BICYCLIC UREA KINASE INHIBITORS AND USES THEREOF

Abstract

The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.

##STR00001##

Claims

1.-62. (canceled)

63. A compound of Formula (III): ##STR00278## or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: R.sup.L is substituted or unsubstituted alkyl; Ring C is unsubstituted phenyl or of the formula: ##STR00279## each instance of R.sup.B1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.d).sub.2, —CN, —SCN, —C(═NR.sup.d)R.sup.a, —C(═NR.sup.d)OR.sup.a, —C(═NR.sup.d)N(R.sup.d).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.d).sub.2, —NO.sub.2, —NR.sup.dC(═O)R.sup.a, —NR.sup.dC(═O)OR.sup.a, —NR.sup.dC(═O)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.d).sub.2; each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; each instance of R.sup.d is independently hydrogen, —C(═O)R.sup.a, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.d are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; R.sup.C is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl; R.sup.D is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl; R.sup.E is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl; R.sup.F is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; Ring A is substituted or unsubstituted phenyl; substituted or unsubstituted, polycyclic aryl; substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl; or substituted or unsubstituted, polycyclic heteroaryl; each instance of R.sup.G is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.b).sub.2, —SR.sup.a, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.b).sub.2; each instance of R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.b are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; n is 0, 1, 2, 3, or 4, as valency permits; R.sup.K is unsubstituted methyl, substituted or unsubstituted heterocyclyl, —OR.sup.a, or —N(R.sup.c).sub.2, wherein each instance of R.sup.c is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.c are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and R.sup.Y is substituted phenyl.

64. The compound of claim 63, wherein R.sup.L is substituted or unsubstituted C.sub.1-6 alkyl.

65. The compound of claim 63, wherein R.sup.L is Me, Et, iPr, or Pr.

66. The compound of claim 63, wherein Ring C is unsubstituted phenyl.

67. The compound of claim 63, wherein Ring C is of the formula: ##STR00280##

68. The compound of claim 63, wherein at least one instance of R.sup.B1 is halogen or substituted or unsubstituted C.sub.1-6 alkyl, or —N(R.sup.d).sub.2, wherein each instance of R.sup.d is hydrogen or —C(═O)R.sup.a.

69. The compound of claim 67, wherein Ring C is of the formula: ##STR00281##

70. The compound of claim 63, wherein R.sup.K is substituted or unsubstituted heterocyclyl.

71. The compound of claim 70, wherein R.sup.K is substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl.

72. The compound of claim 63, wherein R.sup.K is —N(R.sup.c).sub.2.

73. The compound of claim 72, wherein each instance of R.sup.c is substituted or unsubstituted C.sub.1-6 alkyl.

74. The compound of claim 63, wherein at least one instance of R.sup.G is —OR.sup.a, wherein R.sup.a is substituted or unsubstituted C.sub.1-6 alkyl.

75. The compound of claim 63, wherein each one of R.sup.C and R.sup.D is hydrogen.

76. The compound of claim 63, wherein one of R.sup.C and R.sup.D is hydrogen, and the other of R.sup.C and R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl.

77. The compound of claim 63, wherein R.sup.E is hydrogen.

78. The compound of claim 63, wherein R.sup.F is hydrogen.

79. The compound of claim 63, wherein Ring A is substituted or unsubstituted phenyl.

80. The compound of claim 63, wherein Ring A is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl.

81. The compound of claim 80, wherein Ring A is substituted or unsubstituted pyridyl or substituted or unsubstituted pyrazolyl.

82. The compound of claim 63, wherein n is 1.

83. The compound of claim 63, wherein n is 2.

84. The compound of claim 63, wherein at least one instance of R.sup.G is halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted heterocyclyl, or —OR.sup.a.

85. The compound of claim 63, wherein n is 0.

86. The compound of claim 63, wherein R.sup.C is hydrogen.

87. The compound of claim 63, wherein R.sup.D is hydrogen.

88. The compound of claim 63, wherein R.sup.E is hydrogen.

89. The compound of claim 63, wherein R.sup.F is hydrogen.

90. The compound of claim 63, wherein R.sup.C, R.sup.D, R.sup.E, and R.sup.F are each hydrogen.

91. The compound of claim 63, wherein Ring C is unsubstituted phenyl, R.sup.C, R.sup.D, R.sup.E, and R.sup.F are each hydrogen, n is 0, R.sup.L is substituted or unsubstituted C.sub.1-6 alkyl, and R.sup.K is substituted or unsubstituted piperidinyl, or substituted or unsubstituted piperazinyl.

92. The compound of claim 63, wherein Ring C is of the formula: ##STR00282## R.sup.C, R.sup.D, R.sup.E, and R.sup.F are each hydrogen, R.sup.G is —OR.sup.a, methyl, or ethyl, R.sup.L is substituted or unsubstituted C.sub.1-6 alkyl, and R.sup.K is substituted or unsubstituted piperidinyl, or substituted or unsubstituted piperazinyl.

93. The compound of claim 63, wherein the compound is of the formula: ##STR00283## ##STR00284## ##STR00285## or a pharmaceutically acceptable salt thereof.

94. A pharmaceutical composition comprising a compound of claim 63, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.

95. The pharmaceutical composition of claim 94 further comprising an additional pharmaceutical agent.

96. The pharmaceutical composition of claim 95, wherein the additional pharmaceutical agent is a kinase inhibitor.

97. The pharmaceutical composition of claim 96, wherein the additional pharmaceutical agent is a salt-inducible kinase (SIK) inhibitor or a salt-inducible kinase 2 (SIK2) inhibitor.

98. (canceled)

99. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 63, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the disease is associated with aberrant activity of a protein kinase.

100. The method of claim 99, wherein the protein kinase is a salt-inducible kinase (SIK) or salt-inducible kinase 2 (SIK2).

101. (canceled)

102. The method of claim 99, wherein the disease is a genetic disease, a proliferative disease, cancer, benign neoplasm, pathological angiogenesis, an inflammatory disease, a musculoskeletal disease, an autoimmune disease, a hematological disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder.

103.-115. (canceled)

116. A kit comprising: a compound of claim 63, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and instructions for using the compound or pharmaceutical composition.

117. The compound of claim 63, which is ##STR00286## (YKL-06-029), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

118. A pharmaceutical composition comprising a compound of claim 117, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.

119. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 117, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein the disease is associated with aberrant activity of a protein kinase.

120. The method of claim 119, wherein the protein kinase is a salt-inducible kinase (SIK) or salt-inducible kinase 2 (SIK2).

121. The method of claim 119, wherein the disease is a genetic disease, a proliferative disease, cancer, benign neoplasm, pathological angiogenesis, an inflammatory disease, a musculoskeletal disease, an autoimmune disease, a hematological disease, a neurological disease, a painful condition, a psychiatric disorder, or a metabolic disorder.

122. A kit comprising: a compound of claim 117, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and instructions for using the compound or pharmaceutical composition.

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0121] Described herein are bicyclic compounds of Formula (I), (II), and (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. Certain compounds described herein bind protein kinases and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., a SIK kinase) in a subject or cell, in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof, and/or in treating or preventing a disease or condition associated with kinase activity in a subject in need thereof. Also provided are pharmaceutical compositions and kits including a compound described herein.

Compounds

Compounds of Formula (I)

[0122] In one aspect, the present disclosure provides compounds of Formula (I):

##STR00031##

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein:

[0123] R.sup.A is substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,

##STR00032##

substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl, provided that the substituted or unsubstituted heterocyclyl is not substituted or unsubstituted 3-pyrrolidinyl;

[0124] each instance of R.sup.A1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.b).sub.2, —SR.sup.a, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.b)N(R.sup.b).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.b).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.b).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.b).sub.2;

[0125] each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.a are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

[0126] each instance of R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.b are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

[0127] k is 0, 1, 2, 3, or 4;

[0128] each instance of R.sup.B is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.b).sub.2, —SR.sup.a, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.b)N(R.sup.b).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.b).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.b).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.b).sub.2;

[0129] m is 0, 1, 2, 3, 4, or 5;

[0130] R.sup.C is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

[0131] R.sup.D is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

[0132] R.sup.E is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

[0133] R.sup.F is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

[0134] Ring A is substituted or unsubstituted phenyl; substituted or unsubstituted, polycyclic aryl; substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl; or substituted or unsubstituted, polycyclic heteroaryl;

[0135] each instance of R.sup.G is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.b).sub.2, —SR.sup.a, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.b)N(R.sup.b).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.b).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.b).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.b).sub.2;

[0136] n is 0, 1, 2, 3, or 4, as valency permits;

[0137] L is a bond or a substituted or unsubstituted C.sub.1-6 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —S—, —NR.sup.b—, —N═, or ═N—; and

[0138] R.sup.H is substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted heterocyclyl, —OH, or —N(R.sup.c).sub.2, wherein each instance of R.sup.c is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.c are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

[0139] Formula (I) includes substituent R.sup.A. In certain embodiments, R.sup.A is substituted alkenyl. In certain embodiments, R.sup.A is unsubstituted alkenyl. In certain embodiments, R.sup.A is substituted alkynyl. In certain embodiments, R.sup.A is unsubstituted alkynyl. In certain embodiments, R.sup.A is substituted phenyl. In certain embodiments, R.sup.A is of the formula:

##STR00033##

In certain embodiments, k is 0. In certain embodiments, R.sup.A is of the formula:

##STR00034##

In certain embodiments, k is 1. In certain embodiments, R.sup.A is of the formula:

##STR00035##

In certain embodiments, R.sup.A is of the formula:

##STR00036##

In certain embodiments, R.sup.A is

##STR00037##

In certain embodiments, k is 2. In certain embodiments, R.sup.A is of the formula:

##STR00038##

In certain embodiments, k is 3. In certain embodiments, R.sup.A is of the formula:

##STR00039##

In certain embodiments, k is 4. In certain embodiments, R.sup.A is of the formula:

##STR00040##

[0140] In certain embodiments, when R.sup.A is substituted phenyl, R.sup.A includes one or more R.sup.A1 substituents. In certain embodiments, at least one instance of R.sup.A1 is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one R.sup.A1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.A1 is benzyl. In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.A1 is −OR.sup.a (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.A1 is —N(R.sup.b).sub.2, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.b)N(R.sup.b).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.b).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.b).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.b).sub.2.

[0141] In certain embodiments, at least one instance of R.sup.a is hydrogen. In certain embodiments, at least one instance of R.sup.a is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.A1 is benzyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.a is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, at least one instance of R.sup.a is a sulfur protecting group when attached to a sulfur atom.

