, Example 102), dibutoxyvinylborane (0.047 mL, 0.213 mmol), bis(triphenylphosphine)palladium(II) dichloride(6.7 mg, 0.00968 mmol), 2N K2CO3 (0.25 mL), and acetonitrile (0.75mL), were heated via microwave for 10 min at 110C. The product was isolated by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield 25mg, 38%. ¹ H-NMR (300 MHz, DMSO d6) δ 8.19 (s, 2H), 7.47 (d, 2H, J = 8.5 Hz), 7.09 (d, 2H, J = 10.9 Hz), 7.00 (s, 1H), 6.68 (dd, 1H, J = 11.7 Hz, 18.0 Hz), 6.57 (s, 2H), 6.45 (s, 1H), 5.69 (d, 1H, J = 17.4 Hz), 5.32 (d, 1H, J = 11.0 Hz), 1.30 (s, 9H); LC/MS 335.2 [M+H]+. Example 107. Synthesis of 5-methoxy-7-vinylquinazoline-2,4-diamine

Prepared analogously to 5-(4-tert-butylphenoxy)-7-vinylquinazoline-2,4-diamine(Examp le 106). ¹ H-NMR (300 MHz, DMSO d6) δ 11.90 (s, 1h), 8.21 (s, 1H), 7.46 (s, 2H), 6.56 (dd, 1H, J = 11.3 Hz, 17.9 Hz), 6.23 (s, 1H), 6.15 (s, 1H), 5.85 (d, 1H, J = 17.5 Hz), 5.27 (d, 1H, J = 10.8 Hz), 3.43 (s, 3H); LC/MS 217.2 [M+H]+. Example 108. Synthesis of 7-(4-methoxystyryl)-5-methoxyquinazoline-2,4-diamine

Prepared as analogously to 5-(4-tert-butylphenoxy)-7-vinylquinazoline-2,4-diamine (Example 106). ¹ H-NMR (300 MHz, DMSO d6) δ 8.28 (s, 1H), 7.72 (s, 2H), 7.62 (d, 2H, J = 8.7Hz), 7.38 (d, 1H, J = 16.4Hz), 7.13 (d, 1H, J = 16.8Hz), 6.97 (m, 5H), 4.02 (s, 3H), 3.80 (s, 3H); LC/MS 323.2 [M+H]+. Example 109. Synthesis of 7-(3-methoxystyryl)-5-methoxyquinazoline-2,4-diamine

Prepared as analogously to 5-(4-tert-butylphenoxy)-7-vinylquinazoline-2,4-diamine (Example 106)..1H-NMR (300 MHz, DMSO d6) δ 8.25 (s, 1H), 7.63 (s, 2H), 7.15-7.50 (m, 5H), 6.99 (d, 1H, J = 6.2Hz), 6.88 (s, 1H), 6.72 (s, 1H), 4.02 (s, 3H), 3.82 (s, 3H); LC/MS 323.2 [M+H]+. Example 110. Synthesis of 7-(4-chlorostyryl)-5-methoxyquinazoline-2,4-diamine

Prepared as analogously to 5-(4-tert-butylphenoxy)-7-vinylquinazoline-2,4-diamine (Example 106).. ¹ H-NMR (300 MHz, DMSO d6) δ 8.24 (s, 1H), 7.69 (d, 2H, J = 8.5Hz), 7.38-7.56 (m, 4H), 7.13 (d, 1H, J = 16.8Hz), 7.32 (s, 1H), 6.97 (s, 1H), 6.92(s, 1H), 6.49 (s, 2H), 4.01 (s, 3H); LC/MS 327.0 [M+H]+. Example 111. Synthesis of 7-benzyl-5-methoxyquinazoline-2,4-diamine

A mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile (0.20g, 0.869 mmol, Example 91), benzylzinc bromide solution (0.5M, 5.2mL, 2.61 mmol), bis(triphenylphosphine)palladium(II) dichloride(30 mg, 0.0435 mmol), were heated in a microwave for 15 min at 130˚C. To the crude reaction mixture was added guanidine carbonate (31mg, 0.538 mmol), and NMP (1.5mL), which were then heat via microwave at 150˚C for 15 min. The product was isolated by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield 76 mg, 65%. ¹ H-NMR (300 MHz, DMSO d6) δ 8.27 (s, 1H), 7.62 (s, 2H), 7.29 (m, 5H), 6.75 (s, 2H), 6.65 (s, 1H), 6.58 (s, 1H), 3.95 (s, 2H), 3.90 (s, 3H); LC/MS 281.1 [M+H]+. Example 112. Synthesis of 5-methoxy-7-(1-phenylethyl)quinazoline-2,4-diamine

Prepared analogously to 7-benzyl-5-methoxyquinazoline-2,4-diamine(Example 111). ¹ H-NMR (300 MHz, DMSO d6) δ 8.27 (s, 1H), 7.61 (s, 2H), 7.31 (s, 1H), 7.29 (s, 2H), 7.20 (m, 1H), 6.71 (m, 2H), 6.56 (s, 1H), 4.16 (q, 1H, J = 7.3 Hz), 3.89 (s, 3H), 1.59 (d, 3H, J = 7.3 Hz); LC/MS 295.0 [M+H]+. Example 113. Synthesis of 4-benzyl-2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diam ine

Step a). Synthesis of 4-benzyl-6-fluoro-23-dih dro-3-methylbenzofuran-7-carbonitrile

A solution of 4-bromo-6-fluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitri le(0.142g, 0.555mmol, Int-10), benzylzinc bromide THF solution(0.5M, 3.33mL, 1.66mmol), and

bis(triphenylphosphine)palladium(II) dichloride(0.019g, 0.028mmol) were flushed with nitrogen, then heated in a microwave at 130˚C for 15 minutes. LCMS showed clean conversion. The crude reaction mixture was used in the next step with purification. Step b). Synthesis of 4-benzyl-2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diam ine

A mixture of 4-benzyl-6-fluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitr ile(0.129g,

0.483mmol), guanidine carbonate(0.113g, 0.627mmol), and NMP(2mL), were heated in a microwave at 150˚C for 10 minutes. LCMS showed clean conversion. The resulting solution was purified directly by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield 0.090g, 61%. ¹ H-NMR (300 MHz, MeOD) δ 8.52 (s, 1H), 7.29 (m, 5H), 6.58 (s, 1H), 4.56 (dd, 1H, J = 3.8, 9.0Hz), 4.13 (m, 2H), 3.58 (m, 1H), 1.33 (d, 3H, J = 6.8Hz); LC/MS 307.2[M+H]+. Example 114. Synthesis of 2-ethynyl-2,3-dihydro-4-phenoxyfuro[2,3-f]quinazoline-7,9-di amine Step a). Synthesis of (7,9-diamino-2,3-dihydro-4-phenoxyfuro[2,3-f]quinazolin-2- yl)(methoxy)methanol

A solution of 2,3-dihydro-4-phenoxy-2-vinylfuro[2,3-f]quinazoline-7,9-diam ine(0.055g, 0.172mmol, Example 31), dissolved in 1:1 DCM/MeOH (8mL), was cooled to -78˚C and treated with O3 until a pale blue color persists. O2 was bubbled through the mixture for 5 min, then dimethyl sulfide(0.100mL) was added in one portion. This solution was warmed to 25˚C slowly over 20 minutes, at which time LCMS showed mostly desired product. This solution was used in the next step without further purification. Step b). Synthesis of 2-ethynyl-2,3-dihydro-4-phenoxyfuro[2,3-f]quinazoline-7,9-di amine

A solution of (7,9-diamino-2,3-dihydro-4-phenoxyfuro[2,3-f]quinazolin-2- yl)(methoxy)methanol(0.172mmol), in DCM/MeOH(8.0mL), was treated with dimethyl (1-diazo-2- oxopropyl)phosphonate solution (10% in acetonitrile, 0.099g, 0.515mmol). LCMS after 1 hour shows mostly desired product. The reaction was concentrated and purified by reverse phase liquid

chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield 0.019g, 35%. ¹ H-NMR (300 MHz, MeOD) δ 8.51 (s, 1H), 7.50 (t, 2H, J = 8.0Hz), 7.33 (m, 1H), 7.19 (d, 2H, J = 7.7Hz), 6.20 (s, 1H), 5.86 (m, 1H), 3.65 (dd, 1H, J = 9.6, 15.4Hz), 3.27 (d, 1H, J = 6.6Hz); LC/MS 319.0[M+H]+. Example 115. Synthesis of 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3-methylfuro[2,3-f]quin azoline-2,4- diamine

A mixture of 4,6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile (0.060g, 0.3mmol, Int-11), 3-chloro-phenol (0.052g, 0.40mmol), potassium carbonate (140mg, 1mmol) in 2ml NMP were heated at 130˚C in a microwave for 10 minutes. LCMS shows the desired product. The crude reaction was used in the next step without purification. To the above solution was added guanidine carbonate (0.10g, 0.538 mmol), and the resulting solution was heated via microwave for an additional 10 minutes at 150C. The crude reaction was purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield of white powder, 0.020g, yield of 20%. ¹ H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 1H) 7.45(t, J=9Hz, 1H) 7.19(m, 3H) 6.03(s, 1H) 4.87(t, J=9Hz, 1H) 4.36(m, 1H) 3.50(m, 1H) 1.26(d, J=6Hz, 3H) LC/MS 343.1 [M+H] ⁺ . Example 116. Synthesis of 2,3-dihydro-7-phenoxyl-3-methylfuro[2,3-f]quinazoline-2,4-di amine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.25(s, 1H) 7.70(s, 1H) 7.25(s, 2H) 7.15(s, 3H) 6.02(s, 1H) 4.91(s, 1H) 4.41(s, 1H) 3.59(m, 1H) 1.31(s, 3H). LC/MS 309.1 [M+H] ⁺ . Example 117. Synthesis of Synthesis of 4-guanidinyl-6-phenoxyl-2,3-dihydro-3-methylbenzofuran- 7-carbonitrile

The title compound was isolated as a side product in the preparation of 2,3-dihydro-7-(3’-Chloro- phenoxyl)-3-methylfuro[2,3-f]quinazoline-2,4-diamine (Example 116). ¹ H NMR (300 MHz, DMSO-d6) δ 8.25(s, 1H) 7.70(s, 1H) 7.25(s, 2H) 7.15(s, 3H) 6.02(s, 1H) 4.91(s, 1H) 4.41(s, 1H) 3.59(m, 1H) 1.31(s, 3H). LC/MS 309.1 [M+H] ⁺ . Example 118. Synthesis of 2,3-dihydro-7-(2’,5’-di-chloro-phenoxyl)-3-methylfuro[2, 3-f]quinazoline- 2,4-diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.21(s, 1H) 7.70(s, 1H) 7.39(s, 2H) 6.23(s, 1H) 5.85(s, 1H) 4.91(s, 1H) 4.41(s, 1H) 3.62(m, 1H) 1.32(D, J=6Hz, 3H). LC/MS 377.1 [M+H] ⁺ . Example 119. Synthesis of 2,3-dihydro-7-(2,3-furanyl-1-pyridinoxyl)-3-methylfuro[2,3- f]quinazoline-2,4-diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.53(d, J=2.4Hz, 1H) 8.42(d, J=2.1Hz, 1H) 8.15(d, J=1.5Hz, 1H)7.24(dd, J1=0.9Hz, J2=2.7Hz, 1H) 6.15(s, 1H) 5.00(t, J=9Hz, 1H) 4.53(m, 1H) 3.78(m, 1H) 1.40(d, J=7.8Hz) LC/MS 350.2 [M+H] ⁺ . Example 120. Synthesis of 2,3-dihydro-7-(4’methyl-3,5-pymirinoxyl)-3-methylfuro[2,3- f]quinazoline-2,4-diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.62(S, 2H) 8.18(S, 1H) 6.02(s, 2H) 5.949(s, 1H) 4.88(t, J=9Hz, 1H) 4.38(m, 1H) 3.61(m, 1H) 2.65(s, 3H) 1.32(d, J=6.6Hz, 3H) LC/MS 325.2 [M+H] ⁺ . Example 121. Synthesis of 2,3-dihydro-7-(3’,5’-dichloro-phenoxyl)-3-methylfuro[2,3 -f]quinazoline- 2,4-diamine The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.15(s, 1H) 7.43(s, 1H) 7.19(s, 1H) 6.11(s, 1H) 4.87(m, 1H) 4.35(m, 1H) 3.46(m, 1H) 1.24(d, J=6.6Hz) LC/MS 377.1 [M+H] ⁺ . Example 122. Synthesis of 2,3-dihydro-7-(6-trifluoromethyl-pyridnyl-2-oxyl)-3-methylfu ro[2,3- f]quinazoline-2,4-diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.22(d, J=6Hz, 1H) 7.71(d, J=3Hz, 1H) 7.41(d, J=9Hz, 1H) 6.62(s, 1H) 4.85(t, J=9Hz, 1H) 4.32(t, J=6Hz, 1H) 3.43(m, 1H) 1.14(d, J=6Hz, 3H). LC/MS 378.1 [M+H] ⁺ . Example 123. Synthesis of 2,3-dihydro-7-(3’-amide-phenoxyl)-3-methylfuro[2,3-f]quina zoline-2,4- diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.89(s, 1H) 8.08(s, 1H) 7.63(m, 3H) 6.18(s, 1H) 5.00(t, J= 9Hz, 1H) 4.50(m, 1H) 3.65(m, 1H) 1.36(d, J=6.9Hz).

LC/MS 352.1 [M+H] ⁺ . Example 124. Synthesis of 2,3-dihydro-7-(5-Quinolinoxyl)-3-methylfuro[2,3-f]quinazolin e-2,4- diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 9.00(d, J=3.6Hz, 2H) 8.49(m,1H) 8.17(s, 1H) 7.96( m, 1H) 7.85(s, 1H), 7.74(m, 1H)6.22(s, 1H) 4.90(m, 1H) 4.37(m, 1H) 3.52(m, 1H)1.28(d, J=7.2Hz, 3H). LC/MS 360.2 [M+H] ⁺ . Example 125. Synthesis of 2,3-dihydro-7-(3’cyano-phenoxyl)-3-methylfuro[2,3-f]quinaz oline-2,4- diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.16(s, 1H) 7.65(m, 3H) 7.44(d, J=8.4Hz, 1H) 6.03(s, 1H) 4.87(t, J=9Hz, 1H) 4.36(dd, J1= 6Hz, J2=8.4Hz, 1H) 3.51(m, 1H) 1.25(d, J=6Hz, 3H). LC/MS 334.1 [M+H] ⁺ . Example 126. Synthesis of 2,3-dih r -47- h n x l- -m h lf ro[2,3-f]quinazoline-2,4-diamine

Prepared as described for 5-(4-tert-butylphenoxy)-7-vinylquinazoline-2,4-diamine. H-NMR (300 MHz, DMSO d6) δ 8.24 (s, 1H), 7.67 (d, 2H, J = 8.5Hz), 7.61 (bs, 2H), 7.42 (m, 3H), 7.31 (m, 2H), 6.97 (d, 2H, J = 5.1Hz), 6.67(s, 2H), 4.01 (s, 3H); LC/MS 293.1 [M+H]+. Example 127. Synthesis of Synth i f -m h x -7- r l in zoline-2,4-diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.17(s, 1H) 7.56(t, J=9Hz, 1H) 7.15(s, 1H) 6.07(s, 1H) 4.86(t, J=9Hz, 1H) 4.35(t, J=3Hz, 1H) 3.54(m, 1H) 1.24(d, J=6Hz, 3H). LC/MS 393.1 [M+H] ⁺ . Example 128. Synthesis of 2,3-dihydro-7-(3’-methoxyl-5-pentanyl-phenoxyl)-3-methylfu ro[2,3- f]quinazoline-2,4-diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 6.62(s, 1H) 6.48(t, J=9Hz, 1H) 6.00(s, 1H) 5.99(s, 1H) , 4.86(t, J=9Hz, 1H) 4.35(t, J=3Hz, 1H), 3.54(m, 1H), 1.55(m, 5H) 1.64(m, 6H) 0.85(t, J=6Hz, 3H) ). LC/MS 409.2 [M+H] ⁺ . Example 129. Synthesis of 2,3-dihydro-7-(3’-methoxyl-5-fluoro-phenoxyl)-3-methylfuro [2,3- f]quinazoline-2,4-diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.17(s, 1H) 6.66(m, 1H) 6.53(m, 1H) 6.09(s 1H) 6.00(m, 1H) 4.87(t, J= 9Hz) 4.33(m, 1H) 3.77(s, 3H) 3.53(m, 1H) 1.26(d, J9Hz, 3H). LC/MS 357.2 [M+H] ⁺ . Example 130. Synthesis of 2,3-dihydro-7-(3’-(2"-methyl-tetrazole)--phenoxyl)-3-methy lfuro[2,3- f]quinazoline-2,4-diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.25(s, 1H) 87.92(d, J=9Hz, 1H) 7.66(m, 3H) 7.33(m, 1H) 6.13(s, 1H) 4.87(t, J= 9Hz, 1H) 4.40(s, 3H) 4.33(m, 1H) 3.60(m, 1H) 1.28(d, J=6.0Hz, 3H). LC/MS 391.2 [M+H] ⁺ . Example 131. Synthesis of 2,3-dihydro-7-(3’-trifluoromethyl-5’-amide-phenoxyl)-3-m ethylfuro[2,3- f]quinazoline-2,4-diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 8.29(s, 1H) 8.18(s, 1H) 8.02(m, 1H) 7.86(s, 1H) 7.70(s, 1H) 6.06(s, 1H) 4.88(m, 1H) 4.37(m, 1H) 3.43(m, 1H) 1.27(d, J=6.6Hz), 3H). LC/MS 420.2 [M+H] ⁺ . Example 132. Synthesis of 2,3-dihydro-7-(3’-chloro-phenoxyl)-3-ethylfuro[2,3-f]quina zoline-2,4- diamine

The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115). ¹ H NMR (300 MHz, DMSO-d6) δ 7.51(t, J=9.9Hz, 1H) 7.38(m, 3H) 7.32(m, 1H) 7.18(m, 1H) 6.07(s, 1H) 4.72(t, J=9Hz, 1H) 4.62(dd, J1= 3Hz, J2= 9.3Hz, 1H) 3.60(m, 1H) 1.88(m, 1H) 1.61(m, 1H) 0.99(t, J=7.5Hz). LC/MS 357.1 [M+H] ⁺ . Example 133. Synthesis of 7-(3’-Chloro-phenoxyl)-6-methyl-quinazoline-2,4-diamine

A mixture of 2,4-difluoro-3-methyl-benzonitrile (0.150g, 1mmol), 3-Chloro-phenol (0.013g, 1mmol), potassium carbonate (140mg, 1mmol) in 2ml NMP were heated at 130˚C in a microwave for 10 minutes. LCMS shows the desired product. The crude reaction was used in the next step without purification. To the above solution was added guanidine carbonate (0.20g, 1.0 mmol), and the resulting solution was heated via microwave for an additional 10 minutes at 150C. The crude reaction was purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield of white powder, 0.020g, yield of 20%. ¹ H NMR (300 MHz, DMSO-d6) δ 8.22(s, 1H), 7.99(s, 1H) 7.54(s, 1H) 7.45(t, J=9Hz, 1H), 7.27(dd, J1=3Hz, J2=9Hz, 1H) 7.14(t, J=3Hz, 1H) 7.04(dd, J1=3Hz), J2=9Hz, 1H), 6.55(2s, 2H) 2.23(s, 3H). LC/MS 300.1 [M+H] ⁺ . Example 134. Synthesis of 7-(3’-methyl-pymiridnyl)-6-methyl-quinazoline-2,4-diamine

The title compound was prepared analogously to 7-(3’-Chloro-phenoxyl)-6-methyl-quinazoline- 2,4-diamine (Example 133). ¹ H NMR (300 MHz, DMSO-d6) δ 8.62(s, 2H) 8.18(s, 1H) 6.02(s, 2H) 5.94(s, 1H) 4.88(t, J=9Hz, 1H) 4.38(m, 1H) 3.61(m, 1H) 2.65(s, 3H) 1.30(s, 3H). LC/MS 377.1 [M+H] ⁺ . Example 135. Synthesis of Synthesis of 7-(1,5-Naphthyridin-3-oxyl)-6-methyl-quinazoline-2,4- diamine

The title compound was prepared analogously to Synthesis of 7-(3’-Chloro-phenoxyl)-6-methyl- quinazoline-2,4-diamine (Example 133). ¹ H NMR (300 MHz, DMSO-d6) δ 12.24(s, 1H) 9.0(m, 1H) 8.87(s, 1H) 8.72(s, 1H) 8.5(m, 1H) 8.26(s, 1H) 8.07(s, 1H) 7.76(m, 1H) 7.68(s, 1H) 2.38(s, 3H). LC/MS 319.1 [M+H] ⁺ . Example 136. Synthesis of Synthesis of 7-(3’-amide-phenoxyl)-6-methyl-quinazoline-2,4-diamine

The title compound was prepared analogously to 7-(3’-Chloro-phenoxyl)-6-methyl-quinazoline- 2,4-diamine (Example 133). ¹ H NMR (300 MHz, DMSO-d6) δ 11.99(s, 1H) 8.78(s, 1H) 8.64(s, 1H) 8.18(s, 1H) 8.07(s, 1H) 7.82(m, 1H), 7.65(m, 1H) 7.51(m, 1H) 7.39(m, 1H) 6.65(1H) 2.36(s, 3H). LC/MS 310.1 [M+H] ⁺ . Example 137. Synthesis of Synthesis of 7-(3’-cyano-phenoxyl)-6-methyl-quinazoline-2,4-diamine

The title compound was prepared analogously to 7-(3’-Chloro-phenoxyl)-6-methyl-quinazoline- 2,4-diamine (Example 133). ¹ H NMR (300 MHz, DMSO-d6) δ 12.04(s, 1H) 8.81(s, 1H), 8.67(s, 1H) 8.19(s, 1H) 7.77(m, 1H) 7.74(m, 1H) 7.71(s, 1H) 7.65(s, 1H) 7.57m, 1H) 7.52(m, 1H) 2.33(s, 3H). LC/MS 292.1 [M+H] ⁺ . Example 138. Synthesis of 2,3-dihydro-4-(6’-methoxyl-2-naphthyl-methylenyl)-3-methyl furo[2,3- f]quinazoline-2,4-diamine

Step a). Synthesis of 4-(6’-methoxyl-2-naphthyl-methylenyl)-6-difluoro-2,3-dihyd ro-3- methylbenzofuran-7-carbonitrile

4-(bromo-methylenyl)-6-difluoro-2,3-dihydro-3-methylbenzofur an-7-carbonitrile (35mg,

0.013mmol, Int-13) was added into a solution of the boronic acid (0.3 mmol, 2 equiv.) and trans-Bromo(N- succinimidyl)bis-(triphenylphosphine)palladium(II) (20mg, 0.0025mmol 5 mol %) in degassed THF (2.0 mL) under nitrogen. After stirring for 5 min, a solution of sodium carbonate (2M in water, 1 mL) was added. The reaction mixture was then stirred vigorously and heated to 60°C for 4 hour, until complete by TLC. The reaction mixture was cooled to ambient temperature and extracted with ethyl acetate (3 x 5 mL). The organic phase was dried (MgSO4), concentrated under vacuum and the residue purified by column chromatography, using EtOAc/hexane, to provide the desired product (20mg, 44% yield). ¹ H NMR (300 MHz, CDCl3) δ 7.66(t, J=8.7Hz, 2H) 7.56(t, J=8.7Hz, 1H) 7.50(d, J=7.5Hz, 1H) 7.18(m, 1H) 7.04(m, 3H) 6.42(d, J=12Hz, 1H) 4.72(t, J=9Hz) 4.37(dd, J1=3.9Hz J2=9Hz, 1H) 4.07(s, 2H) 3.88(s, 3H) 3.45(m, 1H) 1.23(d, J=6Hz). ) ^. LC/MS 348.1 [M+H] ⁺ . Step b). Synthesis of 2,3-dihydro-4-(6’-methoxyl-2-naphthyl-methylenyl)-3-methyl furo[2,3- f]quinazoline-2,4-diamine

To a solution of 4-(6’-methoxyl-2-naphthyl-methylenyl)-6-difluoro-2,3-dihyd ro-3- methylbenzofuran-7-carbonitrile (16mg, 0.05mmol) in NMP (2mL) was added guanidine carbonate (0.02g, 0.2 mmol) and potassium carbonate (28mg, 0.2mmol). The resulting solution was heated via microwave for 10 minutes at 150C. The crude reaction was purified by reverse phase liquid

chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield of white powder 0.011g, 55%.. ¹ H NMR (300 MHz, CDCl3) δ 8.22(s, 1H) 7.77(s, 1H) 7.75(s, 1H) 7.29(m, 2H) 7.14( dd, J1=2.7Hz, J2=9Hz, 1H) 6.50(s, 1H) 6.37(br, 1H) 4.70(t, J=8.7Hz, 1H) 4.36(m, 1H) 4.12(q, J1= 21.2 <J2= 5.1Hz), 2H) 3.86(s, 2H) 3.41(m, 1H) 1.22(d, J=6.6Hz, 1H). ) ^. LC/MS 386.2 [M+H] ⁺ . Example 139. Synthesis of 2,3-dihydro-4-(3’-Chloro-benzyl)-3-methylfuro[2,3-f]quinaz oline-2,4- diamine

Step a). Synthesis of 4-(3’chloro-benzyl)-6-difluoro-2,3-dihydro-3-methylbenzofu ran-7-carbonitrile

The title compound was prepared analogously to 4-(6’-methoxyl-2-naphthyl-methylenyl)-6- difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile(Examp le 138, Step a). ¹ H NMR (300 MHz, CDCl3) δ 7.27(m, 1H) 7.13(s, 1H) 6.88(m, 1H) 6.74(m, 1H) 6.40(d, J=7.5Hz, 1H) 4.79(t, J=8.7Hz, 1H) 4.42(dd, J1=3.9Hz, J2= 8.7Hz, 1H) 3.96(q, J= 5.1Hz, J2=21Hz, 2H) 3.47(m, 1H)2.32(d, J=6.9Hz, 3H). Step b). Synthesis of 2,3-dihydro-4-(3’-Chloro-benzyl)-3-methylfuro[2,3-f]quinaz oline-2,4- diamine

The title compound was prepared analogously to 2,3-dihydro-4-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 138, Step b). ¹ H NMR (300 MHz, DMSO-d6) δ 12.06(s, 1H) 8.93(s, 1H) 7.76(s, 1H) 7.35(m, 3H) 7.22(d, J=7.5Hz, 1H) 6.52(s, 1H) 4.85(t, J=8.7Hz, 1H) 4.52(dd, J1= 3.6Hz, J2= 9Hz, 1H) 4.10(s, 2H) 3.59(m, 1H) 1.25(d, J=6.6Hz). LC/MS 341.1 [M+H] ⁺ . Example 140. Synthesis of 2,3-dihydro-4-(1,5-Naphthyridin-3-methylenyl)-3-methylfuro[2 ,3- f]quinazoline-2,4-diamine

Step a). Synthesis of 4-(1,5-Naphthyridin-3-methylenyl)-6-difluoro-2,3-dihydro-3- methylbenzofuran-7-carbonitrile

The title compound was prepared analogously to 4-(6’-methoxyl-2-naphthyl-methylenyl)-6- difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile(Examp le 138, Step a). ¹ H NMR (300 MHz, CDCl3) δ 8.94(m, 1H) 8.80(m, 1H) 8.42(m,1H) 8.15(s, 1H) 7.73(m, 1H) 7.60(m,1H) 6.64(d, J=7.2Hz, 1H) 4.84(t, J=8.7Hz, 1H) 4.42(m, 1H) 4.27(q, J1=4.9Hz, J2=21Hz) 3.55(m,1H) 1.35(d, J=6.9Hz, 3H). Step b). Synthesis of 2,3-dihydro-4-(1,5-Naphthyridin-3-methylenyl)-3-methylfuro[2 ,3- f]quinazoline-2,4-diamine

The title compound was prepared analogously to 2,3-dihydro-4-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 138, Step b). ¹ H NMR (300 MHz, DMSO-d6) δ 11.92(s, 1H) 9.02(dd, J1=2.1Hz, J2=4.2Hz, 1H) 8.95(d, J= 2.1Hz, 1H) 8.46(d, J=7.5Hz, 1H) 8.28(s, 1H) 7.78(m, 2H) 6.55(s, 1H) 4.88(t, J=9Hz, 1H) 4.52(dd, J1= 3.6Hz, J2= 9Hz, 1H) 4.40(s, 2H) 3.68(m, 1H) 1.29(d, J=6.6Hz). LC/MS 359.2 [M+H] ⁺ . Example 141. 4-(6-(trifluoromethyl)pyridin-2-yloxy)-2,3-dihydro-2,2-dimet hylfuro[2,3-f]quinazoline- 7,9-diamine

The title compound was prepared from 4,6-difluoro-2,2-dimethyl-1-oxa-7-indancarbonitrile(Int-1) in a manner similar to that described for Example 3.1H-NMR (300 MHz, MeOD d4) δ 8.17 (t, 1H, J=8.1 Hz), 7.65 (d, 1H, J=7.5 Hz), 7.42 (d, 1H, J=8.4 Hz), 6.67 (2, 1H), 2.91 (s, 2H), 1.60 (s, 6H). LC/MS [M+H] ⁺ 392.2. Example 142. Synthesis of 2,3-dihydro-4-(6-methoxyquinolin-4-yl)-3-methylfuro[2,3-f]qu inazoline- 7,9-diamine

A mixture of 4-bromo-6-methoxyquinoline (0.075g, 0.315mmol), and triisopropylborate (0.080mL, 0.346mmol), were flushed with N2, then dissolved in dry THF(1.0 mL). The solution was cooled to -78C and treated with n-Butyl lithium (1.6M in hexanes) dropwise over 30 minutes. LCMS shows the desired boronic acid. The reaction was warmed to room temperature then charged with 4-bromo-2,3-dihydro-3- methylfuro[2,3-f]quinazoline-7,9-diamine(0.050g, 0.169mmol, Example 64),

bis(triphenylphosphine)palladium(II) dichloride(0.0026g, 0.0085mmol), and 2N aq. K2CO3(0.25 mL). This mixture was heated in a microwave at 140C for 10 minutes. The product was isolated by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield 0.014g, 22%. ¹ H NMR (300 MHz, MeOD) δ 8.81 (t, 1H, J = 4.4Hz), 8.50 (bs, 1H), 8.07 (dd, 1H, J = 2.7, 9.3Hz), 7.52 (m, 2H), 6.97 (m, 2H), 5.04 (m, 1H), 4.50 (m, 1H), 3.80 (d, 3H, J = 3.8Hz), 3.42 (m, 1H), 0.74 (dd, 3H, J = 4.4, 6.8Hz); LC/MS 374.2 [M+H]+ . Example 143. Synthesis of 2,3-dihydro-4-(7-methoxyquinolin-4-yl)-3-methylfuro[2,3-f]qu inazoline- 7,9-diamine

The title compound was prepared analogously to 2,3-dihydro-4-(6-methoxyquinolin-4-yl)-3- methylfuro[2,3-f]quinazoline-7,9-diamine(Example 142). ¹ H NMR (300 MHz, MeOD) δ 8.88 (t, 1H, J = 4.6Hz), 8.49 (bs, 1H), 7.64 (m, 1H), 7.51 (m, 1H), 7.42 (m, 1H), 7.29 (m, 1H), 6.86 (d, 1H, J = 16.0Hz), 5.03 (m, 1H), 4.49 (m, 1H), 4.01 (s, 3H), 3.77 (s, 1H), 0.73 (dd, 3H, J = 6.7, 10.3Hz); LC/MS 374.2

[M+H]+ . Example 144. Synthesis of 2,3-dihydro-3-methyl-4-(2-methylquinolin-4-yl)furo[2,3-f]qui nazoline- 7,9-diamine

The title compound was prepared analogously to 2,3-dihydro-4-(6-methoxyquinolin-4-yl)-3- methylfuro[2,3-f]quinazoline-7,9-diamine(Example 142). ¹ H NMR (300 MHz, MeOD) δ 8.46 (bs, 1H), 8.08 (d, 1H, J = 8.3Hz), 7.81 (t, 1H, J = 7.0Hz), 7.63 (m, 2H), 7.48 (d, 1H, J = 16.1Hz), 6.87 (d, 1H, J = 20.5Hz), 5.03 (m, 1H), 4.49 (m, 1H), 3.77 (m, 1H), 2.80 (s, 3H), 0.72 (dd, 3H, J = 6.9, 10.6Hz); LC/MS 358.2 [M+H]+. Example 145. Synthesis of 4-(dibenzo[b,d]thiophen-4-yl)-2,3-dihydro-3-methylfuro[2,3- f]quinazoline-7,9-diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.44 (bs, 1H), 8.35 (m, 2H), 7.89 (m, 1H), 7.66 (t, 1H, 7.5Hz), 7.54 (m, 3H), 7.02 (s, 1H), 5.04 (t, 1H, J = 9.0Hz), 4.50 (dd, 1H, J = 5.1, 9.0Hz), 3.85 (m, 1H), 0.78 (d, 3H, J = 6.9Hz); LC/MS 399.2 [M+H]+ . Example 146. Synthesis of 4-(benzofuran-7-yl)-2,3-dihydro-3-methylfuro[2,3-f]quinazoli ne-7,9- diamine

See Example 65. ¹ H NMR (300 MHz, MeOD) δ 8.52 (bs, 1H), 7.84 (d, 1H, J = 2.2Hz), 7.76 (dd, 1H, J = 2.3, 6.7Hz), 7.42 (m, 2H), 7.00 (m, 2H), 5.05 (t, 1H, J = 8.9Hz), 4.49 (dd, 1H, J = 5.2, 8.9Hz), 3.91 (m, 1H), 0.76 (d, 3H, J = 6.8Hz); LC/MS 333.2 [M+H]+ . Example 147. Synthesis of 4-(2-(trifluoromethyl)quinolin-4-yl)-2,3-dihydro-3-methylfur o[2,3- f]quinazoline-7,9-diamine

A mixture of 4-bromo-2-trifluoromethylquinoline(0.100g, 0.362mmol),

bis(pinacolato)diboron(0.101g, 0.398mmol), potassium acetate(0.107g, 1.087mmol), and 1,1'- bis(diphenylphosphino)ferrocene dichlorpalladium (II) (0.0088g, 0.0109mmol), were flushed with N2, for 5 minutes then treated with DMSO (0.7mL), and placed in a 80C oil bath for 12h. LCMS after 12h shows only the boronic acid (no pinacol boronate). To the crude mixture (black in color) was added 4-bromo- 2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diamine(0.050 g, 0.169mmol, Example 64),

bis(triphenylphosphine)palladium(II) dichloride(0.0026g, 0.0085mmol), and 2N aq. K2CO3(0.25 mL). The mixture was heated in a microwave at 140C for 10 minutes. The product was isolated by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield 0.031g, 44%. ¹ H NMR (300 MHz, MeOD) δ 8.43 (bs, 1H), 8.32 (d, 1H, J = 8.6Hz), 7.98 (m, 1H), 7.90 (m, 1H), 7.80 (m, 1H), 6.91 (d, 1H, J = 20.3), 5.05 (m, 1H), 4.51 (m, 1H), 3.75 (m, 1H), 0.70 (dd, 3H, J = 7.0, 10.8Hz); LC/MS 412.2 [M+H]+ . Example 148. Synthesis of (2,4-diamin - - h n l hi inazolin-7-yl)(phenyl)methanone