[0142] In certain embodiments, at least one instance of R.sup.b is hydrogen. In certain embodiments, at least one instance of R.sup.b is substituted or unsubstituted C.sub.1-6 alkyl (e.g., substituted or unsubstituted methyl, ethyl, or propyl). In certain embodiments, at least one instance of R.sup.b is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, two instances of R.sup.b are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, two instances of R.sup.b are taken together with their intervening atoms to form substituted or unsubstituted piperazinyl. In certain embodiments, two instances of R.sup.b are taken together with their intervening atoms to form

##STR00041##

[0143] In certain embodiments, R.sup.A is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.A is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur (e.g., furanyl, thiophenyl, pyridinyl, or pyrimidinyl, etc.) In certain embodiments, R.sup.A is substituted or unsubstituted furanyl. In certain embodiments, R.sup.A is substituted or unsubstituted thiophenyl. In certain embodiments, R.sup.A is substituted or unsubstituted pyridinyl. In certain embodiments, R.sup.A is of the formula:

##STR00042##

In certain embodiments, k is 0. In certain embodiments, R.sup.A is of the formula:

##STR00043##

In certain embodiments, k is 1. In certain embodiments, R.sup.A is of the formula:

##STR00044##

In certain embodiments, R.sup.A is of the formula:

##STR00045##

In certain embodiments, R.sup.A is of the formula:

##STR00046##

In certain embodiments, R.sup.A is of the formula:

##STR00047##

In certain embodiments, k is 2. In certain embodiments, R.sup.A is of the formula:

##STR00048##

In certain embodiments, R.sup.A is of the formula:

##STR00049##

In certain embodiments, R.sup.A is of the formula:

##STR00050##

In certain embodiments, k is 3. In certain embodiments, R.sup.A is of the formula:

##STR00051##

In certain embodiments, R.sup.A is of the formula:

##STR00052##

In certain embodiments, R.sup.A is of the formula:

##STR00053##

In certain embodiments, k is 4. In certain embodiments, R.sup.A is of the formula:

##STR00054##

In certain embodiments, R.sup.A is not substituted or unsubstituted pyridinyl. In certain embodiments, R.sup.A is not substituted or unsubstituted 2-pyridinyl. In certain embodiments, R.sup.A is not substituted 2-pyridinyl. In certain embodiments, R.sup.A is substituted or unsubstituted pyrimidinyl. In certain embodiments, R.sup.A is substituted or unsubstituted pyrazinyl. In certain embodiments, R.sup.A is substituted or unsubstituted triazinyl. In certain embodiments, R.sup.A is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.A is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur), provided that the substituted or unsubstituted heterocyclyl is not substituted or unsubstituted 3-pyrrolidinyl. In certain embodiments, R.sup.A is substituted or unsubstituted tetrahydropyranyl. In certain embodiments, R.sup.A is unsubstituted tetrahydropyranyl. In certain embodiments, R.sup.A is piperidinyl. In certain embodiments, R.sup.A is substituted or unsubstituted morpholinyl. In certain embodiments, R.sup.A is substituted or unsubstituted piperazinyl.

[0144] Formula (I) includes Ring B. Ring B is described in the Detailed Description for Formula (II) below.

[0145] Formula (I) includes substituents R.sup.C, R.sup.D, R.sup.E, and R.sup.F. Substituents R.sup.C, R.sup.D, R.sup.E, and R.sup.F are described in the Detailed Description for Formula (III) below.

[0146] Formula (I) includes Ring A and one or more instances of substituent R.sup.G. Ring A and substituent R.sup.G are described in the Detailed Description for Formula (III) below.

[0147] Formula (I) includes linker L that connects Ring A to substituent R.sup.H. In certain embodiments, L is a substituted or unsubstituted C.sub.1-6 hydrocarbon chain. In certain embodiments, one or more chain atoms of the hydrocarbon chain of L are independently replaced with —C(═O)—, —O—, —S—, —NR.sup.b—, —N═, or ═N—. In certain embodiments, L is an unsubstituted C.sub.1-3 hydrocarbon chain.

[0148] In certain embodiments, L is of the formula:

##STR00055##

wherein a is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, a is 0. In certain embodiments, L is a bond. In certain embodiments, a is 1. In certain embodiments, a is 2. In certain embodiments, a is 3. In certain embodiments, a is 4. In certain embodiments, a is 5. In certain embodiments, a is 6. In certain embodiments, L is of the formula:

##STR00056##

wherein l.sup.A indicates the point of attachment to Ring A, and l.sup.R indicates the point of attachment to R.sup.H.

[0149] In certain embodiments, L is an unsubstituted C.sub.1-3 hydrocarbon chain, wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O— or —NR.sup.b—. In certain embodiments, L is an unsubstituted C.sub.1-3 hydrocarbon chain, wherein one chain atom of the hydrocarbon chain is replaced with —O—. In certain embodiments, L is of the formula:

##STR00057##

wherein l.sup.A indicates the point of attachment to Ring A, and l.sup.R indicates the point of attachment to R.sup.A. In certain embodiments, L is of the formula:

##STR00058##

In certain embodiments, L is a substituted C.sub.1-6 hydrocarbon chain, wherein one chain atom of the hydrocarbon chain is replaced with —N—. In certain embodiments, L is of the formula:

##STR00059##

wherein l.sup.4 indicates the point of attachment to Ring A, and l.sup.R indicates the point of attachment to R.sup.H. In certain embodiments, L is of the formula:

##STR00060##

In certain embodiments, L is of the formula:

##STR00061##

In certain embodiments, L is of the formula:

##STR00062##

In certain embodiments, L is an unsubstituted C.sub.1-3 hydrocarbon chain, wherein one chain atom of the hydrocarbon chain is replaced with —C(═O)—. In certain embodiments, L is an unsubstituted C.sub.1-3 hydrocarbon chain, wherein one chain atom of the hydrocarbon chain is replaced with —S—. In certain embodiments, L is an unsubstituted C.sub.1-3 hydrocarbon chain, wherein one chain atom of the hydrocarbon chain is replaced with —NR.sup.b—. In certain embodiments, L is an unsubstituted C.sub.1-3 hydrocarbon chain, wherein one chain atom of the hydrocarbon chain is replaced with —N═. In certain embodiments, L is an unsubstituted C.sub.1-3 hydrocarbon chain, wherein one chain atom of the hydrocarbon chain is replaced with ═N—.

[0150] Formula (I) includes substituent R.sup.H. In certain embodiments, R.sup.H is substituted or unsubstituted C.sub.1-6 alkyl (e.g., methyl, ethyl, or propyl). In certain embodiments, R.sup.H is methyl. In certain embodiments, R.sup.H is ethyl. In certain embodiments, R.sup.H is propyl. In certain embodiments, R.sup.H is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.H is substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, R.sup.H is of the formula:

##STR00063##

wherein R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl or —OR.sup.x1, wherein R is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl or nitrogen protecting group; R.sup.x1 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; and x is 0, 1, 2, or 3. In certain embodiments, R.sup.H is of the formula:

##STR00064##

In certain embodiments, R.sup.H is —OH. In certain embodiments, R.sup.H is —N(R.sup.c).sub.2. As generally described herein, R.sup.H may include substituent R.sup.c. In certain embodiments, R.sup.c is hydrogen. In certain embodiments, R.sup.c is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.c is substituted or unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.c is substituted or unsubstituted methyl. In certain embodiments, R.sup.c is methyl. In certain embodiments, R.sup.c is substituted or unsubstituted ethyl. In certain embodiments, R.sup.c is substituted or unsubstituted methyl. In certain embodiments, R.sup.c is a nitrogen protecting group. In certain embodiments, R.sup.H is —NMe.sub.2. In certain embodiments, two instances of R.sup.c are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, two instances of R.sup.c are taken together with their intervening atoms to form a substituted or unsubstituted heteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).

[0151] In certain embodiments, Ring A with linker L and substituent R.sup.H is of the formula:

##STR00065##

In certain embodiments, Ring A with linker L and substituent R.sup.H is of the formula:

##STR00066##

In certain embodiments, Ring A with linker L and substituent R.sup.H is of the formula:

##STR00067## ##STR00068##

In certain embodiments, Ring A with linker L and substituent R.sup.H is not of the formula:

##STR00069##

In certain embodiments, Ring A with linker L and substituent R.sup.H is of the formula:

##STR00070## ##STR00071##

In certain embodiments, Ring A with linker L and substituent R.sup.H is not of the formula:

##STR00072##

[0152] In certain embodiments, Ring A with linker L and substituent R.sup.H is of the formula:

##STR00073##

In certain embodiments, Ring A with linker L and substituent R.sup.H is of the formula:

##STR00074##

In certain embodiments, Ring A with linker L and substituent R.sup.H is of the formula:

##STR00075##

In certain embodiments, Ring A with linker L and substituent R.sup.H is of the formula:

##STR00076##

[0153] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00077##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0154] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00078## ##STR00079##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0155] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00080##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0156] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00081##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0157] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00082##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0158] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00083##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0159] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00084##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0160] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00085##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0161] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00086##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0162] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00087##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, the compound of Formula (I) is of the formula:

##STR00088##

##STR00089##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0163] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00090##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0164] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00091## ##STR00092## ##STR00093## ##STR00094##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0165] In certain embodiments, the compound of Formula (I) is of the formula:

##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0166] In certain embodiments, the compound of Formula (I) is not of the formula:

##STR00118##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

Compounds of Formula (II)

[0167] In one aspect, the present disclosure provides compounds of Formula (II):

##STR00119##

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein:

[0168] R.sup.J is substituted or unsubstituted carbocyclyl;

[0169] each instance of R.sup.B is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.b).sub.2, —SR.sup.a, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.b)N(R.sup.b).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.b).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.b).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.b).sub.2;

[0170] each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;

[0171] each instance of R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.b are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

[0172] m is 0, 1, 2, 3, 4, or 5;

[0173] R.sup.C is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

[0174] R.sup.D is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

[0175] R.sup.E is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

[0176] R.sup.F is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

[0177] Ring A is substituted or unsubstituted phenyl; substituted or unsubstituted, polycyclic aryl; substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl; or substituted or unsubstituted, polycyclic heteroaryl;

[0178] each instance of R.sup.G is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, −OR.sup.a, —N(R.sup.b).sub.2, —SR.sup.a, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.b)N(R.sup.b).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.b).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.b).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.b).sub.2;

[0179] n is 0, 1, 2, 3, or 4, as valency permits;

[0180] R.sup.K is unsubstituted methyl, substituted or unsubstituted heterocyclyl, —OR.sup.a, or —N(R.sup.c).sub.2, wherein each instance of R.sup.c is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.c are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

[0181] Formula (II) includes substituent R.sup.J. In certain embodiments, R.sup.J is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.J is substituted or unsubstituted, C.sub.3-6 carbocyclyl. In certain embodiments, R.sup.J is substituted or unsubstituted cyclopropyl. In certain embodiments, R.sup.J is substituted or unsubstituted cyclobutyl. In certain embodiments, R.sup.J is cyclobutyl. In certain embodiments, R.sup.J is substituted or unsubstituted cyclopentyl. In certain embodiments, R.sup.J is cyclopentyl. In certain embodiments, R.sup.J is substituted or unsubstituted cyclohexyl. In certain embodiments, R.sup.J is cyclohexyl.

[0182] As generally defined herein, as applicable to Formula (I) and (II), Ring B is an unsubstituted phenyl ring (e.g., when m is 0) or a phenyl ring substituted with one or more substituents R.sup.B (e.g., when m is 1, 2, 3, 4, or 5). In certain embodiments, at least two instances of R.sup.B are different. In certain embodiments, all instances of R.sup.B are the same. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, Ring B is of the formula:

##STR00120##

In certain embodiments, Ring B is of the formula:

##STR00121##

In certain embodiments, Ring B is of the formula:

##STR00122##

In certain embodiments, Ring B is of the formula:

##STR00123##

In certain embodiments, Ring B is not of the formula:

##STR00124##

In certain embodiments, Ring B is of the formula:

##STR00125##

In certain embodiments, Ring B is of the formula:

##STR00126##

In certain embodiments, Ring B is of the formula:

##STR00127##

[0183] In certain embodiments, at least one instance of R.sup.B is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.B is F. In certain embodiments, at least one instance of R.sup.B is Cl. In certain embodiments, at least one instance of R.sup.B is Br. In certain embodiments, at least one instance of R.sup.B is I. In certain embodiments, at least one R.sup.B is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.B is methyl. In certain embodiments, m is 2, and both instances of R.sup.B are methyl. In certain embodiments, m is 2, and one instance of R.sup.B is halogen, and the other instance of R.sup.B is methyl. In certain embodiments, m is 2, and one instance of R.sup.B is Cl, and the other instance of R.sup.B is methyl. In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.B is benzyl. In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.B is —OR.sup.a (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.B is —N(R.sup.b).sub.2, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.b)N(R.sup.b).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.b).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.b).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.b).sub.2.

[0184] Formula (II) includes substituents R.sup.C, R.sup.D, R.sup.E, and R.sup.F. Substituents R.sup.C, R.sup.D, R.sup.E, and R.sup.F are described in the Detailed Description for Formula (III) below.

[0185] Formula (II) includes Ring A and one or more instances of substituent R.sup.G. Ring A and substituent R.sup.G are described in the Detailed Description for Formula (III) below.

[0186] As generally defined herein, Formula (II) includes substituent R.sup.K attached to Ring A. Substituent R.sup.K is described in the Detailed Description for Formula (III) below.

[0187] In certain embodiments, Ring A with substituent R.sup.K is of the formula:

##STR00128##

In certain embodiments, Ring A with substituent R.sup.K is of the formula:

##STR00129##

[0188] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00130##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0189] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00131##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0190] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00132## ##STR00133##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0191] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00134##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0192] In certain embodiments, the compound of Formula (II) is of the formula:

##STR00135## ##STR00136##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

Compounds of Formula (III)

[0193] In certain embodiments, the compound is of Formula (III):

##STR00137##

or a pharmaceutically acceptable salt thereof,
wherein:

[0194] R.sup.L is substituted or unsubstituted alkyl;

[0195] Ring C is unsubstituted phenyl or of the formula:

##STR00138##

[0196] each instance of R.sup.B1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R.sup.d).sub.2, —CN, —SCN, —C(═NR.sup.d)R.sup.a, —C(═NR.sup.d)OR.sup.a, —C(═NR.sup.d)N(R.sup.d).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.d).sub.2, —NO.sub.2, —NR.sup.dC(═O)R.sup.a, —NR.sup.dC(═O)OR.sup.a, —NR.sup.dC(═O)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.d).sub.2;

[0197] each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;

[0198] each instance of R.sup.d is independently hydrogen, —C(═O)R.sup.a, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.d are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

[0199] R.sup.C is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

[0200] R.sup.D is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

[0201] R.sup.E is hydrogen, halogen, or substituted or unsubstituted C.sub.1-6 alkyl;

[0202] R.sup.F is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

[0203] Ring A is substituted or unsubstituted phenyl; substituted or unsubstituted, polycyclic aryl; substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl; or substituted or unsubstituted, polycyclic heteroaryl;

[0204] each instance of R.sup.G is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.a, —N(R.sup.b).sub.2, —SR.sup.a, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.a)N(R.sup.a).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.a).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.b).sub.2;

[0205] each instance of R.sup.b is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.b are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

[0206] n is 0, 1, 2, 3, or 4, as valency permits;

[0207] R.sup.K is unsubstituted methyl, substituted or unsubstituted heterocyclyl, —OR.sup.a, or —N(R.sup.c).sub.2, wherein each instance of R.sup.c is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group, or optionally two instances of R.sup.c are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and

[0208] R.sup.Y is substituted phenyl.

[0209] Formula (III) includes Ring C. In certain embodiments, Ring C is unsubstituted phenyl. In certain embodiments, Ring C is of the formula:

##STR00139##

In certain embodiments, at least one instance of R.sup.B1 is halogen. In certain embodiments, at least one instance of R.sup.B1 is halogen. In certain embodiments, at least one instance of R.sup.B1 is F. In certain embodiments, at least one instance of R.sup.B1 is Cl. In certain embodiments, at least one instance of R.sup.B1 is Br. In certain embodiments, at least one instance of R.sup.B1 is I (iodine). In certain embodiments, at least one instance of R.sup.B1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., methyl, ethyl, or propyl). In certain embodiments, at least one instance of R.sup.B1 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.B1 is methyl. In certain embodiments, at least one instance of R.sup.B1 is —N(R.sup.d).sub.2, wherein each instance of R.sup.d is hydrogen or —C(═O)R.sup.a. In certain embodiments, at least one instance of R.sup.B1 is —NH(C(═O)R.sup.a). In certain embodiments, at least one instance of R.sup.B1 is —OR.sup.a (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.B1 is —SR.sup.a, —CN, —SCN, —C(═NR.sup.d)R.sup.a, —C(═NR.sup.d)OR.sup.a, —C(═NR.sup.d)N(R.sup.d).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.d).sub.2, —NO.sub.2, —NR.sup.dC(═O)R.sup.a, —NR.sup.dC(═O)OR.sup.a, —NR.sup.dC(═O)N(R.sup.a).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.d).sub.2. In certain embodiments, Ring C is of the formula:

##STR00140##

In certain embodiments, Ring C is of the formula:

##STR00141##

In certain embodiments, Ring C is of the formula:

##STR00142##

In certain embodiments, R.sup.Y is substituted phenyl. In certain embodiments, R.sup.Y is substituted phenyl. In certain embodiments, R.sup.Y is of the formula:

##STR00143##

wherein R.sup.y1 is halogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.y1 is halogen (e.g., Br, Cl, F). In certain embodiments, R.sup.y1 is substituted or unsubstituted C.sub.1-6 alkyl (e.g., substituted or unsubstituted, methyl, ethyl, or propyl). In certain embodiments, R.sub.y1 is substituted or unsubstituted methyl. In certain embodiments, R.sub.y1 is substituted methyl. In certain embodiments, R.sup.y1 is methyl. In certain embodiments, R.sup.y1 is —CF.sub.3. In certain embodiments, Ring C is of the formula:

##STR00144##

In certain embodiments, Ring C is of the formula:

##STR00145##

[0210] Formula (III) includes substituent R.sup.L. In certain embodiments, R.sup.L is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.L is substituted or unsubstituted methyl. In certain embodiments, R.sup.L is methyl. In certain embodiments, R.sup.L is substituted or unsubstituted ethyl. In certain embodiments, R.sup.L is ethyl. In certain embodiments, R.sup.L is substituted or unsubstituted propyl. In certain embodiments, R.sup.L is propyl. In certain embodiments, R.sup.L is isopropyl. In certain embodiments, R.sup.L is substituted or unsubstituted butyl.

[0211] As generally defined herein, Formula (II) and (III) include substituent R.sup.K attached to Ring A. In certain embodiments, R.sup.K is unsubstituted methyl. In certain embodiments, R.sup.K is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.K is substituted or unsubstituted tetrahydropyranyl. In certain embodiments, R.sup.K is substituted or unsubstituted piperidinyl. In certain embodiments, R.sup.K is substituted or unsubstituted morpholinyl. In certain embodiments, R.sup.K is substituted or unsubstituted piperazinyl. In certain embodiments, R.sup.K is of the formula:

##STR00146##

wherein R.sup.1 is substituted or unsubstituted C.sub.1-6 alkyl or —OR.sup.x1, wherein R is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or nitrogen protecting group; R.sup.x1 is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; and x is 0, 1, 2, or 3. In certain embodiments, R.sup.K is of the formula:

##STR00147##

In certain embodiments, R.sup.K is —OR.sup.a (e.g., —OH or —OMe). In certain embodiments, R.sup.K is —N(R.sup.c).sub.2. In certain embodiments, two instances of R.sup.c are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, two instances of R.sup.c are taken together with their intervening atoms to form a substituted or unsubstituted heteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.K is —NMe.sub.2. In certain embodiments, R.sup.K is —SR.sup.a, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.b)N(R.sup.b).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.b).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.b).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(R.sup.b).sub.2.

[0212] As generally defined herein, Formula (I), (II), and (III) include substituent R.sup.C. In certain embodiments, R.sup.C is hydrogen. In certain embodiments, R.sup.C is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.C is substituted or unsubstituted C.sub.1-6 alkyl (e.g., methyl, ethyl, or propyl). In certain embodiments, R.sup.C is substituted or unsubstituted methyl. In certain embodiments, R.sup.C is methyl. In certain embodiments, R.sup.C is substituted or unsubstituted ethyl. In certain embodiments, R.sup.C is ethyl. In certain embodiments, R.sup.C is substituted or unsubstituted propyl. In certain embodiments, R.sup.C is unsubstituted isopropyl.

[0213] As generally defined herein, Formula (I), (II), and (III) include substituent R.sup.D. In certain embodiments, R.sup.D is hydrogen. In certain embodiments, R.sup.D is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl (e.g., methyl, ethyl, or propyl). In certain embodiments, R.sup.D is substituted or unsubstituted methyl. In certain embodiments, R.sup.D is methyl. In certain embodiments, R.sup.D is substituted or unsubstituted ethyl. In certain embodiments, R.sup.D is ethyl. In certain embodiments, R.sup.D is substituted or unsubstituted propyl. In certain embodiments, R.sup.D is isopropyl.

[0214] As generally defined herein, Formula (I), (II), and (III) include substituent R.sup.E. In certain embodiments, R.sup.E is hydrogen. In certain embodiments, R.sup.E is halogen (e.g., F, Cl, Br, or I). In certain embodiments, R.sup.E is substituted or unsubstituted C.sub.1-6 alkyl (e.g., methyl, ethyl, or propyl). In certain embodiments, R.sup.E is substituted or unsubstituted methyl. In certain embodiments, R.sup.E is methyl. In certain embodiments, R.sup.E is substituted or unsubstituted ethyl. In certain embodiments, R.sup.E is ethyl. In certain embodiments, R.sup.E is substituted or unsubstituted propyl. In certain embodiments, R.sup.E is isopropyl.

[0215] As generally defined herein, Formula (I), (II), and (III) include substituent R.sup.F. In certain embodiments, R.sup.F is hydrogen. In certain embodiments, R.sup.E is substituted or unsubstituted C.sub.1-6 alkyl (e.g., methyl, ethyl, or propyl). In certain embodiments, R.sup.F is substituted or unsubstituted methyl. In certain embodiments, R.sup.F is methyl. In certain embodiments, R.sup.F is substituted or unsubstituted ethyl. In certain embodiments, R.sup.F is ethyl. In certain embodiments, R.sup.F is substituted or unsubstituted propyl. In certain embodiments, R.sup.F is isopropyl. In certain embodiments, R.sup.F is a nitrogen protecting group (e.g., a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0216] In certain embodiments, R.sup.C, R.sup.D, R.sup.E, and R.sup.F are each hydrogen. In certain embodiments, at least one substituent selected from the group consisting of R.sup.C, R.sup.D, R.sup.E, and R.sup.F is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.C is substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.D, R.sup.E, and R.sup.F are each hydrogen. In certain embodiments, R.sup.C is unsubstituted methyl; and R.sup.D, R.sup.E, and R.sup.F are each hydrogen. In certain embodiments, R.sup.C is unsubstituted isopropyl; and R.sup.D, R.sup.E, and R.sup.F are each hydrogen. In certain embodiments, R.sup.D is substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.C, R.sup.E, and R.sup.F are each hydrogen. In certain embodiments, R.sup.E is substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.C, R.sup.D, and R.sup.F are each hydrogen. In certain embodiments, R.sup.F is substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.C, R.sup.D, and R.sup.E are each hydrogen.