Thiophenol (89 mg, 0.82 mmol) was added to a stirring mixture of 2,6-difluoro-4- (hydroxyphenylmethyl)benzonitrile (200 mg, 0.82 mmol, Example 8) and potassium carbonate (112 mg, 0.82 mmol) in NMP (3 mL) and the mixture stirred at ambient temperature for 2 hours at which point guanidine carbonate was added and the mixture was stirred at 150°C for 30 minutes. The reaction was cooled to ambient temperature and purified by RP HPLC (20-95% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient) to afford the product as a light yellow solid. LC/MS [M+H]+ 373.2. Example 149. Synthesis of 4-([1,1'-biphenyl]-3-yl)-3-methyl-2,3-dihydrofuro[2,3-f]quin azoline-7,9- diamine

See Example 65. H-NMR (300 MHz, MeOD) δ 8.41 (s, 1H), 7.81-7.36 (m, 9H), 6.92 (s, 1H), 5.05(t, 1H, J = 8.9Hz), 4.54 (dd, 1H, J = 4.6, 8.9Hz), 4.05 (m, 1H), 0.95 (d, 3H, J = 6.9Hz); LC/MS 369.2 [M+H]+. Example 150. Synthesis of 4-((1,5-naphthyridin-3-oxy)-3-methyl-2,3-dihydrofuro[2,3-f]q uinazoline- 7,9-diamine The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine (Example 115).1H NMR (300 MHz, DMSO-d6) δ ppm 8.90(d, J=3.6Hz, 2H, 1H) 8.46(m, 1H) 8.17(s, 1H) 7.85(m, 2H) 6.22(s, 1H) 4.88(m, 1H) 4.37(m, 1H) 3.52(m, 1H) 1.298(d, J=6.9Hz). LC/MS 360.2 [M+H]+. Example 151. Synthesis of (2,4-diamino-5-(phenylthio)quinazolin-7-yl)(phenyl)methanol

[2,4-Diamino-5-(phenylthio)-7-quinazolinyl]phenylformaldehyd e (35 mg, 0.093 mmol, Example 148) was dissolved in methanol (3 mL) and sodium borohydride (6 mg mL, 0.093 mmol) was added and the mixture was stirred for 15 minutes. Di water (1 mL) was added and the mixture was purified directly by reversed phase HPLC (20 - 90% acetonitrile in DI water containing 0.1% TFA: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a white solid. HNMR (300 MHz, MeOD) δ 7.52 (d, 1H, J=0.6 Hz), 7.48 (d, 1H, J=1.5 Hz), 7.35-7.29 (m, 6H), 7.23-7.21 (m, 2H), 5.81 (s, 1H). LC/MS [M+H]+ 375.0 Example 152. 5-chloro-7-(isoquinolin-4-yl)quinazoline-2,4-diamine

Step a). Synthesis of 7-bromo-5-chloro uinazoline-24-diamine

4-Bromo-2-chloro-6-fluorobenzonitrile (500 mg, 2.1 mmol) and guanidine carbonate (384 mg, 4.3 mmol) were stirred in NMP (6 mL) at 150°C for 1 hour. The reaction was cooled and purified directly by reversed phase HPLC (20-95% acetonitrile in DI water containing 0.1% formic acid: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a light yellow solid. HNMR (300 MHz, MeOD d4) δ 7.08 (d, 1H, J=1.5 Hz), 7.61 (d, 1H, J=1.5 Hz). LC/MS [M+H] ⁺ 272.8 Step b). Synthesis of 5-chloro-7-(isoquinolin-4-yl)quinazoline-2,4-diamine

Prepared as described in the Example 65 where 7-bromo-5-chloroquinazoline-2,4-diamine (Example 152, step a) was substituted for 4-bromo-2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9- diamine. HNMR (300 MHz, MeOD) δ 9.58 (s, 1H), 8.589s, 1H), 8.43 (d, 1H, J=8.1 Hz), 8.05 (s, 1H), 8.03 (s, 1H), 7.95 (m, 1H), 7.74 (d , 1H, J= 1.5 Hz), 7.61 (d, 1H, J=1.5 Hz). LC/MS [M+H]+ = 322.2 Example 153. N ⁷ -benzyl-5-isopropoxyquinazoline-2,4,7-triamine Step a). Synthesis of 4-amino-2-fluoro-6-iso ro ox benzonitrile. To a solution of 4-amino-2,6-difluoro-benzonitrile (154.1 mg, 1 mmol) in isopropyl alcohol (3 ml) was added NaOH (160 mg, 4 mmol). After the mixture was stirred at 600C overnight, it was purified by C18 reverse phase column chromatography (10 to 65 % acetonitrile in water with 0.1 % formic acid). The collected fractions were dried by lyophilizer to afford the title compound as a yellow solid (161.4 mg, 83.1 %). 1H NMR (DMSO, 300 MHz): δ = 6.47 (s, 2 H), 6.11 (s, 1 H), 6.06-6.02 (d, J = 12.18 Hz, 1 H), 4.60- 4.52 (m, 1 H), 1.31-1.29 (d, J = Hz, 6 H); LCMS calcd for C10H11FN2O [M + H]+ 195.09, found 195.2. Step b). Synthesis of 4-(benzylamin -2-fl r - -i r poxybenzonitrile.

A mixture of 4-amino-2-fluoro-6-isopropoxybenzonitrile (194.2 mg, 1 mmol) and K2CO3 (138.2 mg, 1 mmol) in anhydrous DMF (1.4 ml) was heated at 105C. Benzyl bromide (265.5 mg, 1.5 mmol) was added. The resulting mixture was heated for 1 hour, then purified by C18 reverse phase column chromatography (150 g, 10 to 72 % acetonitrile in water with 0.1% formic acid). The collected fractions were dried by lyophilizer to afford the title compound as a light yellow solid (123 mg, 43.3 %). ¹ H NMR (CDCl3, 300 MHz): 7.43-7.32 (m, 5 H), 5.99-5.95 (dd, J = 1.89, 11.28 Hz, 1 H), 5.86 (m, 1 H), 4.73-4.67 (m, 1 H), 4.54-4.45 (m, 1 H), 4.37-4.35 (d, J = 5.43 Hz, 2 H), 1.35-1.33 (d, J = 6.06 Hz, 6 H); LCMS calcd for C17H17FN2O [M + H]+ 285.14, found 285.2 Step c). Synthesis of N ⁷ -benz l-5-iso ro ox uinazoline-247-triamine

A mixture of 4-(benzylamino)-2-fluoro-6-isopropoxybezonitrile (20 mg, 0.07 mmol), guanidine carbonate (12.6 mg, 0.14 mmol), and K2CO3 (19.5 mg, 0.14 mmol) in anhydrous DMF (1 ml) was heated in microwave at 150C for 1 hour. The product was then purified by C18 reverse phase column chromatography (5 to 30 % acetonitrile in water with 0.1 % formic acid). The collected fractions were dried in lyophilizer to afford the title compound as a white formate salt (5.5 mg, 20.3 %). ¹ H NMR (DMSO, 300 MHz): 7.37-7.11 (m, 9 H), 6.11 (s, 1 H), 5.92 (s, 1 H), 4.69-4.55 (m, 1 H), 4.33-4.31 (d, J = 5.85 Hz, 2 H), 1.35-1.33 (d, J = 6.04 Hz, 6 H); LCMS calcd for C18H21N5O [M + H]+ 324.18, found 324.2. Example 154. Synthesis of N ⁷ -benzyl-N ⁷ -ethyl-5-isopropoxyquinazoline-2,4,7-triamine

To a mixture of 4-(benzylamino)-2-fluoro-6-isopropoxybezonitrile (30 mg, 0.1 mmol, Example 153) and K2CO3 (28 mg, 0.2 mmol) in anhydrous DMF (0.8 ml) was added iodoethane (156 mg, 1 mmol). The mixture was heated in microwave at 100 ^o C for 1.5 hours. It was then purified through C18 reverse phase column chromatography (50 g, 10 to 100 % CH3CN in water with 0.1 % HCO2H). The collected fractions were dried by rotary evaporation to afford the intermediate as a yellow solid (7.7 mg). The material was re-dissolved in anhydrous DMF (1 ml) and added with K2CO3 (28 mg, 0.2 mmol) and guanidine carbonate (36 mg, 0.4 mmol). The resulting mixture was heated in microwave at 160 ^o C for 30 minutes. The product was purified by C18 reverse phase column chromatography (5 to 39 % CH3CN in water with 0.1 % HCO2H). The collected fractions were dried by lyophilizer to afford the title compound as a white formate salt (3.6 mg, 8.7 %). ¹ H NMR (DMSO, 300 MHz): 7.36-7.21 (m, 7 H), 6.56 (br, 2 H), 6.00 (s, 2 H), 4.72-4.66 (m, 1 H), 4.62 (s, 2 H), 3.56-3.54 (q, 2 H), 1.26-1.24 (d, J = 5.97 Hz, 6 H), 1.21-1.16 (t, J = 7.05, 14.04 Hz, 3 H); LCMS calcd for C20H25N5O [M + H] ⁺ 352.21, found 532.2. Example 155. Synthesis of N ⁷ -benzyl-N ⁷ -(cyclopropylmethyl)-5-isopropoxyquinazoline-2,4,7- triamine

To a solution of 4-(benzylamino)-2-fluoro-6-isopropoxybezonitrile (33 mg, 0.116 mmol, Example 153) in anhydrous DMF (0.8 ml) was added NaH (12 mg, 0.3 mmol) followed by cyclopropylmethyl bromide (54 mg, 0.4 mmol). The mixture was heated at 40 ^o C overnight. It was then purified by C18 reverse phase column chromatography (10 to 100 % CH3CN in water with 0.1 % HCO2H). The collected fractions were concentrated by rotary evaporation to afford the intermediate as a yellow solid. It was then treated with guanidine carbonate (45 mg, 0.5 mmol), K2CO3 (70 mg, 0.5 mmol), and anhydrous DMF (1 ml). The mixture was heated in microwave at 160 ^o C for 1.2 hours. The product was then purified by C18 reverse phase column chromatography (5 to 45 % CH3CN in water with 0.1 % HCO2H). The collected fractions were dried by lyophilizer to afford the title compound was a white formate salt (4.2 mg, 8.2 %). ¹ H NMR (DMSO, 300 MHz): 7.35-7.19 (m, 7 H), 6.82 (br, 2 H), 6.08 (s, 1 H), 6.05 (s, 1 H), 4.72 (s, 2 H), 4.70-4.63 (m, 1 H), 3.44-3.42 (m, 2 H), 1.24-1.22 (d, J = 5.94 Hz, 6 H), 1.18-1.10 (m, 1 H), 0.54-0.47 (m, 2 H), 0.35-0.29 (m, 2 H); LCMS calcd for C22H27N5O [M + H] ⁺ 378.21, found 378.2. Example 156. 4-{[(1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl]oxy}-3-methyl-2,3-d ihydrofuro[2,3- f]quinazoline-7,9-diamine

A mixture of 4,6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile (100.3 mg, 0.514 mmol, Int-11) and exo-norborneol (69.2 mg, 0.617 mmol) was dissolved in anhydrous DMF (1 ml) and treated with NaH (~ 60 % dispersion in mineral oil, 35.5 mg). The reaction was stirred at room temperature for 10 minutes then heated in microwave at 100 ^o C for 20 minutes. It was directly applied to a C18 reverse phase column (20 to 100 % CH3CN in water with 0.1 % formic acid). The collected fractions were concentrated by rotary evaporation to afford the intermediate as a clear oil. The material was re-dissolved in anhydrous NMP (1.5 ml) and mixed with guanidine carbonate (180.2 mg, 2 mmol) and K2CO3 (139 mg, 1 mmol). After the mixture was heated in microwave at 140 ^o C for 20 minutes, it was purified by C18 reverse phase column chromatography (5 to 35 % CH3CN in water with 0.1 % formic acid). The collected fractions were dried by lyophilizer to afford the title compound as a light yellow solid (17.8 mg, 10.6 %). ¹ H NMR (DMSO, 300 MHz): 8.29 (s, 1 H), 7.51 (br, 1 H), 6.71 (br, 2 H), 6.20 (s, 1 H), 4.85-4.78 (dt, J = 1.77, 9.21 Hz, 1 H), 4.33-4.29 (m, 2 H), 3.57-3.48 (m, 1 H), 2.42 (m, 1 H), 2.31 (br, 1 H), 1.83-1.77 (m, 1 H), 1.56-1.38 (m, 4 H), 1.26-1.08 (m, 6 H); LCMS calcd for C18H22N4O2 [M + H] ⁺ 327.18, found 327.2. Example 157. Synthesis of 4-((S)-tetrahydrofuran-3-yloxy)-2,3-dihydro-3-methylfluro[2, 3- f]quinazoline-7,9-diamine

To a solution of (S)-(+)-3-hydroxytetrahydrofuran (60 mg, 0.68 mmol) in anhydrous DMF (0.5 ml) was added NaH (~60% dispersion in mineral oil, 25 mg). The mixture was stirred at room temperature for 5 minutes, then mixed with 4,6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile (83.5 mg, 0.43 mmol, Int-11). The resulting mixture was stirred for 1 hour and purified by C18 reverse phase column chromatography (50 g, 20 to 80 % CH3CN in water with 0.1 % formic acid). The collected fractions were concentrated by rotary evaporation to afford the intermediate as a clear oil. The material was re- dissolved in NMP (1.5 ml) and mixed with guanidine carbonate (180.2 mg, 2 mmol) and K2CO3 (139 mg, 1 mmol). The mixture was heated in microwave at 140 ^o C for 30 minutes. The reaction was directly purified by C18 reverse phase column chromatography (0 to 14 % CH3CN in water with 01. % formic acid). The collected fractions were dried in lyophilizer to afford the title compound as a light yellow solid (14.1 mg, 10.8 %). ¹ H NMR (DMSO, 300 MHz): 8.17 (s, 1 H), 6.69 (br, 2 H), 6.27 (s, 1 H), 5.13-5.08 (m, 1 H), 4.87-4.81 (t, J = 8.85, 18.03 Hz, 1 H), 4.36-4.32 (q, J = 5.43, 8.82 Hz, 1 H), 3.95-3.90 (q, J = 4.05, 10.23 Hz, 1 H), 3.85-3.75 (m, 4 H), 2.31-2.20 (m, 2 H), 2.07-2.97 (m, 1 H), 1.25-1.23 (d, J = 6.72 Hz, 3 H); LCMS calcd for C15H18N4O3 [M + H] ⁺ 303.15, found 303.2. Example 158. Synthesis of 4-((R)-tetrahydrofuran-3-yloxy)-2,3-dihydro-3-methylfluro[2, 3- f]quinazoline-7,9-diamine

The title compound was prepared analogously to 4-((S)-tetrahydrofuran-3-yloxy)-2,3-dihydro-3- methylfluro[2,3-f]quinazoline-7,9-diamine. The product was a light yellow solid (14.5 mg, 10.4 %). ¹ H NMR (DMSO, 300 MHz): 8.22 (s, 1 H), 6.24 (br, 2 H), 6.18 (s, 1 H), 5.12-5.07 (m, 1 H), 4.84-4.78 (t, J = 8.91, 17.88 Hz, 1 H), 4.33-4.28 (q, J = 5.82, 8.85 Hz, 1 H), 3.95-3.90 (q, J = 4.14, 9.69 Hz, 1 H), 3.86- 3.77 (m, 4 H), 2.30-2.19 (m, 2 H), 2.06-1.93 (m, 1 H), 1.24-1.23 (d, J = 6.66 Hz, 3 H); LCMS calcd for C15H18N4O3 [M + H] ⁺ 303.15, found 303.2. Example 159. Synthesis of 2,3-dihydro-3-methyl-4-(5,6-dimethyl-1H-benzo[d]imidazole-1- yl)furo[2,3-f]quinazoline-7,9-diamine

A mixture of 4,6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile (109 mg, 0.56 mmol, Int- 11) and 5,6-dimethylbenzimidazole (98.1 mg, 0.67 mmol) was dissolved in anhydrous NMP (1 ml) and mixed with K2CO3 (93.8 mg, 0.67 mmol). The resulting mixture was heated in microwave at 100 ^o C for 6 hours, then purified by C18 reverse phase column chromatography (10 to 75 % CH3CN in water with 0.1 % of formic acid). The collected fractions were concentrated by rotary evaporation to afford the intermediate as a yellow solid. The material was then re-dissolved in anhydrous NMP (1.5 ml) and treated with guanidine carbonate (180 mg, 2 mmol) and K2CO3 (140 mg, 1 mmol). The reaction mixture was heated in microwave at 140 ^o C for 20 minutes, then purified by C18 reverse phase column

chromatography (5 to 25 % CH3CN in water with 0.1% formic acid). The collected fractions were dried by lyophilizer to afford the title compound as light yellow solid (18.7 mg, 7.9 %). ¹ H NMR (DMSO, 300 MHz): 8.38 (s, 1 H), 8.18 (s, 1 H), 7.55 (s, 1 H), 7.24 (s, 1 H), 6.75 (s, 1 H), 6.29 (s, 2 H), 4.97-4.91 (t, J = 8.97, 17.91 Hz, 1 H), 4.36-4.31 (q, J = 5.67, 14.49 Hz, 1 H), 3.75-3.68 (m, 2 H), 2.34 (s, 3 H), 2.32 (s, 3 H), 0.58-5.56 (d, J = 6.72 Hz, 3 H); LCMS calcd for C20H20N6O [M + H] ⁺ 361.18, found 361.2. Example 160. Synthesis of 2,3-dihydro-3-methyl-4-(5-methyl-1H-benzo[d]imidazole-1-yl)f uro[2,3- f]quinazoline-7,9-diamine and 2,3-dihydro-3-methyl-4-(6-methyl-1H-benzo[d]imidazole-1- yl)furo[2,3-f]quinazoline-7,9-diamine