[0217] As generally defined herein, Formula (I), (II), and (III) include Ring A. In certain embodiments, Ring A is substituted or unsubstituted phenyl. In certain embodiments, Ring A is not substituted or unsubstituted phenyl. In certain embodiments, Ring A is not substituted phenyl. In certain embodiments, Ring A is not unsubstituted phenyl. In certain embodiments, Ring A is unsubstituted phenyl. In certain embodiments, Ring A is phenyl, and includes one or more R.sup.G substituents. In certain embodiments, Ring A includes one R.sup.G substituent. In certain embodiments, Ring A includes two R.sup.G substituents. In certain embodiments, Ring A is substituted or unsubstituted polycyclic aryl (e.g., naphthalene or anthracene). In certain embodiments, Ring A is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, Ring A is substituted or unsubstituted furan. In certain embodiments, Ring A is substituted or unsubstituted thiophene. In certain embodiments, Ring A is substituted or unsubstituted pyrrole. In certain embodiments, Ring A is substituted or unsubstituted pyrazole. In certain embodiments, Ring A is pyrazole. In certain embodiments, Ring A is substituted or unsubstituted pyridinyl. In certain embodiments, Ring A is pyridinyl. In certain embodiments, Ring A is substituted or unsubstituted polycyclic heteroaryl (e.g., substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).

[0218] As generally defined herein, Formula (I), (II), and (III) include one or more instances of substituent R.sup.G. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, at least one instance of R.sup.G is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R.sup.G is F. In certain embodiments, at least one instance of R.sup.G is Cl. In certain embodiments, at least one instance of R.sup.G is Br. In certain embodiments, at least one instance of R.sup.G is I. In certain embodiments, at least one R.sup.G is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.G is unsubstituted methyl. In certain embodiments, at least one instance of R.sup.G is substituted methyl. In certain embodiments, at least one instance of R.sup.G is —CF.sub.3. In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.G is substituted ethyl. In certain embodiments, at least one instance of R.sup.G is unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted morpholinyl. In certain embodiments, at least one instance of R.sup.G is of the formula:

##STR00148##

In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R.sup.G is of the formula:

##STR00149##

In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.G is benzyl. In certain embodiments, at least one instance of R.sup.G is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.B is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.G is —OR.sup.a, wherein R.sup.a is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.G is —OMe. In certain embodiments, at least one instance of R.sup.G is —OEt. In certain embodiments, at least one instance of R.sup.G is —O(Pr). In certain embodiments, at least one instance of R.sup.G is —O(iPr). In certain embodiments, at least one instance of R.sup.G is —N(R.sup.b).sub.2, —SR.sup.a, —CN, —SCN, —C(═NR.sup.b)R.sup.a, —C(═NR.sup.b)OR.sup.a, —C(═NR.sup.b)N(R.sup.b).sub.2, —C(═O)R.sup.a, —C(═O)OR.sup.a, —C(═O)N(R.sup.b).sub.2, —NO.sub.2, —NR.sup.bC(═O)R.sup.a, —NR.sup.bC(═O)OR.sup.a, —NR.sup.bC(═O)N(R.sup.b).sub.2, —OC(═O)R.sup.a, —OC(═O)OR.sup.a, or —OC(═O)N(RN.

[0219] In certain embodiments, Ring A with substituent R.sup.K is of the formula:

##STR00150##

In certain embodiments, Ring A with substituent R.sup.K is of the formula:

##STR00151##

In certain embodiments, the compound of Formula (III) is of the formula:

##STR00152##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0220] In certain embodiments, the compound of Formula (III) is of the formula:

##STR00153##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0221] In certain embodiments, the compound of Formula (III) is of the formula:

##STR00154##

##STR00155##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0222] In certain embodiments, the compound of Formula (III) is of the formula:

##STR00156##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0223] In certain embodiments, the compound of Formula (III) is of the formula:

##STR00157##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0224] In certain embodiments, the compound of Formula (III) is of the formula:

##STR00158##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0225] In certain embodiments, the compound of Formula (III) is of the formula:

##STR00159##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0226] In certain embodiments, the compound of Formula (III) is of the formula:

##STR00160## ##STR00161## ##STR00162##

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0227] In certain embodiments, a compound described herein is a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiments, a compound described herein is a compound of Formula (I), (II), (III), or a pharmaceutically acceptable salt thereof.

[0228] Certain compounds described herein bind and/or inhibit protein kinases. In certain embodiments, the protein kinase is a SIK. In certain embodiments, the protein kinase is SIK1. In certain embodiments, the protein kinase is SIK2. In certain embodiments, the protein kinase is SIK3. In certain embodiments, the compounds described herein non-covalently bind to the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). In certain embodiments, the compounds described herein reversibly bind to the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK2, or SIK3)). In certain embodiments, the compounds described herein non-reversibly bind to the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). In certain embodiments, the compounds described herein modulate the activity of the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). In certain embodiments, the compounds described herein inhibit the activity of the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)).

[0229] The binding affinity of a compound described herein to a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) may be measured by the dissociation constant (K.sub.d) value of an adduct of the compound and the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) using methods known in the art (e.g., isothermal titration calorimetry (ITC)). In certain embodiments, the adduct comprises the compound and the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)), which are bound (e.g., non-covalently) to each other. In certain embodiments, the K.sub.d value of the adduct is not more than about 100 μM, not more than about 10 μM, not more than about 1 μM, not more than about 100 nM, not more than about 10 nM, or not more than about 1 nM.

[0230] In certain embodiments, the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) is inhibited by a compound described herein. The inhibition of the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) by a compound described herein may be measured by the half maximal inhibitory concentration (IC.sub.50) value of the compound when the compound, or a pharmaceutical composition thereof, is contacted, directly or indirectly, with the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). The IC.sub.50 values may be obtained using methods known in the art (e.g., by a competition binding assay). In certain embodiments, the IC.sub.50 value of a compound described herein is not more than about 1 mM, not more than about 100 μM, not more than about 10 μM, not more than about 1 μM, not more than about 100 nM, not more than about 10 nM, or not more than about 1 nM.

[0231] The compounds described herein may selectively modulate the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). In certain embodiments, the compounds selectively inhibit the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). In certain embodiments, the compounds selectively increase the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). In certain embodiments, the compounds inhibit the activity of two or more protein kinases (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) to the same extent. In certain embodiments, the compounds increase the activity of two or more protein kinases (e.g., kinases of SIK, (e.g., kinases of SIK1, SIK2, or SIK3)) to the same extent.

[0232] The selectivity of a compound described herein in inhibiting the activity of a first protein kinase (e.g., SIK) over a second protein kinase may be measured by the quotient of the IC.sub.50 value of the compound in inhibiting the activity of the second protein kinase (e.g., SIK) over the IC.sub.50 value of the compound in inhibiting the activity of the first protein kinase (e.g., SIK). The selectivity of a compound described herein in modulating the activity of a first protein kinase (e.g., SIK) over a second protein kinase may also be measured by the quotient of the K.sub.d value of an adduct of the compound and the second protein kinase over the K.sub.d value of an adduct of the compound and the first protein kinase (e.g., SIK). In certain embodiments, the selectivity is at least about 1-fold, at least about 3-fold, at least about 10-fold, at least about 30-fold, at least about 100-fold, at least about 300-fold, at least about 1,000-fold, at least about 3,000-fold, at least about 10,000-fold, at least about 30,000-fold, or at least about 100,000-fold.

[0233] It is expected that the compounds described herein may be useful in treating and/or preventing diseases associated with aberrant activity (e.g., increased activity) of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). It is known in the art that protein kinases are implicated in a wide range of diseases, such as proliferative diseases, musculoskeletal diseases, genetic diseases, hematological diseases, neurological diseases, painful conditions, psychiatric disorders, and metabolic disorders. Therefore, the compounds described herein are expected to be useful in treating and/or preventing proliferative diseases, musculoskeletal diseases, genetic diseases, hematological diseases, neurological diseases, painful conditions, psychiatric disorders, and metabolic disorders.

Pharmaceutical Compositions, Kits, and Administration

[0234] The present disclosure provides pharmaceutical compositions comprising a compound of Formula (I), (II) or, (III), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0235] In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a musculoskeletal disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a musculoskeletal disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a in a painful condition subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a painful condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a psychiatric disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a metabolic disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, increased activity) of a protein kinase (e.g., kinase of SIX, (e.g., kinase of SIK1, SIK2, or SIK3)) in a subject or cell.

[0236] In certain embodiments, the subject being administered a compound or composition described herein is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0237] In certain embodiments, the cell being contacted with a compound or composition described herein is present in vitro. In certain embodiments, the cell being contacted with a compound or composition described herein is present in vivo.

[0238] An effective amount of a compound described herein may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration), wherein mg/kg is mg of compound to kg weight of the subject. In certain embodiments, the effective amount per dose varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.

[0239] In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a protein kinase by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a protein kinase by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a protein kinase by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0240] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

[0241] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0242] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0243] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0244] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0245] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0246] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0247] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[0248] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0249] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0250] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium di sodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0251] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0252] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0253] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0254] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0255] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0256] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0257] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0258] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0259] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0260] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0261] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0262] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0263] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0264] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0265] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0266] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[0267] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0268] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0269] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0270] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0271] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0272] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0273] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0274] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[0275] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0276] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0277] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0278] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0279] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. In certain embodiments, a dose described herein is a dose to an adult human whose body weight is 70 kg.

[0280] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and/or in inhibiting the activity of a protein kinase (e.g., SIK) in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

[0281] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound or composition and may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0282] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-musculoskeletal disease agents, anti-cancer agents, cytotoxic agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, and pain-relieving agents. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-musculoskeletal disease agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is an binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

[0283] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0284] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) in a subject or cell.

[0285] In certain embodiments, a kit described herein further includes instructions for using the compound or pharmaceutical composition included in the kit. In certain embodiments, the kit comprises a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein; and instructions for using the compound, pharmaceutically acceptable salt, or pharmaceutical composition. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for modulating (e.g., inhibiting) the activity (e.g., aberrant activity, such as increased activity) of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) in a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

Methods of Treatment and Uses

[0286] The present disclosure provides methods of modulating (e.g., inhibiting or increasing) the activity (e.g., aberrant activity, such as increased or decreased activity) of a protein kinase (e.g., SIK). The present disclosure provides methods of modulating (e.g., inhibiting or increasing) the activity (e.g., aberrant activity, such as increased or decreased activity) of a SIK (e.g., SIK1, SIK2, or SIK3) in a subject or cell. The present disclosure also provides methods for the treatment of a wide range of diseases, such as diseases associated with aberrant activity (e.g., increased activity) of a protein kinase, e.g., proliferative diseases, musculoskeletal diseases, genetic diseases, hematological diseases, neurological diseases, painful conditions, psychiatric disorders, and metabolic disorders in a subject in need thereof.

[0287] In another aspect, the present disclosure provides methods of modulating the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) in a subject or cell. In certain embodiments, provided are methods of inhibiting the activity of a protein kinase in a subject. In certain embodiments, provided are methods of inhibiting the activity of a protein kinase in a cell. In certain embodiments, provided are methods of increasing the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) in a subject. In certain embodiments, provided are methods of increasing the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) in a cell. In certain embodiments, the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) in a subject or cell is inhibited by a method described herein by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In certain embodiments, the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) in a subject or cell is increased by a method described herein by at least about 1%, at least about 3%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) in a subject or cell is selectively inhibited by the method. In some embodiments, the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) in a subject or cell is selectively increased by the method.

[0288] Another aspect of the present disclosure relates to methods of treating a disease in a subject in need thereof. In certain embodiments, the disease is associated with a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). In certain embodiments, the disease is associated with the activity of a protein kinase. In certain embodiments, the disease is associated with the aberrant activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). In certain embodiments, the disease is associated with increased activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)).