5-methybenzimidazole (79.3 mg, 0.6 mmol) was dissolved in anhydrous DMF (0.5 ml) and added to NaH (60% dispersion in mineral oil, 24.8 mg). After the mixture was stirred at room temperature for 10 minutes, it was added with 4,6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile (89.5 mg, 0.46 mmol, Int-11) and an additional amount of anhydrous DMF (0.5 ml). The reaction was stirred at room temperature for 2 hours, then purified by C18 reverse phase column chromatography (50 g, 20 to 63 % CH3CN in water with 0.1 % formic acid). The collected fractions were concentrated by rotary evaporation to afford the mixture of the intermediate as a yellow oil. This material was re-dissolved in anhydrous NMP (1.5 ml) and mixed with guanidine carbonate (180.1 mg, 2 mmol) and K ₂ CO ₃ (140 mg, 1 mmol). The mixture was heated in microwave at 140 ^o C for 25 minutes. It was then purified by C18 reverse phase column chromatography (5 to 15 % CH3CN in water with 0.1 % formic acid). The collected fractions were dried by lyophilizer to afford the mixture of products as a yellow solid (18.8 mg, 11.8 %). ¹ H NMR (DMSO, 300 MHz): 8.47 (s, 1 H), 8.45 (s, 1 H), 8.18 (s, 2 H), 7.67-7.64 (d, J = 8.16 Hz, 1 H) 7.58 (s, 1 H), 7.36-7.33 (d, J = 8.34 Hz, 1 H), 7.26 (s, 1 H), 7.17-7.12 (m, 2 H), 6.76 (s, 2 H), 6.23 (br, 4 H), 4.97-4.90 (m, 2 H), 4.36-4.32 (q, J = 5.43, 8.82 Hz, 2 H), 3.75-3.65 (m , 4 H), 2.45 (s, 3 H), 2.43 (s, 3 H), 0.58-0.56 (d, J = 6.66 Hz, 3 H), 5.57-0.55 (d, J = 6.69 Hz, 3 H); LCMS calcd for C19H18N6O [M + H] ⁺ 347.16, found 347.2. Example 161. Synthesis of 2,3-dihydro-3-methyl-4-(2-methyl-1H-benzo[d]imidazole-1-yl)f uro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared analogously to Example 160. The product was a light yellow solid (6 mg, 3.5 %). ¹ H NMR (DMSO, 300 MHz): 8.25 (s, 1 H), 7.75-7.72 (m, 1 H), 7.35-7.22 (m, 3 H), 6.71 (s, 1 H), 6.19 (s, 2 H), 4.72-4.67 (t, J = 8.76, 17.55 Hz, 1 H), 4.12-4.07 (q, J = 6.18, 8.76 Hz, 1 H), 3.20-3.12 (m, 2 H), 2.29 (s, 3 H), 0.54-0.51 (d, J = 6.87 Hz, 3 H); LCMS calcd for C19H18N6O [M + H] ⁺ 347.16, found 347.2. Example 162. Synthesis of 2,3-dihydro-3-methyl-4-(5-methyl-1H-indol-1-yl)furo[2,3-f]qu inazoline- 7,9-diamine

Prepared analogously to Example 160. The product was light yellow solid (17.5 mg, 10.1 %). ¹ H NMR (DMSO, 300 MHz): 8.20 (s, 1 H), 7.57-7.56 (d, J = 3.21 Hz, 1 H), 7.44 (s, 1 H), 7.27-7.24 (d, J = 8.4 Hz, 1 H), 7.03-7.01 (m, 1 H), 6.71 (s, 1 H), 6.63-6.62 (d, J = 2.94 Hz, 1 H), 6.30 (br, 2 H), 4.95-4.89 (t, J = 8.97, 17.94 Hz, 1 H), 4.34-4.29 (q, J = 5.58, 8.85 Hz, 1 H), 3.73-3.66 (m, 2 H), 2.40 (s, 3 H), 0.53-0.51 (d, J = 6.75 Hz, 3 H); LCMS calcd for C20H19N5O [M + H] ⁺ 346.17, found 346.2. Example 163. Synthesis of 2,3-dihydro-4-(5-methoxy-1H-indol-1-yl)-3-methylfuro[2,3-f]q uinazoline- 7,9-diamine

The title compound was prepared analogously to Example 160. The product was a light yellow solid (12.4 mg, 11.4 %). ¹ H NMR (DMSO, 300 MHz): 8.19 (s, 1 H), 7.58-7.57 (d, J = 3.18 Hz, 1 H), 7.27- 7.24 (d, J = 9.0 Hz, 1 H), 7.17-7.16 (d, J = 2.4 Hz, 1 H), 6.84-6.81 (dd, J = 2.43, 8.91 Hz, 1 H), 6.70 (s, 1 H), 6.64-6.63 (d, J = 3.18 Hz, 1 H), 6.23 (br, 2 H), 4.95-4.89 (t, J = 8.97, 17.88 Hz, 1 H), 4.34-4.30 (q, J = 5.64, 8.91 Hz, 1 H), 3.79 (s, 3 H), 3.73-3.65 (m, 2 H), 0.55-0.53 (d, J = 6.72 Hz, 3 H); LCMS calcd for C20H19N5O2 [M + H] ⁺ 361.16, found 361.2. Example 164. Synthesis of 2,3-dihydro-4-(4-methoxy-1H-indol-1-yl)-3-methylfuro[2,3-f]q uinazoline- 7,9-diamine

The title compound was prepared analogously to Example 160. The product was a light yellow solid (11.9 mg, 11 %). ¹ H NMR (DMSO, 300 MHz): 8.21 (s, 1 H), 7.50-7.49 (d, J = 3.24 Hz, 1 H), 7.15- 7.09 (t, J = 7.98, 16.02 Hz, 1 H), 6.95-6.93 (d, J = 8.28 Hz, 1 H), 6.71-6.69 (d, J = 3.87 Hz, 2 H), 6.66- 6.63 (d, J = 7.77 Hz, 1 H), 6.29 (br, 2 H), 4.95-4.89 (t, J = 8.97, 18 Hz, 1 H), 4.34-4.29 (q, J = 5.67, 8.91 Hz, 1 H), 3.92 (s, 3 H), 3.72-3.64 (m, 2 H), 0.54-0.52 (d, J = 6.72 Hz, 3 H); LCMS calcd for C20H19N5O2 [M + H] ⁺ 361.16, found 361.2. Example 165. Synthesis of 3-methyl-4-(3-(3H-tetrazol-5-yl)phenoxy)-2,3-dihydrofuro[2,3 - f]quinazoline-7,9-diamine

2,3-dihydro-7-(3’cyano-phenoxyl)-3-methylfuro[2,3-f]quinaz oline-2,4-diamine (30mg, 0.09mmol, Example 125), ammonium chloride (50mg, 0.9mmol) and sodium azide (65mg, 1mmol) were dissolved into 3ml DMF. The mixture was heated overnight, then purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield of white powder, 0.015g, yield of 55%. ¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.13(s, 1H) 7.89(d, J=7.5Hz, 1H) 7.68(m, 1H) 7.49(m, 2H) 7.01(d, J=7.5Hz, 1H) 6.22(s, 1H) 4.99(t, J= 9Hz, 1H) 4.50(m, 1H) 3.74 (m, 1H) 1.37(d, J=6.6Hz, 3H). LC/MS 377.1 [M+H] ⁺ . Example 166. Preparation of 2-[2-(2-{2-[3-chloro-5-(8,10-diamino-3,4-dihydro-2H-pyrano[2 ,3- f]quinazolin-5-yl)phenoxy]ethoxy}ethoxy)ethoxy]ethan-1-ol.

Step a) The 2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethan-1-ol (65 mg, 0.64 mmol), 5-(3-chloro-5- hydroxyphenyl)-7-fluoro-3,4-dihydro-2H-1-benzopyran-8-carbon itrile (Int-15) (130 mg, 43 mmol), and potassium carbonate (60 mg, 0.43 mmol) were stirred together in NMP (3 mL) at 80°C for 2 hours. The mixture was applied directly to reversed phase HPLC (20-95% acetonitrile in DI water containing 0.1% formic acid: 20 minute gradient). The pure fractions were pooled and concentrated on the rotary evaporator to afford the carbonitrile intermediate as a clear film. LC/MS [M+H] ⁺ 480.0. Step b) The intermediate was taken up in NMP (2 mL) and guanidine carbonate (155 mg, 1.28 mmol) was added and the mixture was stirred at 150°C for 2 hours, cooled and reversed phase HPLC (10-95% acetonitrile in DI water containing 0.1% formic acid: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a white solid. Yield: 56%, 2 steps. LC/MS [M+H] ⁺ 519.0. Example 167. Preparation of 14-{[4-(8,10-diamino-3,4-dihydro-2H-pyrano[2,3-f]quinazolin- 5- yl)naphthalen-1-yl]oxy}-3,6,9,12-tetraoxatetradecan-1-ol.

The title compound was prepared from 7-fluoro-5-(4-hydroxynaphthalen-1-yl)-3,4-dihydro-2H-1- benzopyran-8-carbonitrile and 14-bromo-3,6,9,12-tetraoxatetradecan-1-ol as described in Example 166. LC/MS [M+H] ⁺ 579.2. Example 168. Preparation of 5-(2,3-dihydro-1,4-benzodioxin-5-yl)-3,4-dihydro-2H-pyrano[2 ,3- f]quinazoline-8,10-diamine.

The title compound was prepared from 5-(2,3-dihydro-1,4-benzodioxin-5-yl)-7-fluoro-3,4-dihydro-2H -1- benzopyran-8-carbonitrile as described in Example 166 step b). LC/MS [M+H] ⁺ 351.2. Example 169. Preparation of 6-phenoxy-2,5-dihydrooxepino[3,2-h]isoquinoline-9,11-diamine .

The title compound was prepared from 6,8-difluoro-2,5-dihydro-1-benzoxepine-9-carbonitrile as described in example 3. ¹ H-NMR (300 MHz, MeOD d4) δ 7.51-7.46 (m, 2H), 7.30 (t, 1H, J=7.5 Hz), 7.18 (d, 2H, J=6.9 Hz), 6.21-6.10 (m, 1H), 6.17 (s, 1H), 5.70 (q, 1H, J=7.5 Hz), 5.51 (d, 1H, J=17.1 Hz), 5.37 (d, 1H, J=10.4 Hz), 3.51 (dd, 1H, J=15.5, 9.5 Hz), 3.06 (dd, 1H, J=15.5, 7.4 Hz). LC/MS [M+H] ⁺ 321.2. Example 170. Synthesis of 1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)-1H- indole-4-carbaldehyde Step a). Synthesis of 6-fluoro-4-(4-formyl-1H-indol-1-yl)-2,3-dihydro-3-methylbenz ofuran-7- carbonitrile

A 25 ml reaction flask was filled with nitrogen and charged with 4,6-difluoro-2,3-dihydro-3- methylbenzofuran-7-carbonitrile (195.2 mg, 1 mmol), indole-4-carboxaldehyde (159.7 mg, 1.1 mmol) and anhydrous DMF (1 ml). After the mixture was cooled in an ice-water bath, NaH (60% in mineral oil, 48 mg, 1.2 mmol) was slowly added. The reaction was stirred under nitrogen for 2 hours. The desired product was less polar and separated from its isomer through RPLC (50 g, 5 to 75 % CH3CN in water with 0.1 % formic acid). The collected fractions were concentrated by rotary evaporation and further dried in high vacuum to afford the title compound as a white solid (188.6 mg, 58.9 %). ¹ H NMR (CDCl3, 300 MHz): δ = 10.30 (s, 1 H), 7.78-7.75 (dd, J = 0.81, 7.17 Hz, 1 H), 7.59-7.56 (m, 2 H), 7.48-7.46 (m, 1 H), 7.43- 7.42 (d, J = 3.21 Hz, 1 H), 6.83 (d, J = 9.66 Hz, 1 H), 5.02-4.96 (t, J = 9.12 Hz, 1 H), 4.42-4.37 (q, J = 5.73, 9.12 Hz, 1 H), 3.78-3.65 (m, 1 H), 0.71-0.69 (d, J = 6.8 Hz, 3 H); LCMS: C19H13FN2O2 [M + H] ⁺ =321. Step b). Synthesis of 1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)-1H-indole-4- carbaldehyde

A mixture of 6-fluoro-4-(4-formyl-1H-indol-1-yl)-2,3-dihydro-3-methylbenz ofuran-7-carbonitrile (33 mg, 0.103 mmol), guanidine carbonate (46 mg, 0.511 mmol), and K2CO3 (60 mg, 0.43 mmol) in NMP (0.5 ml) and water (0.1 ml) was heated in microwaved at 140 ^o C for 20 minutes. It was then purified through HPLC (5 to 25 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the title compound as light yellow solid. ¹ H NMR (DMSO, 300 MHz): δ = 10.27 (s, 1 H), 8.20 (s, 1 H), 7.91-7.90 (d, J = 2.88 Hz, 1 H), 7.83-7.70 (m, 2H), 7.46-7.41 (dd, J = 7.3, 8.2 Hz, 1 H), 7.37-7.36 (d, J = 3.2 Hz, 1 H), 6.73 (s, 2 H), 6.29 (s, 2 H), 4.96-4.90 (t, J = 9.06 Hz, 1 H), 4.35-4.30 (q, J = 5.64, 8.91 Hz, 1 H), 3.69-3.61 (m, 1 H), 0.50-0.48 (d, J = 6.72 Hz, 3 H); LCMS: C20H17FN5O2 [M + H] ⁺ = 360. Example 171. Synthesis of 1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)-1H- indole-3-carbaldehyde The title compound was prepared analogously to 1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)-1H-indole-4-carbaldehyde. The product was a light yellow solid. ¹ H NMR (DSMO, 300 MHz): δ = 10.04 (s, 1 H), 8.62 (s, 1 H), 8.23-8.20 (m, 1 H), 7.53 (br, 1 H), 7.43-7.34 (m, 3 H), 6.79 (s, 2 H), 6.28 (s, 2 H), 4.97 (t, J = 8.97 Hz, 1 H), 4.36-4.32 (q, J = 5.76, 8.88 Hz, 1 H), 3.70-3.61 (m, 1 H), 0.57- 0.55 (d, J = 6.72 Hz, 3 H); LCMS: C20H17FN5O2 [M + H] ⁺ = 360. Example 172. Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)-1H-indol- 4-yl)methanol Step a). Synthesis of 6-fluoro-2,3-dihydro-4-(4-(hydroxymethyl)-1H-indol-1-yl)-3- methylbenzofuran-7-carbonitrile

6-fluoro-4-(3-formyl-1H-indol-1-yl)-2,3-dihydro-3-methylbenz ofuran-7-carbonitrile (30 mg, 0.094 mmol) was dissolved in a 1:1 mixture of MeOH:DCM (~4 ml) by gently heated with a heat gun. After the solution was cooled to room temperature then to -78 ^o C, it was added with NaBH4 (31 mg, 0.82 mmol). The resulting mixture was slowly warmed to room temperature over one hour. It was then quenched with formic acid (~0.1 ml) and concentrated by rotary evaporation. The residue was directly purified through HPLC (5 - 55 % CH3CN in water with 0.1 % formic acid). The collected fractions were concentrated by rotary evaporation to afford the title compound as a white solid (16.5 mg, 54.5 %). ¹ H NMR (MeOD4, 300 MHz): δ = 7.48-7.47 (d, J = 3.39 Hz, 1 H), 7.32-7.21 (m, 3 H), 6.98-6.95 (d, J = 10.44 Hz, 1 H), 6.92-6.91 (d, J = 3.36 Hz, 1 H), 5.03-4.97 (t, J = 9.06 Hz, 1 H), 4.95 (s, 2 H), 4.43-4.38 (q, J = 5.49, 6.3 Hz, 1 H), 3.89-3.77 (m, 1 H), 0.66-0.63 (d, J = 6.87 Hz, 3 H); LCMS: C ₁₉ H ₁₅ FN ₂ O ₂ [M + H] ⁺ =323. Step b). Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)-1H-indol-4- yl)methanol

A mixture of 6-fluoro-2,3-dihydro-4-(4-(hydroxymethyl)-1H-indol-1-yl)-3-m ethylbenzofuran-7- carbonitrile (16 mg, 0.05 mmol), guanidine carbonate (29 mg, 0.32 mmol), and K2CO3 (22 mg, 0.16 mmol) in NMP (0.5 ml) was heated in microwave at 140 ^o C for 20 minutes. It was then directly purified through HPLC (0 - 20 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the product as a white solid (5.4 mg, 33.5 %). ¹ H NMR (DMSO, 300 MHz): δ = 8.23 (s, 1 H), 7.61-7.60 (d, J = 3.24 Hz, 1 H), 7.51 (br, 1 H), 7.25-7.13 (m, 3 H), 6.80-6.79 (d, J = 3.24 Hz, 2 H), 6.70 (s, 1 H), 6.32 (s, 2 H), 4.95 (t, J = 8.94 Hz, 1 H), 4.81 (s, 2 H), 4.35-4.30 (q, J = 5.52, 8.79 Hz, 1 H), 3.75-3.65 (m, 1 H), 0.55-0.53 (d, J = 6.69 Hz, 3 H); LCMS: C20H19N5O2 [M + H] ⁺ =362. Example 173. Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)-1H-indol- 3-yl)methanol

The title compound was prepared analogously to (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)-1H-indol-4-yl)methanol. The compound was a white solid (4.3 mg, 35 %). ¹ H NMR (DMSO, 300 MHz): δ = 8.21 (s, 1 H), 7.74-7.72 (d, J = 7.35 Hz, 1 H), 7.51 (s, 2 H), 7.35-7.32 (d, J = 7.92 Hz, 1 H), 7.22-7.11 (m, 2 H), 6.77 (br, 1 H), 6.69 (s, 1 H), 6.32 (s, 2 H), 4.95-4.89 (t, J = 8.97 Hz, 1 H), 4.72 (s, 2 H), 4.35-4.31 (q, J = 5.46, 8.88 Hz, 1 H), 3.72-3.65 (m, 1 H), 0.57-0.55 (d, J = 6.72 Hz, 3 H); LCMS: C20H19N5O2 [M + H] ⁺ = 362. Example 174.4-(1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazo lin-4-yl)-1H-indol-4-yl)but-3- en-2-one

To a solution of 1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)-1H-indole-4- carbaldehyde (30 mg, 0.08 mmol) in DMF (0.5 ml) and acetone (1 ml) was added piperidine (145 mg, 1.7 mmol). The mixture was heated in microwave at 100 ^o C for 2 hours. After acetone was removed by rotary evaporation, the mixture was purified through HPLC (5 to 25 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the title compound as a yellow solid (6.6 mg, 20.7 %). ¹ H NMR (DMSO, 300 MHz): δ = 8.23 (s, 1 H), 8.03-7.98 (d, J = 16.4 Hz, 1 H), 7.80-7.79 (d, J = 3.3 Hz, 1 H), 7.60-7.58 (d, J = 7.35 Hz, 1 H), 7.45-7.42 (d, J = 8.16 Hz, 1 H), 7.29-7.24 (t, J = 7.89 Hz, 1 H), 7.17- 7.16 (d, J = 3.18 Hz, 1 H), 6.99-6.94 (d, J = 16.4 Hz, 1 H), 6.73 (s, 2 H), 6.22 (br, 2 H), 4.96-4.90 (t, J = 8.91 Hz, 1 H), 4.34-4.29 (q, J = 5.64, 8.88 Hz, 1 H), 3.73-3.63 (m, 1 H), 2.43 (s, 3 H), 0.52-0.49 (d, J = 6.72 Hz, 3 H); LCMS: C23H21N5O2 [M + H] ⁺ = 399. Example 175. Synthesis of 4-(1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin- 4-yl)-1H- indol-4-yl)butan-2-one

To a solution of 1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)-1H-indole-4- carbaldehyde (30 mg, 0.08 mmol) in DMF (0.5 ml) and acetone (1 ml) was added piperidine (145 mg, 1.7 mmol). The mixture was heated in microwave at 100 ^o C for 2 hours. It was then treated with the acetic acid (~0.2 ml) and hydrogenated in the presence of Pd/C for 1 hour. The solid was filtered off, and the substrate was concentrated by rotary evaporation. The residue was purified through HPLC (5 to 25 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the title compound as a white solid (6 mg, 18.9 %). ¹ H NMR (MeOD, 300 MHz): δ = 7.49-7.48 (d, J = 3.39 Hz, 1 H), 7.26-7.23 (d, J = 8.31 Hz, 1 H), 7.19-7.14 (t, J = 7.02 Hz, 1 H), 7.03-7.00 (d, J = 7.05 Hz, 1 H), 6.94 (s, 1 H), 6.85-6.84 (d, J = 3.33 Hz, 1 H), 5.09-5.03 (t, J = 9.03 Hz, 1 H), 4.50-4.46 (q, J = 5.43, 8.97 Hz, 1 H), 3.90-3.77 (m, 1 H), 3.23-3.18 (t, J = 7.38 Hz, 1 H), 2.99-2.94 (t, J = 7.8 Hz, 1 H), 2.17 (s, 3 H), 0.68-0.66 (d, J = 6.78 Hz, 3 H); LCMS: C23H23N5O2 [M + H] ⁺ = 402. Example 176. Synthesis of 1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)-1H- pyrrole-3-carbaldehyde

1H-pyrrole-3-carbaldehyde (58 mg, 0.61 mmol) and 4,6-difluoro-2,3-dihydro-3-methylbenzofuran- 7-carbonitrile (97.6 mg, 0.5 mmol) were dissolved in DMF (1 ml) and cooled in ice-water bath. NaH (40 mg) was slowly added. The reaction was stirred for 1 hour then directly purified through RPLC (5 to 54 % CH3CN in water with 0.1 % formic acid). The fractions of the mixture of the desired product and its isomer were concentrated by rotary evaporation to a white solid. The mixture was re-dissolved in NMP (1 ml) and added with guanidine carbonate (80 mg), K2CO3 (140 mg), and water (0.2 ml). The resulting mixture was heated in microwave at 130 ^o C for 40 minutes. It was then purified through RPLC (50 g, 5 - 20 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the product as a white solid (23mg, 14.9 %). ¹ H NMR (DMSO, 300 MHz): δ = 9.79 (s, 1 H), 8.21 (s, 1 H), 8.09-8.07 (t, J = 1.65 Hz, 1 H), 7.36-7.35 ( t, J = 2.22 Hz, 1 H), 6.69-6.68 (m, 3 H), 6.22 (br, 2 H), 4.93-4.87 (t, J = 8.97 Hz, 1 H), 4.42-4.37 (q, J = 5.07, 8.91 Hz, 1 H), 4.00-3.91 (m, 1 H), 0.80-0.78 (d, J = 6.72 Hz, 3 H); LCMS: C16H15N5O2 [M + H] ⁺ = 310. Exapmle 177. Synthesis of 4-(1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin- 4-yl)-1H- pyrrol-3-yl)but-3-en-2-one

The title compound was prepared analogously to 4-(1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)-1H-indol-4-yl)but-3-en-2-one. The compound was a yellow solid (6.6 mg, 20.7 %). ¹ H NMR (DMSO, 300 MHz): δ = 8.25 (s, 1 H), 7.69-7.68 (t, J = 1.95 Hz, 1 H), 7.60-7.54 (d, J = 16.1 Hz, 1 H), 7.41 (br, 1 H), 7.29-7.28 (t, J = 2.52 Hz, 1 H), 6.72-6.71 (q, J = 1.53, 2.91 Hz, 1 H), 6.64 (s, 1 H), 6.52- 6.47 (d, J = 16.1 Hz, 1 H), 6.15 (br, 2 H), 4.91-4.85 (t, J = 8.88 Hz, 1 H), 4.41-4.37 (q, J = 4.89, 9.0 Hz, 1 H), 3.99-3.92 (m, 1 H), 2.26 (s, 3 H), 0.82-0.00 (d, J = 6.72 Hz, 3 H); LCMS: C19H19N5O2 [M + H] ⁺ = 350. Example 178. Synthesis of 4-(4-bromo-1H-indol-1-yl)-2,3-dihydro-3-methylfuro[2,3-f]qui nazoline- 7,9-diamine

A solution of 4-bromoindole (392 mg, 2 mmol) in anhydrous DMF (1 ml) was cooled in an ice- water bath and slowly treated with NaH (88 mg, 2.2 mmol). After stirred for 10 minutes, it was added to a solution of 4,6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile (440 mg, 2.2 mmol) in anhydrous DMF (0.5 ml) at 0 ^o C. The resulting mixture was stirred for 50 minutes, then directly purified through RPLC (20 to 100 % CH3CN in water with 0.1 % formic acid). The collected fractions were concentrated by rotary evaporation to a white solid intermediate (421 mg). The material was then added with guanidine carbonate (270 mg, 3 mmol), K2CO3 (420 mg, 3 mmol), and NMP (2 ml). The mixture was heated in 150 oC oil bath for 2 hours. After cooled to room temperature, it was purified through RPLC (100 g, 5 to 50 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the product as a white solid (443 mg, 54.0 %). ¹ H NMR (DMSO, 300 MHz): δ = 8.18 (s, 1 H), 7.78-7.77 (d, J = 3.3 Hz, 1 H), 7.39-7.36 (d, J = 7.86 Hz, 2 H), 7.17-7.11 (t, J = 7.98 Hz, 1 H), 6.76 (br, 1 H), 6.72 (s, 1 H), 6.69-6.68 (d, J = 3.27 Hz, 1 H), 6.28 (br, 2 H), 4.95-4.89 (t, J = 9.0 Hz, 1 H), 4.35-4.30 (q, J = 5.79, 8.82 Hz,1 H), 3.69-3.61 (m, 1 H), 0.53-0.51 (d, J = 6.72 Hz, 3 H); LCMS: C19H16BrN5O [M + H] ⁺ = 410. Example 179. Synthesis of 2,3-dihydro-3-methyl-4-(4-vinyl-1H-indol-1-yl)furo[2,3-f]qui nazoline-7,9- diamine

A microwave tube was filled with nitrogen and charged with a mixture of 4-(4-bromo-1H-indol-1- yl)-2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diamine (20 mg, 0.049 mmol), vinylboronic acid dibutyl ester (36.8 mg, 0.2 mmol), K2CO3 (70 mg, 0.5 mmol), Pd(PPh3)2Cl2 (6 mg), NMP (1 ml), and water (0.4 ml). The mixture was heated in microwaved at 140 ^o C for 20 minutes then directly purified through RPLC (100 g, 5 to 36 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the product as a white solid (7.17 mg.41 %). ¹ H NMR (DMSO, 300 MHz): δ = 8.25 (s, 1 H), 7.68- 7.67 (d, J = 3.3 Hz, 1 H), 7.57-7.49 (m, 1 H), 7.35-7.33 (d, J = 7.11 Hz, 1 H), 7.29-7.27 (d, J = 7.98 Hz, 1 H), 7.23-7.13 (m, 2 H), 6.99-6.98 (d, J = 3.27 Hz, 1 H), 6.72 (s, 1 H), 6.33 (br, 2 H), 6.01-5.94 (dd, J = 1.08, 17.7 Hz, 1 H), 5.44-5.40 (dd, J = 1.05, 11.1 Hz, 1 H), 4.96-4.90 (t, J = 9.0 Hz, 1 H), 4.35-4.30 (q, J = 5.61, 8.85 Hz, 1 H), 3.72-3.64 (m, 1 H), 0.53-0.51 (d, J = 6.75 Hz, 3 H); LCMS: C21H19N5O [M + H] ⁺ = 358. Example 180. Synthesis of 4-(4-(1H-pyrazol-4-yl)-1H-indol-1-yl)-2,3-dihydro-3-methylfu ro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared analogously to 2,3-dihydro-3-methyl-4-(4-vinyl-1H-indol-1- yl)furo[2,3-f]quinazoline-7,9-diamine. ¹ H NMR (DMSO, 300 MHz): δ = 8.25 (s, 1 H), 8.17 (s, 2 H), 7.80 (br, 1 H), 7.69-7.67 (d, J = 3.36 Hz, 1 H), 7.36-7.33 (dd, J = 2.13, 6.18 Hz, 1 H), 7.30-7.17 (m, 2 H), 7.03-7.02 (d, J = 3.27 Hz, 2 H), 6.80-6.77 (m, 3 H), 4.98-4.92 (t, J = 9.03 Hz, 1 H), 4.37-4.32 (q, J = 5.67, 8.91 Hz, 1 H), 3.78-3.69 (m, 1 H), 0.57-0.55 (d, J = 6.75 Hz, 3 H); LCMS: C22H19N4O [M + H] ⁺ = 398. Example 181. Synthesis of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalene-1-carbaldehyde

A microwave-reaction tube was filled with nitrogen and charged with a mixture of 4-bromo-2,3- dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diamine (150 mg, 0.5 mmol), 4-formylnaphthalene-1-boronic acid (120 mg, 0.6 mmol), K2CO3 (280 mg, 2 mmol), Pd(PPh3)2Cl2 (35.1 mg, 0.05 mmol), NMP (1.5 ml) and water (0.5 ml). The mixture was heated at 140 ^o C in microwave for 20 minutes. It was then directly purified through RPLC (100 g, 5 to 35 % CH3CN in water with 0.1 % formic acid). The collected fraction was dried in lyophilizer to afford the product as a yellow solid (61.4 mg, 33.2 %). ¹ H NMR (DMSO, 300 MHz): δ = 10.46 (s, 1 H), 9.29-9.26 (d, J = 8.58 Hz, 1 H), 8.30-8.26 (dd, J = 3.18, 7.35 Hz, 1 H), 8.18 (s, 1 H), 7.87-7.61 (m, 5 H), 6.69-6.60 (d, J = 28 Hz, 1 H), 6.37 (br, 2 H), 4.93-4.4.83 (m, 1 H), 4.35-4.23 (dq, J = 5.37, 8.88, 14.4 Hz, 1 H), 3.17-3.09 (m, 1 H), 0.57-0.50 (dd, J =6.75, 12.4 Hz, 3 H); LCMS: C22H18N4O2 [M + H] ⁺ = 371. Example 182. Synthesis of 4-(1-((dimethylamino)methyl)naphthalen-4-yl)-2,3-dihydro-3- methylfuro[2,3-f]quinazoline-7,9-diamine

A mixture of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)naphthalene-1- carbaldehyde (20 mg, 0.054 mmol) and dimethylhydrochloride (42 mg, 0.5 mmol) in anhydrous EtOH (1 ml) was heated at 1500C in microwave for 2 hours. After cooled in an ice-water bath, it was added with NaBH4 (38 mg, 1 mmol) and MeOH (~0.5 ml). The resulting mixture was stirred at 0 ^o C to room temperature for 2 hours. It was quenched with 0.1 % formic acid in CH3CN. The solution was concentrated by rotary evaporation and purified through HPLC (5 to 15 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the title product as a white formate salt (5.7 mg, 23.7 %). ¹ H NMR (MeOD, 300 MHz): δ = 8.39-8.35 (dd, J = 4.02, 8.52 Hz, 1 H), 7.80-7.52 (m, 5 H), 6.91-6.83 (d, J = 25.6 Hz, 1 H), 5.07-4.99 (m, 1 H), 4.59-4.39 (m, 3 H), 3.77-3.70 (m, 0.5 H), 3.30-3.26 (m, 0.5 H), 2.77 (s, 3 H), 2.68 (s, 3 H), 0.66-0.65 ( dd, J = 2.7, 6.8 Hz, 3 H); LCMS: C24H25N5O [M + H] ⁺ = 400. Example 183. Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalen-4-yl)methanol The title compound was a side product in the preparation of 4-(1- ((dimethylamino)methyl)naphthalen-4-yl)-2,3-dihydro-3-methyl furo[2,3-f]quinazoline-7,9-diamine. ¹ H NMR (MeOD, 300 MHz): δ = 8.27-8.23 (dd, J = 2.07, 8.46 Hz, 1 H), 7.77-7.45 (m, 5 H), 6.85-6.78 (d, J = 28.9 Hz, 1 H), 5.18 (s, 2 H), 5.03-4.95 (m, 1 H), 4.48-4.37 (dq, J = 5.22, 8.97, 14.2 Hz, 1 H), 3.79-3.61 (m, 1 H), 0.68-0.64 (dd, J = 4.62, 6.78 Hz, 3 H); LCMS: C22H20N4O2 [M + H] ⁺ = 373. Example 184. Synthesis of 2,3-dihydro-3-methyl-4-(1-((piperidin-1-yl)methyl)naphthalen -4- yl)furo[2,3-f]quinazoline-7,9-diamine

The title compound was prepared analogously to 4-(1-((dimethylamino)methyl)naphthalen-4-yl)- 2,3-dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diamine. ¹ H NMR (MeOD, 300 MHz): δ = 8.43-8.39 (m, 1 H), 7.78-7.44 (m, 5 H), 6.85-6.78 (d, J = 21.5 Hz, 1 H), 5.03-4.95 (m, 1 H), 4.68-4.61 (m, 1 H), 4.48-4.36 (dq, J = 5.22, 8.85, 14.2 Hz, 1 H), 4.20-4.07 (m, 2 H), 2.75-2.66 (m, 4 H), 1.72-1.63 (m, 4 H), 1.59-1.51 (m, 2 H), 0.66-0.63 (dd, J = 2.01, 6.78 Hz, 3 H); LCMS: C27H29N5O 1/2[M + H] ⁺ = 220. Example 185. Synthesis of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalene-1-carboxylic acid

A microwave-reaction tube was filled with nitrogen and charged with a mixture of 4-bromo-2,3- dihydro-3-methylfuro[2,3-f]quinazoline-7,9-diamine (295.1 mg, 1 mmol), 4-carboxynaphthalene-1-boronic acid pinacol ester (365 mg, 1.22 mmol), K2CO3 (560 mg, 4 mmol), Pd(PPh3)2Cl2 (90 mg, 0.13 mmol), NMP (2.5 ml), and water (0.7 ml). The mixture was heated at 150 ^o C in microwave for 20 minutes. It was then directly purified through RPLC (3 to 30 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the title product as a white solid (328 mg, 84.9 %). ¹ H NMR (DMSO, 300 MHz): δ = 8.86-8.80 (t, J = 9.42 Hz, 1 H), 8.18 (s, 1 H), 7.96-7.91 (t, J = 8.1 Hz, 1 H), 7.73-7.40 (m, 6 H), 6.82- 6.73 (d, J = 25.0 Hz, 1 H), 4.97-4.88 (q, J = 9.12, 18 Hz, 1 H), 4.40-4.27 (dm, 1 H), 3.66-3.59 (m, 1 H), 3.33-3.13 (m, 1 H), 0.55-0.52 (dd, J = 3.27, 6.69 Hz, 3 H); LCMS: C22H18N4O3 [M + H] ⁺ = 387. Example 186. Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalen-4-yl)(piperidin-1-yl)methanone