[0289] In certain embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. In certain embodiments, the disease is a benign neoplasm. In certain embodiments, the disease is or is associated with pathological angiogenesis. In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the disease is an autoimmune disease. In certain embodiments, the disease is a musculoskeletal disease. In certain embodiments, the disease is a genetic disease. In certain embodiments, the disease is a hematological disease. In certain embodiments, the disease is a neurological disease. In certain embodiments, the disease is a painful condition. In certain embodiments, the disease is a psychiatric disorder. In certain embodiments, the disease is a metabolic disorder.

[0290] In still another aspect, the present disclosure provides methods of preventing a disease described herein in a subject in need thereof.

[0291] In certain embodiments, the methods of the disclosure include administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the method of treating a disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein the disease is associated with aberrant activity of a protein kinase. In certain embodiments, the subject being administered a compound or pharmaceutical composition described herein is a human. In certain embodiments, the subject being administered a compound or pharmaceutical composition described herein is a non-human animal. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a protein kinase by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a protein kinase by not more than 10%, not more than 20%, not more than 30%, not more than 40%, not more than 50%, not more than 60%, not more than 70%, not more than 80%, not more than 90%, not more than 95%, or not more than 98%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of a protein kinase by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.

[0292] In certain embodiments, the methods of the disclosure include administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the methods of the disclosure include administering to a subject in need thereof a prophylactically effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the methods of the disclosure include contacting a cell with an effective amount of a compound or pharmaceutical composition described herein.

[0293] In another aspect, the present disclosure provides the compounds described herein for use in a method described herein (e.g., method of inhibiting a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)), method of treating a disease (e.g., proliferative disease, musculoskeletal disease), method of preventing a disease (e.g., proliferative disease, musculoskeletal disease), or method of screening a library of compounds).

[0294] In still another aspect, the present disclosure provides the pharmaceutical compositions described herein for use in a method described herein (e.g., a method of inhibiting a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)), a method of treating a disease (e.g., a proliferative or musculoskeletal disease), a method of preventing a disease (e.g., a proliferative or musculoskeletal disease), or a method of screening a library of compounds).

Methods of Screening a Library of Compounds

[0295] Another aspect of the disclosure relates to methods of screening a library of compounds, and pharmaceutical acceptable salts thereof, to identify a compound, or a pharmaceutical acceptable salt thereof, that is useful in a method described herein. In certain embodiments, the methods of screening a library include obtaining at least two different compounds described herein; and performing at least one assay using the different compounds described herein. In certain embodiments, at least one assay is useful in identifying a compound that is useful in a method described herein.

[0296] Typically, the methods of screening a library of compounds involve at least one assay. In certain embodiments, the assay is performed to detect one or more characteristics associated with the treatment and/or prevention of a disease described herein or with the modulation (e.g., inhibition) of the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). The characteristic may be a desired characteristic (e.g., a characteristic associated with the treatment of a disease, a characteristic associated with the prevention of a disease, or a characteristic associated with the inhibition of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3))). The characteristic may be an undesired characteristic (e.g., a characteristic associated with an untreated disease, a characteristic associated with a disease having not been prevented, or a characteristic associated with the non-modulation of the activity of a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). The assay may be an enzymatic activity assay, immunoassay, such as a sandwich-type assay, competitive binding assay, one-step direct test, two-step test, or blot assay. The step of performing at least one assay may be performed robotically or manually. In certain embodiments, the assay comprises (a) contacting a library of compounds with a protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)); and (b) detecting the binding of the library of compounds to the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). In certain embodiments, the assay comprises detecting the specific binding of the library of compounds to the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)). In certain embodiments, the detected binding of the library of compounds to the protein kinase (e.g., kinase of SIK, (e.g., kinase of SIK1, SIK2, or SIK3)) is useful in identifying the compound that is useful in a method described herein. In certain embodiments, the step of detecting the binding comprises using differential scanning fluorimetry (DSF), isothermal titration calorimetry (ITC), and/or an amplified luminescence proximity homogeneous assay (ALPHA). The step of performing at least one assay may be performed in a cell in vitro or in vivo.

EXAMPLES

[0297] In order that the disclosure may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, uses, and methods provided herein and are not to be construed in any way as limiting their scope.

Experimental Procedures

Example I. Selected Compounds and Biological Activity

SIK2 Protein Production and Purification

[0298] A lentiviral expression construct encoding the human SIK2 open reading frame (Clone TRCN0000491575) was obtained from the Broad Institute Genetic Perturbation Platform. Human SIK2 was amplified by PCR and cloned into a baculovirus expression vector, pCoofy29, as described previously (Scholz, et al., BMC Biotechnol., 13, 12 (2013)), resulting a His6-MBP-tagged SIK2 construct for Spodoptera frugiperda (Sf9) insect cell expression. High-titer recombinant baculovirus was obtained using the Bac-to-Bac Baculovirus Expression System (Invitrogen). Sf9 cells at a cell density of 3×106 cells/mL were infected with P1 virus at a multiplicity of infection of 5. Cells were harvested by centrifugation at 48 h post-infection at 27° C. The cell pellet was lysed by homogenization in lysis buffer containing 5 mM Tris 7.5, 250 mM NaCl, 5% Glycerol, 0.5 mM TCEP, and 1 tablet of EDTA-free protease inhibitor (Roche). The His6-MBP-tagged SIK2 protein was isolated from the cell lysate by incubating with Ni-NTA superflow resin (Qiagen) at 4° C. for 2 h. After extensive washes, the bound protein was eluted by buffered imidazole. The eluted protein was further purified by FPLC using superdex 200 gel filtration column (GE Healthcare) with buffer containing 50 mM Tris 7.5, 150 mM NaCl, 0.5 mM TCEP, and 2% Glycerol. The monomeric species was collected and analyzed by Coomassie blue stained SDS-PAGE gel indicating sample purity greater than 80%. This preparation was used for caliper assay and compound IC.sub.50 measurement.

SIK2 Kinase Activity Assay

[0299] IC.sub.50's for selected compounds in Table 5 below were measured by Caliper-based mobility shift assay (PerkinElmer). For these experiments, full length His6-MBP-tagged hSIK2 (4 nM) was incubated with HG-9-91-01 derivatives in buffer 5 containing 100 mM HEPES 7.5, 10 mM MgCl2, 2.5 mM DTT, 0.004% Tween20, 0.003% Brij-35, 30 μM ATP and 1.5 μM ProfilerPro FL-Peptide 10 (5-FAMKKKVSRSGLYRSPSMPENLNRPR-COOH, PerkinElmer, Catalog No. 760354) at rt. Reactions were quenched by adding 20 mM EDTA (pH 8) after 1 hr, and percentage of substrate conversion was measured by LabChip EZ Reader II (PerkinElmer). IC.sub.50's for SIK2 inhibition were calculated using SmartFit nonlinear regression in Genedata Screener software suite (Genedata). The IC.sub.50's for selected compounds are listed in Table 5 below.

Compound Characterization

[0300] The urea formation was performed using a Biotage® Initiator.sup.+ Microwave Synthesizer. All reactions were monitored by thin layer chromatography (TLC) with 0.25 mm E. Merck pre-coated silica gel plates (60 F.sub.254) and Waters LCMS system (Waters 2489 UV/Visible Detector, Waters 3100 Mass, Waters 515 HPLC pump, Waters 2545 Binary Gradient Module, Waters Reagent Manager, Waters 2767 Sample Manager) using SunFire™ C18 column (4.6×50 mm, 5 μm particle size): solvent gradient=97% A at 0 min, 0% A at 5 min; solvent A=0.035% TFA in Water; solvent B=0.035% TFA in Acetonitrile; flow rate: 2.5 mL/min. Purification of reaction products was carried out by flash chromatography using CombiFlash® Rf with Teledyne Isco RediSep® Rf High Performance Gold or Silicycle SiliaSep™ High Performance columns (4 g, 12 g, 24 g, 40 g, 80 g or 120 g). The purity of all compounds was over 95% and was analyzed with Waters LCMS system. .sup.1H NMR and .sup.13C NMR spectra were obtained using a Varian Inova-600 (600 MHz for .sup.1H, and 125 MHz for .sup.13C) spectrometer. Chemical shifts are reported relative to chloroform (δ=7.24) for .sup.1H NMR or dimethyl sulfoxide (δ=2.50) for .sup.1H NMR and dimethyl sulfoxide (δ=39.51) for .sup.13C NMR. Data are reported as (br=broad, s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet).

Example II. Preparation of YKL-04-114 and YKL-05-093

[0301] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance spectra (.sup.1H NMR) were obtained on Bruker AVANCE spectrometer at 400 MHz for proton. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. The solvent peak was used as the reference peak for proton spectra. LC-MS spectra were obtained on Agilent 1100 HPLC LC-MS ion trap electrospray ionization (ESI) mass spectrometer.

##STR00163## ##STR00164##

2,4-dichloro-5-(iodomethyl)pyrimidine (2)

[0302] A mixture of 2,4-dichloro-5-(chloromethyl)pyrimidine (15.0 g, 76.0 mmol), NaI (13.7 g, 91.4 mmol) in acetone was stirred at 60° C. for 45 min. The resulting precipitate (NaCl) was removed by filtration and washed with acetone. The combined filtrate was concentrated to give light yellow solid, which was purified by column chromatography on silica gel (eluting with DCM) to obtain 2,4-dichloro-5-(iodomethyl)pyrimidine 2 as a light yellow solid (30.8 g, yield 96%). LCMS (m/z): 289.3 [M+H].sup.+.

N-((2,4-dichloropyrimidin-5-yl)methyl)-2,6-dimethylaniline (3)

[0303] A mixture of 2,4-dichloro-5-(iodomethyl)pyrimidine 2 (7.0 g, 24.2 mmol), 2,6-dimethylaniline (3.8 g, 31.4 mmol), K.sub.2CO.sub.3 (5.0 g, 36.2 mmol) in acetone (60 mL) was stirred at 55° C. overnight. The solvent was removed and the residue was extracted with EtOAc (150 mL×3). The combined organic phase was washed with brine (80 mL>3), dried with Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=8/1, 4/1, 1/1) to get N-((2,4-dichloropyrimidin-5-yl)methyl)-2,6-dimethylaniline 3 as a light brown solid (4.5 g, yield 66%). LCMS (m/z): 282.3 [M+H].sup.+.

1-((2,4-dichloropyrimidin-5-yl)methyl)-3-(2,4-dimethoxyphenyl)-1-(2,6-dimethylphenyl)urea (4)

[0304] A round bottomed flask with a Dean-Stark apparatus was charged with N-((2,4-dichloropyrimidin-5-yl)methyl)-2,6-dimethylaniline 3 (3.0 g, 10.6 mmol), 1-isocyanato-2,4-dimethoxybenzene (2.5 g, 14.0 mmol), toluene (3 mL). The mixture was stirred at 130° C. for 2 d, cooled to rt, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=4/1, 2/1, 1/1, EA) to get 1-((2,4-dichloropyrimidin-5-yl)methyl)-3-(2,4-dimethoxyphenyl) (2,6-dimethylphenyl)urea 4 as a light brown solid (4.1 g, yield 84%). LCMS (m/z): 461.4 [M+H].sup.+.