A mixture of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)naphthalene-1- carboxylic acid (10 mg, 0.026 mmol) and HATU (20 mg, 0.053 mmol) was dissolved in anhydrous DMSO (~0.3 ml) and stirred at room temperature for 30 minutes. Piperidine (0.85 mg, 0.1 mmol) was added, and the resulting mixture was stirred for 30 minutes. It was then directly purified through HPLC (4 to 35 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the product was a white solid (9.7 mg, 82.3 %). ¹ H NMR (MeOD, 300 MHz): δ = 7.94-7.90 (dd, J = 3.09, 8.34 Hz, 1 H), 7.83-7.54 (m, 5 H), 6.88-6.78 (dd, J = 6.06, 18.3 Hz, 1 H), 5.06-4.95 (m, 1 H), 4.49-4.38 (dq, J = 5.28, 8.94 Hz, 1 H), 3.93-3.91 (m, 2 H), 3.79-3.66 (m, 0.5 H), 3.26-3.22 (m, 2.5 H), 1.86-1.73 (m, 4 H), 1.58- 1.45 (m, 2 H), 0.71-0.64 (q, J = 6.96, 13.7 Hz, 3 H); LCMS: C27H27N5O2 [M + H] ⁺ = 454. Example 187. Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalen-4-yl)(morpholino)methanone

The title compound was prepared analogously to (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalen-4-yl)(piperidin-1-yl)methanone. ¹ H NMR (MeOD, 300 MHz): δ = 7.98-7.94 (dd, J = 3.51, 8.31 Hz, 1 H), 7.84-7.55 (m, 5 H), 6.86-6.78 (m, 1 H), 5.05-4.97 (m, 1 H), 4.49-4.37 (dq, J = 5.0, 8.6 Hz, 1 H), 4.07-3.87 (m, 4 H), 3.77-3.53 (m, 2 H), 3.29-3.20 (m, 1 H), 0.71-0.64 (m, 3 H); LCMS: C26H25N5O3 [M + H] ⁺ = 456.20. Example 188. Synthesis of tert-butyl {1-[4-(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin - 4-yl)naphthalene-1-carbonyl]azetidin-3-yl}carbamate

The title compound was prepared analogously to (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalen-4-yl)(piperidin-1-yl)methanone. ¹ H NMR (MeOD, 300 MHz): δ = 8.20-8.16 (dd, J = 3.72, 9.15 Hz, 1 H), 7.82-7.54 (m, 5 H), 6.86-6.79 (d, J = 21.6 Hz, 1 H), 5.05-4.97 (m, 1 H), 4.66- 4.38 (m, 4 H), 4.25-4.13 (m, 2 H), 3.94-3.83 (m, 1 H), 1.46 (s, 9 H), 0.67-0.63 (t, J = 6.63 Hz, 3 H); LCMS: C30H32N6O4 [M + H] ⁺ = 540. Example 189. Synthesis of tert-butyl 3-(4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin- 4- yl)naphthalene-1-carboxamido)azetidine-1-carboxylate

The title compound was prepared analogously to (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalen-4-yl)(piperidin-1-yl)methanone. ¹ H NMR (MeOD, 300 MHz): δ = 8.33-8.29 (m, 1 H), 7.79-7.53 (m, 5 H), 6.87-6.79 (d, J = 23.8 Hz, 1 H), 5.06-4.95 (m, 1 H), 4.89-4.84 (m, 1 H), 4.52- 4.35 (m, 3 H), 4.04-3.99 (q, J = 5.52, 8.82 Hz, 2 H), 3.75-3.68 (m, 0.5 H), 3.31-3.23 (m, 0.5 H), 1.48 (s, 9 H), 0.70-0.65 (q, J = 6.87, 9.36 Hz, 3 H); LCMS: C30H32N6O4 [M + H] ⁺ = 540.26. Example 190. Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalen-4-yl)((S)-3-hydroxypyrrolidin-1-yl)methanone

The title compound was prepared analogously to (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalen-4-yl)(piperidin-1-yl)methanone. ¹ H NMR (DMSO, 300 MHz): δ = 8.22 (s, 1 H), 7.91-7.85 (m, 1 H), 7.79-7.48 (m, 6 H), 6.96 (br, 1 H), 6.70-6.63 (d, J = 19 Hz, 1 H), 4.93-4.84 (q, J = 8.7, 17.3 Hz, 1 H), 4.40-4.20 (m, 3 H), 3.75-3.58 (m, 8 H), 3.33-3.06 (m, 4 H), 2.96-2.87 (m, 1 H), 2.09- 1.69 (m, 3 H), 0.57-0.52 (q, J = 6.72, 11.1 Hz, 3 H); LCMS: C26H25N5O3 [M + H] ⁺ = 456. Example 191. Synthesis of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)-N-(2- (dimethylamino)ethyl)naphthalene-1-carboxamide

The title compound was prepared analogously to (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalen-4-yl)(piperidin-1-yl)methanone. ¹ H NMR (MeOD, 300 MHz): δ = 8.39-8.35 (m, 1 H), 7.81-7.53 (m, 5 H), 6.86-6.78 (d, J = 21.8 Hz, 1 H), 5.06-4.95 (m, 1 H), 4.52-4.40 (dq, J = 5.25, 9.0 Hz, 1 H), 3.76-3.72 (t, J = 6.45 Hz, 2 H), 3.32-3.25 (m, 1 H), 2.98-2.94 (t, J = 6.21 Hz, 2 H), 2.61 (s, 6 H), 0.71-0.65 (q, J = 6.9, 8.55 Hz, 3 H); LCMS: C26H28N6O2 [M + H] ⁺ = 457. Example 192. Synthesis of 4-(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin-4-y l)-N-[(4- sulfamoylphenyl)methyl]naphthalene-1-carboxamide

The title compound was prepared analogously to (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalen-4-yl)(piperidin-1-yl)methanone. ¹ H NMR (MeOD, 300 MHz): δ = 8.31-8.27 (q, J = 4.47, 8.34 Hz, 1 H), 7.97-7.94 (d, J = 8.4 Hz, 2 H), 7.79-7.53 (m, 7 H), 6.85-6.78 (d, J = 22.1 Hz, 1 H), 5.04-4.96 (m, 1 H), 4.77 (s, 2 H), 4.70-4.58 (br, 1 H), 4.58-4.38 (dq, J = 5.22, 9.0 Hz, 1 H), 0.71-0.65 (q, J = 6.87, 9.7 Hz, 3 H); LCMS: C29H26N6O4S [M + H] ⁺ = 555. Example 193. Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalen-4-yl)(3-hydroxyazetidin-1-yl)methanone

A mixture of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)naphthalene-1- carboxylic acid (10 mg, 0.026 mmol) and HATU (20 mg, 0.053 mmol) was dissolved in anhydrous DMSO (~0.3 ml) and stirred at room temperature for 30 minutes. 3-hydroxyazetidine HCl (11 mg, 0.1 mmol) and DIPEA (26 mg, 0.2 mmol) were added, and the resulting mixture was stirred for 1 hour. It was then directly purified through HPLC (4 to 27 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the product was a white solid (6.1 mg, 53.1 %). ¹ H NMR (MeOD, 300 MHz): δ = 8.17-813 (dd, J = 3.93, 9.3 Hz, 1 H), 7.81-7.54 (m, 5 H), 6.88-6.80 (d, J = 22.3 Hz, 1 H), 5.05-4.94 (m, 1 H), 4.71-4.64 (m, 1 H), 4.59-4.52 (m, 1 H), 4.50-4.38 (dq, J = 5.31, 14.3 Hz, 1 H), 4.22-4.08 (m, 2 H), 3.86-3.68 (m, 2 H), 0.67-0.63 (t, J = 6.82 Hz, 3 H); LCMS: C25H23N5O3 [M + H] ⁺ = 442. Example 194. Synthesis of 1-[4-(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin- 4- yl)naphthalene-1-carbonyl]pyrrolidin-3-one

The title compound was prepared analogously to (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalen-4-yl)(3-hydroxyazetidin-1-yl)me thanone. The compound was a tan-color solid. ¹ H NMR (DMSO, 300 MHz): δ = 8.21 (s, 1 H), 8.02-7.92 (m, 1 H), 7.82-7.49 (m, 6 H), 6.87 (br, 1 H), 6.69-6.63 (d, J = 18.9 Hz, 1 H), 6.52-6.43 (br, 1 H), 4.92-4.83 (m, 1 H), 4.34-4.23 (m, 1 H), 4.09-4.06 (m, 2 H), 3.61-3.59 (m, 2 H), 2.73-2.68 (t, J = 8.16 Hz, 1 H), 2.60-2.55 (t, J = 7.71 Hz, 1 H), 0.58-0.50 (m, 3 H). LCMS: C26H23N5O3 [M + H] ⁺ = 454. Example 195. Synthesis of (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)naphthalen-4-yl)((S)-3-hydroxypiperidin-1-yl)methanone

The title compound was prepared analogously to (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalen-4-yl)(3-hydroxyazetidin-1-yl)me thanone. ¹ H NMR (MeOD, 300 MHz): δ = 8.10-7.89 (m, 1 H), 7.82-7.54 (m, 5 H), 6.87-6.77 (m, 1 H), 5.04-4.96 (m, 1 H), 4.50-4.39 (m, 1 H), 4.33- 3.91 (m, 2 H), 3.81-354 (m, 2 H), 3.50-3.39 (m, 1 H), 3.26-3.15 (m, 1 H), 3.12-2.96 (m, 1 H), 2.06-1.95 (m, 2 H), 1.80-1.59 (m, 2 H), 1.47-1.32 (m, 1 H), 0.75-0.61 (m, 3 H); LCMS: C26H23N5O3 [M + H] ⁺ = 454. Example 196. Synthesis of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)-N- (cyanomethyl)naphthalene-1-carboxamide

The title compound was prepared analogously to (1-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalen-4-yl)(3-hydroxyazetidin-1-yl)me thanone. ¹ H NMR (DMSO, 300 MHz): δ = 8.30-8.26 (m, 1 H), 8.20 (s, 1 H), 7.80-7.51 (m, 6 H), 6.87 (br, 1 H), 6.65-6.58 (d, J = 21.7 Hz, 1 H), 6.42 (br, 2 H), 4.92-4.83 (q, J = 8.91, 17.6 Hz, 1 H), 4.44-4.42 (d, J = 5.58 Hz, 2 H), 4.35-4.24 (dq, J = 5.46, 8.82 Hz, 1 H), 3.19-3.09 (m, 1 H), 0.60-0.53 (dd, J = 6.75, 14.2 Hz, 3 H); LCMS: C24H20N6O2 [M + H] ⁺ = 424. Example 197 Synthesis of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4- yl)benzaldehyde

The title compound was prepared analogously to 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalene-1-carbaldehyde. ¹ H NMR (DMSO, 300 MHz): δ = 10.08 (s, 1 H), 8.25 (s, 1 H), 8.03-8.01 (d, J = 8.19 Hz, 2 H), 7.80-7.77 (d, J = 8.1 Hz, 2 H), 6.94 (br, 1 H), 6.73 (s, 1 H), 6.67 (br, 2 H), 4.92-4.86 (t, J = 8.82 Hz, 1 H), 4.40-4.36 (q, J = 4.62, 8.82 Hz, 1 H), 3.98-3.89 (m, 1 H), 0.78-0.76 (d, J = 6.75 Hz, 3 H); LCMS: C18H16N4O2 [M + H] ⁺ = 321. Example 198. Synthesis of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)benzoic acid

The title compound was prepared analogously to 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3- f]quinazolin-4-yl)naphthalene-1-carbaldehyde. ¹ H NMR (DMSO, 300 MHz): δ = 8.53 (br, 1 H), 8.20 (s, 1 H), 8.08-8.05 (d, J = 8.16 Hz, 2 H), 7.96-7.46 (m, 5 H), 6.86 (s, 1 H), 4.98-4.92 (t, J = 8.88 Hz, 1 H), 4.46- 4.42 (q, J = 4.59, 8.94 Hz, 1 H), 4.03-3.96 (m, 1 H), 0.80-0.78 (d, J = 6.75 Hz, 3 H); LCMS: C18H16N4O3 [M + H] ⁺ = 337. Example 199. Dimethyl 4-[2-(2-{[4-(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quin azolin-4- yl)naphthalene-1-carbonyl]amino}ethoxy)ethoxy]pyridine-2,6-d icarboxylate TFA Step a). Synthesis of 6-(methoxycarbonyl)-4-((2-(2-aminoethoxy)ethoxy)methyl)pyrid ine-2- carboxylic acid

A mixture of dimethyl-4-hydroxypyridine-2,6-dicarboxylate (106 mg, 0.5 mmol), K2CO3 (70 mg, 0.5 mmol), and N-Boc-PEG2-SO2Me (135,2 mg, 0.6 mmol) in anhydrous DMF (1 ml) was heated at 80 ^o C for 4 hours. After cooled to room temperature, it was purified through RPLC (50 g, 10 to 65 % CH3CN in water with 0.1 % formic acid). The collected fractions were extracted with DCM (~ 50 ml). The aqueous layer was back-extracted with DCM (~20 ml). The combined organic layers were concentrated by rotary evaporation to clear oil. The material was then treated with TFA (0.5 ml) and DCM (~ 1 ml). The solution was heated at 40 ^o C for 10 minutes, then concentrated by rotary evaporation. The residue was re- dissolved in CH3CN (~15 ml) and water (~5 ml). It was lyophilized to afford the product as a yellow solid (119.6 mg, 60.5 %). LCMS: C13H18N2O6 [M + H] ⁺ = 299. Step b). Synthesis of dimethyl 4-[2-(2-{[4-(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quin azolin- 4-yl)naphthalene-1-carbonyl]amino}ethoxy)ethoxy]pyridine-2,6 -dicarboxylate

A mixture of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)naphthalene-1- carboxylic acid (20 mg, 0.052 mmol) and HATU (40 mg, 0.105 mmol) in anhydrous DMSO (~0.5 ml) was stirred at room temperature for 30 minutes. Dimethyl 4-[2-(2-{[4-(7,9-diamino-3-methyl-2,3- dihydrofuro[2,3-f]quinazolin-4-yl)naphthalene-1-carbonyl]ami no}ethoxy)ethoxy]pyridine-2,6-dicarboxylate TFA (26.5 mg, 0.067 mmol) and DIPEA (52 mg, 0.4 mmol) were added. The resulting mixture was stirred for 30 minutes, then directly purified though HLPC (0 to 25 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the product as a white solid (18.3 mg, 52.8 %). ¹ H NMR (MeOD, 300 MHz): δ = 8.36-8.25 (m, 1 H), 7.82-7.42 (m, 7 H), 6.89-6.77 (t, J = 12.6 Hz, 1 H), 5.04-4.94 (m, 1 H), 4.48-4.37 (m, 3 H), 4.01-3.64 (m, 12 H), 3.30-3.23 (m, 1 H), 0.70-0.61 (m, 3 H); LCMS:

C35H34N6O8 [M + H] ⁺ = 667. Example 200. Synthesis of 4-[2-(2-{[4-(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quin azolin-4- yl)naphthalene-1-carbonyl]amino}ethoxy)ethoxy]pyridine-2,6-d icarboxylic acid

A mixture of 4-(7,9-diamino-2,3-dihydro-3-methylfuro[2,3-f]quinazolin-4-y l)naphthalene-1- carboxylic acid (20 mg, 0.052 mmol) and HATU (40 mg, 0.105 mmol) in anhydrous DMSO (~0.5 ml) was stirred at room temperature for 30 minutes. Dimethyl 4-[2-(2-{[4-(7,9-diamino-3-methyl-2,3- dihydrofuro[2,3-f]quinazolin-4-yl)naphthalene-1-carbonyl]ami no}ethoxy)ethoxy]pyridine-2,6-dicarboxylate TFA (26.5 mg, 0.067 mmol) and DIPEA (52 mg, 0.4 mmol) were added. The resulting mixture was stirred for 30 minutes, then treated with LiOH solution (40 mg, 1 mmol) in water (0.4 ml). The reaction was heated at 60 ^o C overnight. After cooled to room temperature, it was added with 3N HCl solution to re- dissolve the precipitate. The solution was directly purified though HLPC (0 to 25 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the product as a white solid (15.6 mg, 47 %). LCMS: C33H30N6O8 [M + H] ⁺ = 639. Example 201.4-[(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazoli n-4-yl)oxy]-N- methylbenzene-1-sulfonamide Step a).4-[(7-cyano-6-fluoro-3-methyl-2,3-dihydro-1-benzofuran-4- yl)oxy]benzene-1-sulfonamide

A mixture of 4,6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile (220 mg, 1.1 mmol), 4- hydroxybenzenesulfonamide (173.2 mg, 1 mmol), and K2CO3 (140 mg, 1 mmol) in anhydrous NMP (1 ml) was heated at 70 ^o C in microwave for 40 minutes. It was then purified through RPLC (50 g, 5 to 60 % CH3CN in water with 0.1 % formic acid). The collected fractions were concentrated by rotary evaporation to afford the product as a white solid (48.9 mg, 14.0 %). LCMS: C16H13N5O4S [M + H] ⁺ = 349. Step b).4-[(7-cyano-6-fluoro-3-methyl-2,3-dihydro-1-benzofuran-4- yl)oxy]-N-methylbenzene-1- sulfonamide

4-[(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin-4- yl)oxy]-N-methylbenzene-1- sulfonamide (48 mg, 0.138 mmol) was dissolved in DMSO:THF (1:1, 1 ml) and added with K2CO3 (77.2 mg, 0.55 mmol) and excess MeI. The reaction was stirred at room temperature overnight, and then purified through RPLC (50 g, 10 to 80% CH3CN in water with 0.1 % formic acid). The collected fractions were concentrated by rotary evaporation to afford the mono-methylated product as white solid (21.5 mg, 43 %) and di-methylated product as a light yellow oil (11 mg, 21.2 %). LCMS: C17H15N2O4S [M + H] ⁺ = 363. Step c).4-[(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin -4-yl)oxy]-N-methylbenzene-1- sulfonamide A mixture of 4-[(7-cyano-6-fluoro-3-methyl-2,3-dihydro-1-benzofuran-4-yl) oxy]-N-methylbenzene- 1-sulfonamide (21.5 mg, guanidine carbonate (90 mg), K2CO3 (120 mg) in anhydrous NMP (1 ml) was heated at 140 ^o C in microwave for 20 minutes. The reaction was then purified through RPLC (50 g, 5 to 45 % CH3CN in water with 0.1 % formic acid). The collected fractions were lyophilized to afford the product as a white solid. LCMS: C18H19N5O4S [M + H] ⁺ = 402. Example 202. Synthesis of 4-[(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin-4- yl)oxy]-N,N- dimethylbenzene-1-sulfonamide The title compound was synthesized as a side product from the preparation of 4-[(7,9-diamino-3- methyl-2,3-dihydrofuro[2,3-f]quinazolin-4-yl)oxy]-N-methylbe nzene-1-sulfonamide. LCMS: C19H21N5O4S [M + H] ⁺ = 416. Example 203. Synthesis of 4-(6-methoxyquinolin-4-yl)-3-methyl-2,3-dihydrofuro[2,3-f]qu inazoline- 7,9-diamine.

Prepared similarly to example 65. The synthesis of (6-methoxyquinolin-4-yl)boronic acid is described below. LC/MS 374.4 [M+H]+. Synthesis of (6-methoxyquinolin-4-yl)boronic acid. A solution of 4-bromo-6- methoxyquinoline(0.075g, 0.315 mmol), and triisopropyl borate(0.079mL, 0.347 mmol), in dry THF(1mL) at -78C was treated with n-butyl lithium 1.6M (0.236mL, 0.378mmol) dropwise over 30 minutes, then allowed to warm to room temperature slowly over 30 minutes. The resulting solution was made slightly acidic with concentrated HCl, then purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% formic acid as the modifier. Yield 0.040g, 63%. LC/MS 204.0 [M+H]+. Example 204. Synthesis of 4-(dibenzo[b,d]thiophen-2-yl)-3-methyl-2,3-dihydrofuro[2,3- f]quinazoline-7,9-diamine.

Prepared similarly to example 65. LC/MS 399.5 [M+H]+. Example 205. Synthesis of 4-(1-benzofuran-7-yl)-3-methyl-2,3-dihydrofuro[2,3-f]quinazo line-7,9- diamine. Prepared similarly to example 65. LC/MS 333.4 [M+H]+. Example 206. Synthesis of 4-(6-methoxyquinolin-4-yl)-3-methyl-2,3-dihydrofuro[2,3-f]qu inazoline- 7,9-diamine.

Prepared similarly to example 65. LC/MS 412.4 [M+H]+. Example 207. Synthesis of 4-(1,2-dihydroacenaphthylen-5-yl)-3-methyl-2,3-dihydrofuro[2 ,3- f]quinazoline-7,9-diamine.

Prepared similarly to example 65. LC/MS 368.4 [M+H]+. Example 208. Preparation of 3-chloro-5-(8,10-diamino-3,4-dihydro-2H-pyrano[2,3-f]quinazo lin-5- yl)phenol.

Prepared similarly to the compound of example 65. LC/MS 343.2 [M+H]+.

Example 209. Synthesis of 4-[(7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin-4- yl)oxy]pyridine-2,6-dicarboxylic acid A mixture of di-methyl 4-hydroxypyridine-2,6-dicarboxylate (84.8 mg, 0.4 mmol), 4,6-difluoro-2,3- dihydro-3-methylbenzofuran-7-carbonitrile (100 mg, 0.5 mmol), K2CO3 (140 mg, 1 mmol) in NMP (1 ml) and water (0.2 ml) was heated at 130 ^o C in microwave for 20 minutes. It was then directly purified through RPLC (50 g, 5 to 70 % CH3CN and water, using 0.1 % formic acid as modifier). The collected fractions were concentrated by rotary evaporation at 40 ^o C to a white solid intermediate. The material was re- dissolved in NMP (1 ml) and added with guanidine carbonate (90 mg) and K2CO3 (140 mg). The mixture was heated at 140 ^o C in microwave for 20 minutes. The product was precipitated as the reaction was cooled to room temperature. Water (~0.3 ml) was added to the reaction mixture, and it was gently heated by a heat gun to re-dissolve the product. The solution was then purified through HPLC (0 to 18 % CH3CN and water, using 0.1 % formic acid as modifier). The collected fractions were lyophilized to afford the product as a white solid (5.6 mg, 3.5 %). LCMS: C18H15N5O6 [M + H] ⁺ = 397. Example 210. Synthesis of 4-(2,1,3-benzoxadiazol-5-yl)-3-methyl-2,3-dihydrofuro[2,3- f]quinazoline-7,9-diamine

A sealed tube was filled with nitrogen and charged with a mixture of 4-bromo-2,3-dihydro-3- methylfuro[2,3-f]quinazoline-7,9-diamine (30 mg, 0.1 mmol), benzofurazan-5-boronic acid (29.5 mg, 0.15 mmol), K2CO3 (70 mg, 0.5 mmol), Pd(PPh3)4 (9.5 mg) , ter-butyl methyl ether (2 ml) and water (0.5 ml). The suspension was refluxed at 80 ^o C overnight. The product was precipitated upon the removal of tert- butyl methyl ether by evaporation. The yellow cake was isolated and purified through RPLC (5 to 39 % CH3CN and water, using 0.1 % formic acid as modifier). The collected fractions were lyophilized to afford the product as a yellow solid. Yield 8.6 mg, 25.7%. LCMS: C17H14N6O2 [M + H] ⁺ = 335. Example 211. Synthesis of 4-(2,1,3-benzothiadiazol-5-yl)-3-methyl-2,3-dihydrofuro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared analogously to 4-(2,1,3-benzoxadiazol-5-yl)-3-methyl-2,3- dihydrofuro[2,3-f]quinazoline-7,9-diamine where benzo[c][1,2,5]thiadiazole-5-boronic acid pinacol ester was used. LCMS: C17H14N6OS [M + H] ⁺ = 351. Example 212. Preparation of 7-(3-chlorophenoxy)-N5-(4-methoxybenzyl)-N5-methylquinazolin e- 2,4,5-triamine

Step a) Synthesis of 2,4-difluoro-6-{[(4-methox henyl)methyl](methyl)amino}benzonitrile

A mixture of 2,4,6-trifluorobenzonitrile (0.65g, 4mmol), P-methoxyl-benzyl methyl amine(600mg, 4mmol) were stirred at 10ml ethanol for overnight at room temperature, the resulting solution was isolated and purified to give products. Yield of products, ¹ H NMR (300 MHz, CDCl3) δ ppm 7.20(d, J=8.4Hz, 2H) 6.92(d, J=8.7Hz, 2H) 6.36(m, 2H) 4.59(s, 2H) 3.82(s, 3H) 3.03(a, 3H) LC/MS 289.1 [M+H] ⁺ . Step b) Preparation of 7-(3-chlorophenoxy)-N5-(4-methoxybenzyl)-N5-methylquinazolin e-2,4,5- triamine. A mixture of 2,4-difluoro-6-{[(4-methoxyphenyl)methyl](methyl)amino}benzo nitrile (0.030g, 0.16mmol), 3-Chloro-phenol (0.03g, 0.20mmol), potassium carbonate (70mg, 0.5mmol) in 2ml NMP were heated at 130˚C in a microwave for 10 minutes. LCMS shows the desired product. The crude reaction was used in the next step without purification. To the above solution was added guanidine carbonate (0.10g, 0.054 mmol), and the resulting solution was heated via microwave for an additional 10 minutes at 150C. The crude reaction was purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% trifluoroacetic acid as the modifier. Yield of white powder, 0.020g, ¹ H NMR (300 MHz, DMSO) δ ppm ¹ H NMR (300 MHz, DMSO-d6) δ ppm 8.17(s, 1H) 7.43(t, J=7.8Hz, 1H) 7.35(m, 1H) 7.27(d, J=9Hz, 1H) 7.14(d, J=9Hz, 2H) 6.98(d, J=7.8Hz, 1H) 6.87(d, J=8.7Hz, 2H) 6.55(d, J=2.4Hz, 1H) 6.35(d, J=2.4Hz, 1H) 6.06(s, 2H)4.08(dd, J1=13.2Hz, J2=36Hz, 2H) 3.72(s, 3H) 2.56(s, 3H) LC/MS 436.1 [M+H] ⁺ . Example 213. Preparation of 7-(3-chlorophenoxy)-N5-methylquinazoline-2,4,5-triamine. 7-(3-chlorophenoxy)-N5-(4-methoxybenzyl)-N5-methylquinazolin e-2,4,5-triamine (Example 212) (30mg, 0.07mmol) was heated with 3ml TFA and 0.1 ml thioanisole at 50°, for 30 min, then the solution was concentrated and purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% trifluoroacetic acid as the modifier. Yield of white powder, 0.020g, ¹ H NMR (300 MHz, DMSO) δ ppm 12.20(s, 1H) 12.02(s, 1H) 7.56( m, 3H) 7.43(s, 2H) 7.28d, J=8.1Hz, 1H) 6.74(s, 1H) 6.45(s, 1H) LC/MS 316.1 [M+H] ⁺ . Example 214. Preparation of 4-(3-chlorophenoxy)-1H-pyrrolo[2,3-f]quinazoline-7,9-diamine

Step a) Synthesis of 7-bromo-4,6-difluoro-1H-indole To the solution of 3,5-difluoro-6-bromo-1-nitro-benzene (600mg, 0.3mmol) was added into vinyl magnesium bromide in THF(1M, 5ml) at -78°. The resulted solution was stirred overnight and warmed to room temperature. Then quenched the reaction by added acetic acid. then the solution was concentrated and purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% trifluoroacetic acid as the modifier. Yield of white powder 400g, 62% yield, ¹ H NMR (300 MHz, CDCl3) δ ppm 8.44(b, 1H) 7.21(m, 1H) 6.70(m,2H) LC/MS 232 [M+H] ⁺ . Step b) Synthesis of 4,6-difluoro-1H-indole-7-carbonitrile To a solution of 3,5-difluoro-6-bromo-1-nitro-benzene (230mg, 1mmol) in DMF (3 mL), then N,N,N’,N’ -tetramethylethylenediamine (30µL, 0.2mmol, 0.2 equiv), zinc cyanide (70mg, 0.6 mmol), tris(dibenzylideneacetaone)dipalladium(0) (5mg, 0.05 mmol) and Xantphos (2mg, 0.04 mmol) were added successively. The reaction tube was sealed and heated to 160 °C under microwave irradiation. After cooling under a stream of compressed air, the reaction mixture was concentrated and purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% trifluoacetic acid as the modifier. Yield of white powder 120g, 65% yield, ¹ H NMR (300 MHz, CDCl3) δ ppm 9.58(s, 1H) 7.44(s, 1H) 6.72(m, 2H) LC/MS 179 [M+H] ⁺ . Step c) Synthesis of 4-(3-chlorophenoxy)-1H-pyrrolo[2,3-f]quinazoline-7,9-diamine A mixture of 4,6-difluoro-7-cyano-indole(0.030g, 0.16mmol), 3-Chloro-phenol (0.03g, 0.20mmol), potassium carbonate (70mg, 0.5mmol) in 2ml NMP were heated at 130˚C in a microwave for 10 minutes. LCMS shows the desired product. The crude reaction was used in the next step without purification. To the above solution was added guanidine carbonate (0.10g, 0.538 mmol), and the resulting solution was heated via microwave for an additional 10 minutes at 150C. The crude reaction was purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% trifluoroacetic acid as the modifier. Yield of white powder, 0.010g, LC/MS 326.1 [M+H] ⁺ . Example 215. Prepartion of 4-((6-methoxynaphthalen-2-yl)oxy)-1H-pyrrolo[2,3-f]quinazoli ne-7,9- diamine

The title compound was prepared analogously to Example 228. ¹ H NMR (300 MHz, DMSO) δ ppm 8.20(s, 1H) 7.86(d, J=9.3Hz, 1H) 7.76(d, J=8.1Hz, 1H) 7.50(t, J= 7.8Hz, 1H) 7.44(d, J=2.1Hz, 1H) 7.36(d, J=3Hz, 1H) 7.16(dd, J1=2.1Hz, J2=9Hz, 1H) 7.08(d, J=7.8Hz, 1H) 7.06(s, 1H) 6.66(d, J=3Hz, 1H) 6.04(s, J=2H) 3.89(s, 3H). LC/MS 372.1 [M+H] ⁺ . Exampl 21 . Pr r i n f - - hl r h n x - - ih r f r 2-f in z lin -1 - i min

Step a) Synthesis of 1-(allyloxy)-5- r m -24- ifl r nzene

NaH (60% in mineral oil, 1.21g, 30.3 mmol) was added in one portions to 2,4-difluoro-5-bromo- phenol (2.1g, 10 mmol) in 20ml THF, then ally bromide (2.4g, 20 mmol) in 20 ml THF under the ice water bath, the mixture was stirred for overnight, then quenched with acetic acid, then the mix solution was coated with silica gel and concentrated to remove all of the solvents. The resulted residue was loaded into ISCO to purify by washing with ethyl acetate in hexane to provide desired products (3.2g, 80% yield ¹ H NMR (300 MHz, Chloroform-d) δ 7.15 (dd, J = 8.5, 6.6 Hz, 1H), 6.96 (dd, J = 10.6, 8.1 Hz, 1H), 6.05 (ddt, J = 17.4, 10.7, 5.4 Hz, 1H), 5.44 (dq, J = 17.2, 1.5 Hz, 1H), 5.35 (dq, J = 10.4, 1.3 Hz, 1H), 4.58 (dt, J = 5.5, 1.5 Hz, 2H). LC/MS, 249.0 [M+H] ⁺ . Step b) Synthesis of 2-allyl-3-bromo-4,6-difluorophenol

A solution of 1-(allyloxy)-5-bromo-2,4-difluorobenzene (2.4g, 10mmol), dissolved in ortho- dichlorobenzene (20ml), was equipped with an air condenser and heated in a 180C oil bath for overnight, then the solution was cooled down and was coated with silica gel and concentrated to remove all of the solvents. The resulted residue was loaded into ISCO by washing with ethyl acetate in hexane to provide desired products (1.6g, 67% yield). ¹ H NMR (300 MHz, Chloroform-d) δ 6.89 (dd, J = 10.0, 8.0 Hz, 1H), 5.93 (ddt, J = 17.7, 9.4, 6.1 Hz, 1H), 5.40 (d, J = 2.7 Hz1H), 5.16– 5.03 (m, 2H), 3.66 (d, J = 5.8 Hz, 2H), LC/MS, 249.0 [M+H] ⁺ . Step c) Synthesis of 3-bromo-4,6-difluoro-2-(2-hydroxyethyl)phenol

2-allyl-3-bromo-4,6-difluorophenol (420mg, 2mmol), was dissolved in 1:1 DCM/MeOH (10mL), cooled to -78C and treated with O3 until a pale blue color persists. O2 was bubbled through the mixture for 5 min, then NaBH4 was added slowly (bubbles vigorously) and the mixture was warmed to room temperature slowly over 15 min. Work-up: diluted with EtOAc, washed with 1N HCl, 1N NaHCO3, brine, dried over Na2SO4. This material was used without further purification. Mass recovery = 350mg, 85%. ¹ H NMR (300 MHz, Chloroform-d) δ 6.91 (dd, J = 10.0, 8.2 Hz, 1H), 4.02 (t, J = 5.6 Hz, 2H), 3.23 (t, J = 5.6 Hz, 2H). LC/MS, 252.1 [M+H] ⁺ . Step d) Synthesis of 4-bromo-5,7-difluoro-23-dih drobenzofuran

DIAD (0.7 mL, 3.5 mmol) was added dropwise to a ⁰ C solution of 3-bromo-4,6-difluoro-2-(2- hydroxyethyl)phenol (700mg, 2.7 mmol), and triphenylphosphine (800mg, 3mmol) in THF (20mL). LCMS after 10 min. shows complete conversion. The solution was concentrated and purified by normal phase chromatography (0 to 25% ethyl acetate/hexanes). Yield 600 mg (86%) of white solid. ¹ H NMR (300 MHz, Chloroform-d) δ 6.80 (t, J = 9.3 Hz, 1H), 4.74 (t, J = 8.8 Hz, 2H), 3.29 (t, J = 8.8 Hz, 2H). LC/MS, 235 [M+H] ⁺ . Step e) Synthesis of 5,7-difluoro-2,3-dihydrobenzofuran-4-carbonitrile

The title compound was prepared analogously to 4,6-difluoro-1H-indole-7-carbonitrile. ¹ H NMR (300 MHz, Chloroform-d) δ 6.84 (t, J = 9.4 Hz, 1H), 4.80 (t, J = 8.9 Hz, 2H), 3.47 (t, J = 8.9 Hz, 2H). LC/MS 182.1 [M+H] ⁺ . Step f) Synthesis of 6-(3-chlorophenoxy)-8,9-dihydrofuro[3,2-f]quinazoline-1,3-di amine