7-chloro-1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (5)

[0305] To the solution of 1-((2,4-dichloropyrimidin-5-yl)methyl)-3-(2,4-dimethoxyphenyl)-1-(2,6-dimethylphenyl) urea 4 (3.1 g, 6.7 mmol) in DCM (20 mL) was added Bu.sub.4NOH (174 mg, 0.67 mmol), NaOH (474 mg, in 2 mL H.sub.2O, 11.8 mmol). The mixture was stirred at rt for 4 h. The final mixture was diluted with H.sub.2O (20 mL), extracted with DCM (80 mL×3). The combined organic phase was washed with brine (50 mL×2), dried with Na.sub.2SO.sub.4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH=20/1) to give 7-chloro-1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one 5 as an off-white solid (2.4 g, yield 85%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 8.37 (s, 1H), 7.16-7.19 (m, 4H), 6.68 (d, J=2.4 Hz, 1H), 6.58 (dd, J=8.8, 2.4 Hz, 1H), 4.74 (dd, J=5.5, 1.6 Hz, 2H), 3.81 (s, 3H), 3.70 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H); LCMS (m/z): 425.4 [M+H].sup.+.

##STR00165##

[0306] A mixture of 7-chloro-1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one 5 (10 mg, 0.024 mmol), 3-methoxy-4-(4-methylpiperazin-1-yl)aniline (7.8 mg, 0.035 mmol), and TFA (5.5 mg, 0.048 mmol) in 2-BuOH (0.5 mL) was stirred at 100° C. overnight. The reaction was cooled and concentrated. The residue was purified by prep-HPLC (MeOH/H.sub.2O 5:95-100:0), followed by column chromatography on silica gel (0-10% MeOH in DCM) to afford YKL-04-114 as a white solid (8.0 mg, 56%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 9.21 (s, 1H), 8.20 (s, 1H), 7.25-7.22 (m, 4H), 7.03 (d, J=8.4 Hz, 1H), 6.98 (s, 1H), 6.77 (d, J=2.8 Hz, 1H), 6.68 (dd, J=8.8, 2.8 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 4.73 (d, J=14.4 Hz, 1H), 4.59 (d, J=14.4 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), 2.94 (m, 4H), 2.58 (m, 4H), 2.34 (s, 3H), 2.32 (s, 3H), 2.29 (s, 3H); LCMS (m/z): 610.7 [M+H].sup.+.

##STR00166##

[0307] A mixture of 7-chloro-1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one 5 (100 mg, 0.24 mmol), 3-methoxy-4-(1-methylpiperidin-4-yl)aniline (78 mg, 0.35 mmol), and TFA (55 mg, 0.48 mmol) in 2-BuOH (5 mL) was stirred at 100° C. overnight. The reaction was cooled and concentrated. The residue was purified by prep-HPLC (MeOH/H.sub.2O 5:95-100:0), followed by column chromatography on silica gel (0-10% MeOH in DCM) to afford YKL-05-093 as a white solid (127 mg, 89%). .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 9.16 (s, 1H), 8.09 (s, 1H), 7.12-7.09 (m, 4H), 6.95 (d, J=8.0 Hz, 1H), 6.86 (s, 1H), 6.65-6.62 (m, 2H), 6.55 (dd, J=8.4, 2.4 Hz, 1H), 4.60 (d, J=14.8 Hz, 1H), 4.47 (d, J=14.8 Hz, 1H), 3.78 (s, 3H), 3.60 (s, 3H), 3.54 (s, 3H), 2.81 (m, 2H), 2.66-2.57 (m, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H), 1.95-1.90 (m, 2H), 1.56-1.46 (m, 4H); LCMS (m/z): 609.7 [M+H].sup.+.

Bicyclic Ureas

[0308] ##STR00167## ##STR00168##

1-methyl-4-(4-nitrobenzyl)piperazine

[0309] ##STR00169##

[0310] To a solution of 1-(bromomethyl)-4-nitrobenzene (4.0 g, 18.5 mmol) and 1-methylpiperazine (1.7 g, 17.0 mmol) in CH.sub.3CN was added K.sub.2CO.sub.3 (3.8 g, 27.5 mmol), the mixture was stirred at 85° C. overnight. After completion, removed the solvent, extracted with ethyl acetate (150 mL×3), washed with water (80 mL×2), brine (80 mL×2), dried with Na.sub.2SO.sub.4, purified by silica gel (DCM/MeOH=50/1, 30/1), light brown solid 1-methyl-4-(4-nitrobenzyl)piperazine (3.3 g) was obtained, yield 76%. LC/MS (ESI) m/z=236 (M+H).sup.+.

4-((4-methylpiperazin-1-yl)methyl)aniline

[0311] ##STR00170##

[0312] A suspension of 1-methyl-4-(4-nitrobenzyl)piperazine (1.0 g, 4.25 mmol), Pd/C (200 mg) in EtOH (20 mL) was stirred at room temperature under H.sub.2 (1 atm) for 6 h, then filtered, removed the solvent to give 4-((4-methylpiperazin-1-yl)methyl)aniline as light brown solid (785 mg), yield 90%. LC/MS (ESI) m/z=206 (M+H).sup.+.

5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione

[0313] ##STR00171##

[0314] To a suspension of uracil (37.0 g, 330 mmol) and paraformaldehyde (12.3 g, 410 mmol) was added a solution of KOH (10.5 g, 187 mmol) in water (290 mL), the mixture was stirred at 55° C. for 3 d, after concentration at 60° C. under vacuum to a volume of 100 mL, the residue was diluted with acetone (200 mL), the resulting precipitate was collected by filtration, washed with acetone and dried to give 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione as white solid (38 g), yield 81%.

2,4-dichloro-5-(chloromethyl)pyrimidine

[0315] ##STR00172##

[0316] To a suspension of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (35.0 g, 246.3 mmol) in toluene (100 mL) was added POCl.sub.3 (105 mL, 1147 mmol) followed by slow addition of DIPEA (120 mL, 689 mmol), the mixture was stirred at 110-120° C. for 8 h. Then the reaction mixture was poured to a mixture of water (100 mL) and ethyl acetate (200 mL), extracted with ethyl acetate (1 L×2), washed with brine (200 mL×3), died with Na.sub.2SO.sub.4. Purified by silica gel (DCM) to give 2,4-dichloro-5-(chloromethyl)pyrimidine as light yellow solid (22 g), yield 46%. LC/MS (ESI) m/z=197 (M+H).sup.+.

2,4-dichloro-5-(iodomethyl)pyrimidine

[0317] ##STR00173##

[0318] To a solution of 2,4-dichloro-5-(chloromethyl)pyrimidine (22.0 g, 111.4 mmol) in acetone (120 mL) was added NaI (20.1 g, 134.1 mmol), the mixture was stirred at 50° C. for 30 min, then filtered, the filtrate was removed the solvent, purified by silica gel (DCM) to give 2,4-dichloro-5-(iodomethyl)pyrimidine as light brown solid (31 g), yield 97%. LC/MS (ESI) m/z=289 (M+H).sup.+.

N-((2,4-dichloropyrimidin-5-yl)methyl)-2,6-dimethylaniline

[0319] ##STR00174##

[0320] To a solution of 2,6-dimethylaniline (3.8 g, 31.4 mmol) and 2,4-dichloro-5-(iodomethyl)pyrimidine (7.0 g, 24.2 mmol) in acetone was added K.sub.2CO.sub.3 (5.0 g, 36.2 mmol), the mixture was stirred at 50° C. for 6 h. then removed acetone, extracted with ethyl acetate (150 mL×3), washed with water (80 mL×2), brine (80 mL×2), dried with Na.sub.2SO.sub.4. Purified by silica gel (PE/DCM=2/1, 1/1, DCM) to give N-((2,4-dichloropyrimidin-5-yl)methyl)-2,6-dimethylaniline as a light yellow solid (4.5 g), yield 66%. LC/MS (ESI) m/z=282 (M+H).sup.+.

1-((2,4-dichloropyrimidin-5-yl)methyl)-3-(2,4-dimethoxyphenyl)-1-(2,6-dimethylphenyl)urea

[0321] ##STR00175##

[0322] A round-bottomed flask was charged with N-((2,4-dichloropyrimidin yl)methyl)-2,6-dimethylaniline (3.0 g, 10.6 mmol), 1-isocyanato-2,4-dimethoxybenzene (2.5 g, 14.0 mmol) and toluene (3 mL), the mixture was stirred at 130° C. for 2 d. then purified by silica gel (PE/ethyl acetate=4/1, 2/1, 1/1, ethyl acetate) to give 1-((2,4-dichloropyrimidin-5-yl)methyl)-3-(2,4-dimethoxyphenyl) (2,6-dimethylphenyl)urea as light brown solid (4.1 g), yield 84%. LC/MS (ESI) m/z=461 (M+H).sup.+.

7-chloro-1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

[0323] ##STR00176##

[0324] To a solution of 1-((2,4-dichloropyrimidin-5-yl)methyl)-3-(2,4-dimethoxyphenyl)-1-(2,6-dimethylphenyl)urea (2.0 g, 4.34 mmol) in DCM (30 mL) was added NaOH (260 mg, 6.5 mmol) and Bu.sub.4NOH (338 mg, 1.30 mmol), the mixture was stirred room temperature for 3 h. then extracted with DCM (80 mL×3), washed with water (50 mL×2), brine (50 mL×2), dried with Na.sub.2SO.sub.4. Purified by silica gel (PE/ethyl acetate=3/1, 1/1) to give 7-chloro-1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as off-white solid (1.5 g), yield 81%. LC/MS (ESI) m/z=425 (M+H).sup.+.

1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-7-(4-((4-methylpiperazin-1-yl)methyl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one

(YKL-04-136-1)

[0325] ##STR00177##

[0326] A sealed-tube was charged with 7-chloro-1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (100 mg, 0.235 mmol), 4-((4-methylpiperazin-1-yl)methyl)aniline (72 mg, 0.351 mmol), Pd.sub.2(dba).sub.3 (22 mg, 0.0240 mmol), Xant-Phos (28 mg, 0.0484 mmol), Cs.sub.2CO.sub.3 (200 mg, 0.614 mmol) and dioxane (2 mL), the mixture was stirred at 150° C. for 1 h under microwave condition. Then filtered, removed the solvent, purified by prep-HPLC to give 1-(2,4-dimethoxyphenyl)-3-(2,6-dimethylphenyl)-7-(4-((4-methylpiperazin-1-yl)methyl)phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as white solid (30 mg), yield 22%. Rt=2.07 min; .sup.1H NMR 600 MHz (DMSO-d.sub.6) δ 9.42 (s, 1H), 8.16 (s, 1H), 7.26-7.16 (m, 6H), 6.90 (d, 2H), 6.74 (d, 1H), 6.65 (dd, 1H), 4.70 (d, 1H), 4.56 (d, 1H), 3.87 (s, 3H), 3.66 (s, 3H), 3.32 (s, 2H), 2.30 (m, 8H), 2.26 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H); LC/MS (ESI) m/z=594.80 (M+H).sup.+.

TABLE-US-00001 TABLE 1 The following compounds were produced by using the corresponding starting compounds according to a method similar to that described for YKL-04- 136-1: YKL-04-136-1 [00178] embedded image .sup.1H NMR 600 MHz (DMSO-d.sub.6) δ 9.42 (s, 1H), 8.16 (s, 1H), 7.26- 7.16 (m, 6H), 6.90 (d, 2H), 6.74 (d, 1H), 6.65 (dd, 1H), 4.70 (d, 1H), 4.56 (d, 1H), 3.87 (s, 3H), 3.66 (s, 3H), 3.32 (5, 2H), 2.30 (m, 8H), 2.26 (s, 3H), 2.23 (s, 3H), 2.14 (5, 3H); MS m/z: 594.4 [M + 1]. Chemical Formula: C.sub.34H.sub.39N.sub.7O.sub.3 Exact Mass: 593.31 YKL-04-136-2 [00179] embedded image .sup.1H NMR 600 MHz (DMSO-d.sub.6) δ 9.43 (s, 1H), 8.10 (s, 1H), 7.24- 7.11 (m, 5H), 6.78 (d, 2H), 6.68 (d, 1H), 4.68 (d, 1H), 4.53 (d, 1H), 3.84 (m, 4H), 3.67 (s, 3H), 3.32 (s, 2H), 2.50 (m, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 2.12 (s, 6H); MS m/z: 543.3 [M + 1]. Chemical Formula: C.sub.29H.sub.34N.sub.8O.sub.3 Exact Mass: 542.28 YKL-04-136-3 [00180] embedded image .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 9.23 (s, 1H), 8.13 (s, 1H), 7.45 (dd, J.sub.1 = 7.6 Hz, J.sub.2 = 1.2 Hz, 1H), 7.30-7.35 (m, 2H), 7.15-7.18 (m, 3H), 6.75 (d, J = 2.4 Hz, 1H), 6.64 (td, J.sub.1 = 8.4 Hz, J.sub.2 = 3.2 Hz, 1H), 6.57 (d, J = 4.8 Hz, 2H), 4.55-4.78 (m, 2H), 3.86 (s, 3H), 3.67 (s, 3H), 2.98 (t, 4.4 Hz, 4H), 2.44 (t, J = 4.4 Hz, 4H), 2.30 (d, J = 10.8 Hz, 3H), 2.22 (s, 3H) ppm. MS m/z: 600.3 [M + 1]. Chemical Formula: C.sub.32H.sub.34ClN.sub.7O.sub.3 Exact Mass: 599.24 YKL-04-136-4 [00181] embedded image .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 9.48 (s, 1H), 8.12 (s, 1H), 7.43 (dd, J.sub.1 = 7.2 Hz, J.sub.2 = 1.6 Hz, 1H), 7.28-7.34 (m, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.10 (s, 1 H), 6.75 (s, 2H), 6.69 (d, J = 8.4 Hz, 1H), 4.53-4.77 (m, 2H), 3.84 (s, 3H), 3.80 (s, 2H), 3.66 (d, J= 2.8 Hz, 3H), 2.51 (s, 2H), 2.28 (d, J = 12.0 Hz, 2H), 2.11 (s, 6H) ppm. MS m/z: 563.3 [M + 1]. Chemical Formula: C.sub.28H.sub.31CIN.sub.8O.sub.3 Exact Mass: 562.22 YKL-04-136-5 [00182] embedded image .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 7.99 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.08-7.19 (m, 5H), 6.82 (s, 1H), 6.70 (d, J = 8.8 Hz, 2H), 6.62 (dd, J.sub.1 = 8.8 Hz, J.sub.2 = 2.4 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.53-4.66 (m, 2H), 3.80 (t, J = 4.4 Hz, 2H), 3.73 (s, 3H), 3.65 (t, J = 4.4 Hz, 2H), 3.21-3.27 (m, 4H), 3.10 (t, J = 4.2 Hz, 4H), 2.57 (1, J = 4.8 Hz, 4H), 2.35 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H) ppm. MS m/z: 676.4 [M + 1]. Chemical Formula: C.sub.38H.sub.45N.sub.9O.sub.3 Exact Mass: 675.36 YKL-04-136-6 [00183] embedded image .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 9.26 (bs, 1H), 8.31 (d, J = 3.2 Hz, 1H), 8.16 (s, 1H), 7.60 (dd, J = 9.2 Hz, J.sub.2 = 3.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.12-7.21 (m, 3H), 7.06 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 8.4 Hz, 2H), 4.61 (s, 2H), 3.92 (s, 3H), 2.97 (t, J = 4.8 Hz, 4H), 2.51 (m, 2H), 2.43 (t, J = 4.8 Hz, 4H), 2.25 (s, 6H), 2.20 (s, 3H) ppm. MS m/z: 551.3 [M + 1]. Chemical Formula: C.sub.31H.sub.34N.sub.9O.sub.2 Exact Mass: 550.28 YKL-04-136-7 [00184] embedded image .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 9.40 (s, 1H), 8.09 (s, 1H), 7.06- 7.20 (m, 5H), 6.83 (s, 1H), 6.73 (s, 1H), 6.64 (d, J = 8.0 Hz, 1H), 4.46-4.68 (m, 2H), 3.81 (bs, 2H), 3.66 (s, 2H), 3.61 (m, 4H), 3.17- 3.31 (m, 5H), 2.24 (s, 3H), 2.21 (s, 3H), 2.10 (s, 6H), 2.05 (s, 3H) ppm. MS m/z: 639.4 [M + 1]. Chemical Formula: C.sub.34H.sub.42N.sub.10O.sub.3 Exact Mass: 638.34 YKL-04-136-8 [00185] embedded image .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ 9.49 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.12- 7.22 (m, 3H), 7.05 (s, 1H), 6.66 (s, 1H), 4.61 (s, 2H), 3.92 (s, 3H), 3.81 (s, 1H), 2.47 (s, 2H), 2.24 (s, 6H), 2.11 (s, 6H) ppm. MS m/z: 514.3 [M + 1]. Chemical Formula: C.sub.27H.sub.31N.sub.9O.sub.2 Exact Mass: 513.26 YKL-04-136-9 [00186] embedded image .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 8.04 (m, 1H), 7.30-7.35 (m, 1H), 7.23 (d, J = 10.4 Hz, 1H), 7.18- 7.20 (m, 4H), 7.00-7.05 (m, 3H), 6.59-6.62 (m, 2H), 4.48-4.91 (m, 2H), 3.89 (s, 3H), 3.73 (d, J = 6.0 Hz, 3H), 3.42 (s, 2H), 2.25-2.62 (bs, 8H), 2.37 (s, 3H), 2.30 (s, 3H) ppm. MS m/z: 614.3 |M + 1]. Chemical Formula: C.sub.33H.sub.36ClN.sub.7O.sub.3 Exact Mass: 613.26 YKL-04-136-10 [00187] embedded image .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 8.36 (d, J = 2.8 Hz, 1H), 8.06 (s, 1H), 7.34-7.40 (m, 2H), 7.11-7.18 (m, 5H), 7.04 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 5.6 Hz, 1H), 4.62 (s, 2H), 3.97 (s, 3H), 3.41 (s, 2H), 2.21-2.67 (bs, 4H), 2.32 (s, 6H), 2.29 (s, 3H), 1.55-1.74 (bs, 4H) ppm. MS m/z: 565.3 (M + 1]. Chemical Formula: C.sub.32H.sub.36N.sub.9O.sub.2 Exact Mass: 564.30 YKL-04-136-11 [00188] embedded image .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 8.02 (s, 1H), 7.20-7.23 (m, 3H), 7.11-7.14 (m, 3H), 7.04 (d, J = 8.4 Hz, 2H), 6.96 (s, 1H), 6.61 (td, J.sub.1 = 8.8 Hz, J.sub.2 = 2.4 Hz, 2H), 4.55-4.68 (m, 2H), 3.83 (t, J = 4.8 Hz, 2H), 3.74 (s, 3H), 3.67 (t, J = 4.8 Hz, 2H), 3.39 (s, 2H), 3.24-3.29 (m, 4H), 2.30-2.60 (bs, 6H), ), 2.33 (s, 6H), 2.28 (s, 3H), 2.17 (s, 3H) ppm. MS m/z: 690.4 [M + 1] Chemical Formula: C.sub.39H.sub.47N.sub.9O.sub.3 Exact Mass: 689.38 YKL-04-103 [00189] embedded image .sup.1H NMR 600 MHz (DMSO-d.sub.6) δ 9.67 (s, 1H), 8.17 (s, 1H), 7.64 (d, J = 9.0 Hz. 1H), 7.56 (s, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.14-7.11 (m, 3H), 6.69 (d, J = 3.0 Hz, 1H), 6.60 (dd, J = 9.0, 3.0 Hz, 1H), 4.67 (d, J = 14.4 Hz, 1H), 4.53 (d, J = 13.8 Hz, 1H), 3.85 (s, 3H), 3.63 (s, 3H), 3.42 (s, 2H), 2.45- 2.25 (m, 8H), 2.23 (s, 3H), 2.20 (s, 3H), 0.97 (1, J = 7.2 Hz, 3H); MS m/z: 676.3 [M + 1]. Chemical Formula: C.sub.36H.sub.40F.sub.3N.sub.7O.sub.3 Exact Mass: 675.31 YKL-04-104 [00190] embedded image .sup.1H NMR 400 MHz (DMSO-d.sub.6) δ 9.61 (s, 1H), 8.18 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.16- 7.13 (m, 3H), 7.07 (d, J = 9.2 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.62 (dd, J = 8.8, 2.4 Hz, 1H), 4.68 (d, J = 12.8 Hz, 1H), 4.54 (d, J = 12.8 Hz, 1H), 3.85 (s, 3H), 3.68-3.64 (m, 7H), 2.75-2.71 (m, 4H), 2.24 (s, 3H), 2.21 (s, 3H); MS m/z: 635.3 [M + 1]. Chemical Formula: C.sub.33H.sub.33F.sub.3N.sub.6O.sub.4 Exact Mass: 634.25 YKL-04-105 [00191] embedded image .sup.1H NMR 600 MHz (DMSO-d.sub.6) δ 9.39 (s, 1H), 8.08 (s, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.15-7.10 (m, 4H), 6.80 (s, 1H), 6.73 (s, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.63 (d, J = 14.4 Hz, 1H), 4.48 (d, J = 14.4 Hz, 1H), 3.96-3.91 (m, 2H), 3.85-3.79 (m, 4H), 3.64 (s, 3H), 3.41 (q, J = 10.2 Hz, 2H), 2.22 (s, 3H), 2.18 (s, 3H), 1.81-1.75 (m, 2H), 1.70-1.63 (m, 2H); MS m/z: 556.3 [M + 1]. Chemical Formula: C.sub.30H.sub.33N.sub.7O.sub.4 Exact Mass: 555.26 YKL-04-106 [00192] embedded image .sup.1H NMR 400 MHz (DMSO-d.sub.6) δ 9.35 (s, 1H), 8.12 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.11-7.08 (m, 4H), 6.90 (s, 1H), 6.80 (t, J = 8.4 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 6.56 (dd, J = 8.4, 2.8 Hz, 1H), 6.44 (dd, J = 8.4, 2.4 Hz, 1H), 4.62 (d, J = 15.2 Hz, 1H), 4.48 (d, 15.2 Hz, 1H), 4.16 (t, J = 8.4 Hz, 2H), 3.94-3.86 (m, 2H), 3.78 (s, 3H), 3.61 (s, 3H), 3.51-3.45 (m, 4H), 3.44-3.36 (m, 2H), 3.19- 3.08 (m, 2H), 2.19 (s, 3H), 2.16 (s, 3H); MS m/z: 611.3 [M + 1]. Chemical Formula: C.sub.34H3.sub.8N.sub.6O.sub.5 Exact Mass: 610.29 YKL-04-107 [00193] embedded image .sup.1H NMR 400 MHz (DMSO-d.sub.6) δ 9.22 (s, 1H), 8.08 (s, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.11-7.08 (m, 3H), 6.96-6.94 (m, 2H), 6.63 (d, J = 2.8 Hz, 1H), 6.55 (dd, J = 8.4, 2.8 Hz, 1H), 4.60 (d, J = 14.4 Hz, 1H), 4.47 (d, J = 14.8 Hz, 1H), 3.90 (t, 5.2 Hz, 4H), 3.75 (s, 3H), 3.70-3.52 (m, 2H), 3.61 (s, 3H), 3.52-3.45 (m, 4H), 3.20-3.10 (m, 2H), 2.18 (s, 3H), 2.16 (s, 3H), 1.97 (s, 3H), 1.97 (s, 3H); MS m/z: 639.3 [M + 1]. Chemical Formula: C.sub.36H.sub.42N.sub.6O.sub.5 Exact Mass: 638.32 YKL-04-108 [00194] embedded image .sup.1H NMR 400 MHz (DMSO-d.sub.6) δ 9.40 (s, 1H), 8.21 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.8 Hz, 1H), 7.23-7.21 (m, 3H), 6.87 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 2.4 Hz, 1H), 6.70 (dd, J = 8.4, 2.8 Hz, 1H), 4.74 (d, J = 15.2 Hz, 1H), 4.59 (d, J = 15.2 Hz, 1H), 3.92 (s, 3H), 3.73 (s, 3H), 3.66- 3.62 (m, 4H), 2.52 (t, J = 7.6 Hz, 2H), 2.44-2.36 (m, 4H), 2.35-2.29 (m, 2H), 2.32 (s, 3H), 2.29 (s, 3H), 1.71 (quit, J = 7.6 Hz, 2H); MS m/z: 609.3 [M + l]. Chemical Formula: C.sub.35H.sub.40N.sub.9O.sub.4 Exact Mass: 608.31 YKL-04-112 [00195] embedded image .sup.1H NMR 400 MHz (DMSO-d.sub.6) δ 9.35 (s, 1H), 8.17 (s, 1H), 7.44 (s, 1H), 7.21 (s, 1H), 7.12-7.08 (m, 4H), 6.75 (s, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.49 (dd, J = 8.8, 2.8 Hz, 1H), 4.61 (d, J = 14.8 Hz, 1H), 4.50 (d, J = 14.8 Hz, 1H), 3.73 (s, 3H), 3.73-3.65 (m, 2H), 3.61 (s, 3H), 3.48-3.40 (m, 2H), 3.11-3.00 (m, 2H), 2.92 (t, J = 12.0 Hz, 2H), 2.79 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H); MS m/z: 648.3 [M + 1]. Chemical Formula: C.sub.34H.sub.36F.sub.3N.sub.7O.sub.3 Exact Mass: 647.28 YKL-04-113 [00196] embedded image .sup.1H NMR 400 MHz (DMSO-d.sub.6) δ 9.37 (s, 1H), 8.20 (s, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 7.17-7.12 (m, 4H), 6.69 (s, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.54 (dd, J = 8.4, 2.8 Hz, 1H), 4.65 (d, J = 15.2 Hz, 1H), 4.54 (d, J = 15.2 Hz, 1H), 3.78 (s, 3H), 3.72-3.67 (m, 4H), 3.65 (s, 3H), 3.06-3.01 (m, 4H), 2.23 (s, 3H), 2.20 (s, 3H); MS m/z: 635.3 [M + 1]. Chemical Formula: C.sub.33H.sub.33F.sub.3N.sub.6O.sub.4 Exact Mass: 634.25 YKL-04-114 [00197] embedded image .sup.1H NMR 400 MHz (DMSO-d.sub.6) δ 9.21 (s, 1H), 8.20 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.23-7.21 (m, 3H), 7.03 (d, J = 8.4 Hz, 1H), 6.98 (s, 1H), 6.77 (d, J = 2.8 Hz, 1H), 6.68 (dd, J = 8.8, 2.8 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 4.73 (d, J = 14.8 Hz, 1H), 4.59 (d, J = 14.8 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), 2.97- 2.90 (m, 4H), 2.63-2.55 (m, 4H), 2.34 (s, 3H), 2.32 (s, 3H), 2.29 (s, 3H); MS m/z: 610.3 [M + 1], Chemical Formula: C.sub.34H.sub.39N.sub.7O.sub.4 Exact Mass: 609.31 YKL-04-115 [00198] embedded image .sup.1H NMR 600 MHz (DMSO-d.sub.6) δ 9.15 (s, 1H), 8.13 (s, 1H), 7.17- 7.13 (m, 4H), 6.98-6.95 (m, 1H), 6.94-6.90 (m, 1H), 6.70 (d, J = 3.0 Hz, 1H), 6.61 (dd, J = 8.4, 2.4 Hz, 1H), 6.43 (d, J = 7.2 Hz, 1H), 4.65 (d, J = 14.4 Hz, 1H), 4.51 (d, J = 15.0 Hz, 1H), 3.84 (s, 3H), 3.68 (t, 4.8 Hz, 4H), 3.67 (s, 3H), 3.61 (s, 3H), 2.82 (t, J = 4.8 Hz, 4H), 2.24 (s, 3H), 2.21 (s, 3H); MS m/z: 597.3 [M + 1]. Chemical Formula: C.sub.33H.sub.36N.sub.6O.sub.5 Exact Mass: 596.27 YKL-04-118 [00199] embedded image .sup.1H NMR 600 MHz (DMSO-d.sub.6) δ 9.83 (s, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 7.23-7.20 (m, 1H), 7.15-7.13 (m, 3H), 6.68 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 8.4, 3.0 Hz, 1H), 4.67 (d, J = 15.6 Hz, 1H), 4.56 (d, J = 14.4 Hz, 1H), 4.17-4.04 (m, 2H), 3.98-3.84 (m, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 3.64-3.55 (m, 4H), 3.06-2.92 (m, 2H), 2.23 (s, 3H), 2.20 (s, 3H); MS m/z: 649.3 [M + 1], Chemical Formula: C.sub.34H.sub.35F.sub.3N.sub.6O.sub.4 Exact Mass: 648.27 YKL-04-125 [00200] embedded image .sup.1H NMR 600 MHz (DMSO-d.sub.6) δ 9.77 (s, 1H), 8.21 (s, 1H), 7.63- 7.60 (m, 2H), 7.20 (d, J = 9.0 Hz, 1H), 7.15-7.13 (m, 3H), 7.13 (s, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 9.0, 3.0 Hz, 1H), 4.67 (d, J = 15.6 Hz, 1H), 4.55 (d, J = 15.6 Hz, 1H), 3.81 (s, 3H), 3.65 (s, 3H), 3.41-3.34 (m, 4H), 3.05-2.97 (m, 2H), 2.90-2.83 (m, 2H), 2.77 (s, 3H), 2.38-2.29 (m, 2H), 2.23 (s, 3H), 2.20 (s, 3H); MS m/z: 662.3 [M + 1]. Chemical Formula: C.sub.35H.sub.38F.sub.3N.sub.7O.sub.3 Exact Mass: 661.30 YKL-05-57 [00201] embedded image .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.08 (s, 1H), 7.48 (s, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.19-7.09 (m, 4H), 6.70 (d, J = 2.7 Hz, 1H), 6.61 (dd, J = 8.6, 2.6 Hz, 1H), 6.51 (d, J = 2.6 Hz, 1H), 6.05 (d, J = 8.8 Hz, 1H), 4.71-4.59 (m, 2H), 4.50 (dd, J = 14.2, 0.9 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.65 (s, 3H), 3.58 (td, J = 8.9, 4.4 Hz, 1H), 3.44-3.34 (m, 2H), 2.73 (ddd, J = 12.6, 10.3, 2.9 Hz, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.80 (ddt, J = 11.3, 6.0, 3.0 Hz, 2H), 1.47 (did, J= 12.9, 9.7, 3.8 Hz, 2H); MS m/z: 611.3 [M + 1]. Exact Mass: 610.29 Molecular Weight: 610.72

##STR00202##

[0327] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.10 (s, 1H), 7.42 (s, 1H), 7.31 (d, J=8.9 Hz, 1H), 6.72 (d, J=2.7 Hz, 1H), 6.62 (dd, J=8.6, 2.6 Hz, 1H), 6.55 (d, J=2.6 Hz, 1H), 5.99 (d, J=8.9 Hz, 1H), 4.72-4.63 (m, 1H), 4.60 (p, J=6.1 Hz, 1H), 4.51 (d, =14.4 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 3H), 2.99 (t, J=5.0 Hz, 4H), 2.43 (t, J=5.0 Hz, 4H), 2.24 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H). MS m/z: 638.4 [M+1].

##STR00203##

[0328] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.14 (d, J=0.9 Hz, 1H), 7.55 (s, 1H), 7.34 (s, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.18-7.11 (m, 3H), 6.72-6.67 (m, 2H), 6.61 (dd, J=8.6, 2.7 Hz, 1H), 4.67 (dd, J=14.3, 0.9 Hz, 1H), 4.57-4.51 (m, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 3.09 (d, J=11.9 Hz, 2H), 2.71 (td, J=11.9, 3.1 Hz, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 1.93-1.86 (m, 3H), 1.62-1.48 (m, 4H), 1.28-1.20 (m, 7H). MS m/z: 638.4 [M+1].

##STR00204##

[0329] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.06 (s, 1H), 7.43 (s, 1H), 7.24 (d, J=8.9 Hz, 1H), 7.18-7.10 (m, 4H), 6.68 (d, J=2.6 Hz, 1H), 6.60 (dd, J=8.6, 2.6 Hz, 1H), 6.26 (d, J=2.6 Hz, 1H), 5.85 (s, 1H), 4.63 (dd, J=14.2, 1.0 Hz, 1H), 4.50 (d, J=15.0 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.65 (s, 3H), 3.35-3.31 (m, 2H), 2.83 (s, 3H), 2.36-2.30 (m, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 2.17 (s, 6H). MS m/z: 612.4 [M+1].

##STR00205##

[0330] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.13 (s, 1H), 7.59 (s, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.21-7.11 (m, 4H), 6.78 (d, J=1.9 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 6.62 (dd, J=8.6, 2.6 Hz, 1H), 6.41-6.34 (m, 1H), 4.67 (dd, J=14.4, 1.0 Hz, 1H), 4.53 (dd, J=14.4, 0.9 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.65 (s, 3H), 2.87 (d, J=11.0 Hz, 2H), 2.40-2.28 (m, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.98 (t, J=11.4 Hz, 2H), 1.68 (t, J=7.5 Hz, 2H), 1.60 (qd, J=12.2, 3.7 Hz, 2H). MS m/z: 609.3 [M+1].

##STR00206##

[0331] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (s, 1H), 7.57 (s, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.15 (s, 2H), 6.83 (d, J=1.7 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 6.63 (dd, J=8.6, 2.6 Hz, 1H), 6.38 (dd, J=8.4, 1.7 Hz, 1H), 4.69 (dd, J=14.4, 1.0 Hz, 1H), 4.63-4.49 (m, 2H), 3.86 (s, 3H), 3.64 (s, 3H), 3.32 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 2.14 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H). MS m/z: 652.4 [M+1].

##STR00207##

[0332] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.15 (s, 1H), 7.63 (s, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.14 (s, 3H), 6.82 (d, J=1.7 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 6.62 (dd, J=8.6, 2.6 Hz, 1H), 6.44 (dd, J=8.4, 1.7 Hz, 1H), 4.68 (dd, J=14.4, 1.0 Hz, 1H), 4.57-4.47 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.64 (s, 3H), 3.33 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 2.14 (s, 3H). MS m/z: 624.3 [M+1].

##STR00208##

[0333] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23 (s, 1H), 7.63 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 7.24 (s, 2H), 6.88 (d, J=1.9 Hz, 1H), 6.82 (d, J=2.6 Hz, 1H), 6.72 (dd, J=8.6, 2.6 Hz, 1H), 6.