The title compound was prepared analogously to 4-(3-bromophenoxy)-3-methyl-2,3-dihydrofuro[2,3- f]quinazoline-7,9-diamine. ¹ H NMR (300 MHz, Methanol-d4) δ 7.44 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.83– 6.73 (m, 1H), 4.81 (t, J = 9.0 Hz, 2H), 3.77 (t, J = 8.8 Hz, 2H). LC/MS 329.1[M+H] ⁺ . Example 217. Preparation of 6-(3-cyan h n x - - ih r furo[3,2-f]quinazoline-1,3-diamine

The title compound was prepared analogously to EXAMPLE 221 4-(3-bromophenoxy)-3-methyl- 2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine. ¹ H NMR (300 MHz, Methanol-d4) δ 8.54 (s, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.49– 7.31 (m, 3H), 6.82 (s, 1H), 4.76 (t, J = 8.8 Hz, 2H), 3.76 (t, J = 9.0 Hz, 2H). LC/MS 329.1[M+H] ⁺ . Example 218. Preparation of 6-phen x - - ih r f r 2-f]quinazoline-1,3-diamine

The title compound was prepared analogously to EXAMPLE 221 4-(3-bromophenoxy)-3-methyl- 2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine. LC/MS 295.1[M+H] ⁺ . Example 219. Preparation of 6-(1,1'-biphenyl]-3-yloxy)-8,9-dihydrofuro[3,2-f]quinazoline -1,3- diamine

The title compound was prepared analogously to EXAMPLE 221 4-(3-bromophenoxy)-3-methyl- 2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine. LC/MS 371.1[M+H] ⁺ . Example 220. Preparation of 3-methyl-4-(5-pyrimidinyl-3-yl)phenoxy)-2,3-dihydrofuro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared analogously to Example 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine. ¹ H NMR (300 MHz, DMSO-d6) δ 9.19 (d, J = 6.3 Hz, 3H), 8.27 (s, 1H), 7.74– 7.52 (m, 3H), 7.21 (ddd, J = 8.1, 2.4, 1.2 Hz, 1H), 6.74 (s, 2H), 6.09 (s, 1H), 4.89 (q, J = 10.4, 9.7 Hz, 1H), 4.40 (dd, J = 8.9, 5.6 Hz, 1H), 3.68– 3.52 (m, 1H), 2.70 (s, 0H), 2.24– 2.05 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H), 1.21 (dd, J = 12.9, 7.0 Hz, 0H). LC/MS 387.2 [M+H] ⁺ . Example 221. Preparation of 4-(3-bromophenoxy)-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin e-7,9-

A mixture of 4, 6-difluoro-2,3-dihydro-3-methylbenzofuran-7-carbonitrile (0.060g, 0.3mmol), 3- Chloro-phenol (0.052g, 0.40mmol), potassium carbonate (140mg, 1mmol) in 2ml NMP were heated at 130˚C in a microwave for 10 minutes. LCMS shows the desired product. The crude reaction was used in the next step without purification. To the above solution was added guanidine carbonate (0.10g, 0.538 mmol), and the resulting solution was heated via microwave for an additional 10 minutes at 150C. The crude reaction was purified by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% trifluoroacetic acid as the modifier. Yield of white powder. ¹ H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.48 (s, 1H), 7.46– 7.33 (m, 2H), 7.37– 7.23 (m, 1H), 7.20– 7.05 (m, 1H), 6.68 (s, 1H), 6.34 (s, 1H), 6.04 (s, 1H), 4.86 (t, J = 9.3 Hz, 1H), 4.37 (dd, J = 8.9, 5.7 Hz, 1H), 3.51(m, 1H), 1.26 (d, J =6Hz, 3H). LC/MS 387.1 [M+H] ⁺ . Example 222. Preparation of 4-((3'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-3-yl)oxy)-3-methyl -2,3- dihydrofuro[2,3-f]quinazoline-7,9-diamine

The title compound was prepared analogously to EXAMPLE 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.19 (d, J = 11.5 Hz, 2H), 8.01 (d, J = 7.6 Hz, 1H), 7.64– 7.53 (m, 4H), 7.50 (t, J = 7.7 Hz, 1H), 7.37 (s, 3H), 7.22 (d, J = 4.1 Hz, 1H), 6.31 (s, 1H), 4.86 (t, J = 9.0 Hz, 1H), 4.41– 4.32 (m, 1H), 3.61 (d, J = 8.0 Hz, 2H), 1.21 (d, J = 6.8 Hz, 3H). LC/MS 453.2 [M+H] ⁺ . Example 223. Preparation of (E)-4-(3-(3-methoxystyryl)phenoxy)-3-methyl-2,3-dihydrofuro[ 2,3- f]quinazoline-7,9-diamine

The title compound was prepared analogously to EXAMPLE 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . ¹ H NMR (300 MHz, DMSO-d6) δ 7.45 (d, J = 7.7 Hz, 2H), 7.37– 7.22 (m, 4H), 7.22– 7.12 (m, 2H), 7.07– 6.96 (m, 1H), 6.88– 6.79 (m, 1H), 6.11 (s, 2H), 5.99 (d, J = 1.6 Hz, 1H), 4.88 (t, J = 9.0 Hz, 1H), 4.44– 4.32 (m, 1H), 3.79 (s, 3H), 3.58 (q, J = 7.0 Hz, 3H), 1.31 (d, J = 6.7 Hz, 3H).. LC/MS 441.2 [M+H] ⁺ . Example 224. Preparation fof 3-methyl-4-(3-(4-methylnaphthalen-1-yl)phenoxy)-2,3- dihydrofuro[2,3-f]quinazoline-7,9-dia

The title compound was prepared analogously to EXAMPLE 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . ¹ H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.66– 7.13 (m, 8H), 5.99 (d, J = 7.4 Hz, 3H), 4.75 (t, J = 8.9 Hz, 1H), 4.24 (dd, J = 8.9, 5.5 Hz, 1H), 3.31 (t, J = 7.1 Hz, 11H), 2.70 (s, 4H), 2.18 (t, J = 7.9 Hz, 1H), 1.16 (d, J = 6.8 Hz, 3H). LC/MS 449.2 [M+H] ⁺ . Example 225. Preparation of 3'-((7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin-4 -yl)oxy)- [1,1'-biphenyl]-3-carboxamide

The title compound was prepared analogously to EXAMPLE 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . ¹ H NMR (300 MHz, DMSO-d6) δ 8.23– 8.05 (m, 2H), 7.86 (t, J = 8.1 Hz, 2H), 7.65– 7.50 (m, 3H), 7.45 (s, 1H), 7.13 (d, J = 7.1 Hz, 1H), 6.14 (s, 2H), 6.02 (s, 1H), 4.89 (t, J = 8.9 Hz, 1H), 4.39 (dd, J = 9.0, 5.5 Hz, 1H), 3.61 (m, 1H), 1.30 (dd, J = 13.2, 6.7 Hz, 3H). LC/MS 428.2 [M+H] ⁺ . Example 226. Preparation of 3-methyl-4-(3-(pyridin-3-ylethynyl)phenoxy)-2,3-dihydrofuro[ 2,3- f]quinazoline-7,9-diamine

The title compound was prepared analogously to EXAMPLE 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . ¹ H NMR (300 MHz, Methanol-d4) δ 8.74 (d, J = 15.1 Hz, 1H), 8.58– 8.45 (m, 1H), 8.38 (s, 1H), 7.99 (dt, J = 8.0, 1.9 Hz, 1H), 7.62– 7.42 (m, 3H), 7.39 (d, J = 2.3 Hz, 1H), 7.26 (dt, J = 7.6, 2.1 Hz, 1H), 6.21 (s, 1H), 5.04 (t, J = 9.1 Hz, 1H), 4.57 (dd, J = 9.0, 5.5 Hz, 1H), 3.84– 3.68 (m, 2H), 1.42 (dd, J = 18.3, 6.8 Hz, 4H). LC/MS 410.2 [M+H] ⁺ . Example 227. Preparation of 3-methyl-4-(3-(pyridin-3-yl)phenoxy)-2,3-dihydrofuro[2,3- f]quinazoline-7,9-diamine

The title compound was prepared analogously to EXAMPLE 228 4-([1,1'-biphenyl]-3-yloxy)-3-methyl- 2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.23 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 26.8, 8.2 Hz, 3H), 7.15 (d, J = 7.4 Hz, 1H), 6.01 (d, J = 3.2 Hz, 2H), 4.88 (t, J = 9.0 Hz, 1H), 4.37 (dd, J = 8.7, 5.5 Hz, 1H), ), 3.61 (m, 1H), 1.31 (d, J = 6.7 Hz, 2H). LC/MS 386.2 [M+H] ⁺ . Example 228. Preparation of 4-([1,1'-biphenyl]-3-yloxy)-3-methyl-2,3-dihydrofuro[2,3-f]q uinazoline- 7,9-diamine

4-(3-bromophenoxy)-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin e-7,9-diamine (60 mg, 0.13 mmol) and isoxazole-4-boronic acid (22 mg, 0.19 mmol) were dissolved in the mix solvents of NMP (2 mL and 2M K2CO3 (2 mL), then followed by tetrakis(triphenylphosphine)palladium (4 mg, 0.0077 mmol) were heated in a microwave at 140˚C for 10 min, with stirring. The resulting black/brown colored solution was purified directly by reverse phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 10% to 100% acetonitrile and water, using 0.1% trifluoacetic acid as the modifier. The title compound was prepared analogously to 2,3-dihydro-7-(3’-Chloro-phenoxyl)-3- methylfuro[2,3-f]quinazoline-2,4-diamine . ¹ H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J = 7.5 Hz, 1H), 7.54 – 7.30 (m, 2H), 7.11 (s, 1H), 6.03 (s, 1H), 4.88 (t, J = 9.1 Hz, 1H), 4.46– 4.29 (m, 1H), 3.59 (s, 1H), 1.31 (d, J = 6.7 Hz, 1H). LC/MS 385.2 [M+H] ⁺ . Example 229. Preparation of 4-(3-ethynylphenoxy)-3-methyl-2,3-dihydrofuro[2,3-f]quinazol ine-7,9- diamine

The title compound was prepared analogously to Example 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . LC/MS 333.2 [M+H] ⁺ . Example 230. Preparation of 3-methyl-4-(3-vinylphenoxy)-2,3-dihydrofuro[2,3-f]quinazolin e-7,9- diamine

The title compound was prepared analogously to Example 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . ¹ H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.49 – 7.18 (m, 4H), 7.12– 6.93 (m, 1H), 6.90– 6.63 (m, 2H), 6.13 (s, 2H), 5.97– 5.82 (m, 2H), 5.37– 5.21 (m, 1H), 4.87 (t, J = 9.0 Hz, 1H), 4.37 (dd, J = 8.9, 5.6 Hz, 1H), 1.25 (dd, J = 24.5, 7.0 Hz, 3H). LC/MS 335.2 [M+H] ⁺ . Example 231. Preparation of (E)-3-methyl-4-(3-styrylphenoxy)-2,3-dihydrofuro[2,3-f]quina zoline- 7,9-diamine

The title compound was prepared analogously to Example 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . ¹ H NMR (300 MHz, DMSO-d6) δ 7.69– 7.19 (m, 12H), 5.96 (s, 2H), ), 4.88 (t, J = 9.1 Hz, 1H), 4.46– 4.29 (m, 1H), 3.59 (s, 1H), 1.31 (d, J = 6.5 Hz, 3H). LC/MS 411.2 [M+H] ⁺ . Example 232. Preparation of (E)-4-(3-(3-chlorostyryl)phenoxy)-3-methyl-2,3-dihydrofuro[2 ,3- f]quinazoline-7,9-diamine

The title compound was prepared analogously to Example 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . ¹ H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.71 (s, 1H), 7.70– 7.51 (m, 8H), 7.51– 7.23 (m, 7H), 7.07– 6.98 (m, 1H), 6.12 (s, 2H), 5.99 (s, 1H), 4.88 (t, J = 9.1 Hz, 1H), 4.38 (dd, J = 8.8, 5.6 Hz, 1H), 1.30 (d, J = 6.7 Hz, 3H). LC/MS 445.2 [M+H] ⁺ . Example 233. Preparation of 3'-((7,9-diamino-3-methyl-2,3-dihydrofuro[2,3-f]quinazolin-4 -yl)oxy)- [1,1'-biphenyl]-3-carbonitrile

The title compound was prepared analogously to Example 228 4-([1,1'-biphenyl]-3-yloxy)-3- methyl-2,3-dihydrofuro[2,3-f]quinazoline-7,9-diamine . LC/MS 410.2 [M+H] ⁺ . Example 234. Inhibition of Dihydrofolate Reductase (DHFR) by Selected Compounds in Examples 2-233

Part A. Generation, expression and purification of DHFR proteins

Full length DHFR ORFs were PCR amplified and cloned into the NcoI and XhoI sites of pET28a (Novagen). The resulting clones contained a C-terminal hexahistadine tag. Sequence verified clones were transformed to the expression strain, E. coli BL21(DE3). Fermentation and purification conditions for all proteins were as follows: Cells were grown at 37°C in 1 liter of Terrific Broth and induced with 1 mM IPTG once an OD600 of 0.8 was reached. The cells were harvested after an additional 12 hours of growth at 18°C. The cell pellets were resuspended in 50 mM Tris pH 8.0, 200 mM NaCl. Sonication was used to lyse the cells and the lysate was cleared by centrifugation. The supernatant was loaded onto a bed of Ni-NTA agarose and eluted with a gradient of imidazole in 50 mM Tris pH 8.0, 200 mM NaCl. The final chromatographic step was anion exchange (HiTrap Q HP from GE Healthcare) using a linear gradient of 25 mM Tris pH 8.0, 25-500 mM NaCl, while collecting fractions over 10 column volumes. The full-length DHFR proteins were soluble when overexpressed and were purified to > 98% purity (as determined by SDS-PAGE). Part B. DHFR Inhibition Assay

DHFR enzyme activity assays were performed at 25°C by monitoring the change in UV absorbance at 340 nM in a solution containing 25 mM Tris (hydroxymethyl)methyl-2aminoethanesulfonic acic (pH 8.0), 25 mM NaCl, 1 mg/ml bovine serum albumin, 200 µM NADPH, and 5-8 nM DHFR enzyme. Inhibitor potency was determined by incubating the target enzyme in the presence of various concentrations of inhibitor ranging between 1.5 nM and 50 µM for 10 minutes prior to addition of 150 µM dihydrofolate. The final concentration of DMSO was kept constant at 2.0% (v/v). Enzyme activity in the presence of inhibitor was expressed relative to the no-inhibitor control and Ki values determined using Morrison tight-binding equation to account for ligand depletion. All analysis was carried out using GraphPad Prism 6.0. All assay components were purchased from Sigma.

The DHFR inhibition of selected compounds in Examples 2-233 using enzyme derived from C. albicans, C. neoformans, A. fumigatus and H. sapiens as described above is indicated in Table 1. Table 1. Inhibition of DHFR by Selected Compounds in Examples 2-233

Example 235. Antifungal Activities of Selected Compounds in Examples 2-233

Minimum inhibitory concentration (MIC) and minimum effective concentration (MEC) assays were performed according to CLSI broth microdilution guidelines (M27-A3, M27-S4, and M38-A2) with the exception of using a 100 µL assay volume and preparing stock compounds at 50X final concentration. Briefly, starting solutions of all antifungal compounds were prepared in 100% DMSO. Stock

concentrations were made at 50X the highest final assay concentration and serially diluted 2-fold, 12 times in a 96-well PCR plate (VWR cat. no.83007-374). Candida, Cryptococcus and Aspergillus suspensions from Sabouraud dextrose agar plate cultures were prepared in 0.85% saline at ~0.1 OD530 nm or at ~0.16 OD530 nm for Mucorales, Fusarium and Scedosporium strains. Candida and

Cryptococcus suspensions were diluted 1:500 in RPMI (MP Biomedicals, cat no.1060124; buffered with MOPS and adjusted with NaOH to pH 7.0) to a concentration of 0.5-2.5 x 103 CFU/mL and Aspergillus, Mucorales, Fusarium, and Scedosporium suspensions were diluted 1:50 in RPMI to 0.4-5 x 104 CFU/mL final concentration. 98 µL of each cell suspension in RPMI were added to test wells in a 96-well assay plate (Costar cat. no.3370). A Beckman Multimek 96 liquid handling robot was used to dispense 2 µL of each 50X stock compound into the plate containing 98 µL of each strain in RPMI (2% final solvent concentration). Plates were shaken then incubated at 35°C for 24 h (Candida, Aspergillus, and

Mucorales), 48 h (Fusarium), or 72 h (Cryptococcus and Scedosporium) prior to reading. MIC values were read visually at 50% and 100% growth inhibition for DHFR inhibitors, 100% for Amphotericin B and Voriconazole, and 50% for Fluconazole and Caspofungin. MEC values were read for caspofungin with the aid of a microscope at the lowest drug concentration where rounded/compact hyphal morphology was observed. The antifungal activities of selected compounds in Examples 2-233 against various fungal species are shown in Tables 2, 3 and 4. Table 2. Antifungal Activities of Selected Compounds in Examples 2-233 against C. albicans, A.

fumigatus, and C. neoformans.

Table 3. Antifungal Activities of Compounds in Examples 47, 69, 83, and 149 against Mucorales Moulds Table 4. Antifungal Activities of Compounds in Examples 47, 69, 83, and 149 against Fusarium and Scedosporium Moulds

Other Embodiments

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth.

All publications, patents, and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Other embodiments are within the following claims.

What is claimed is: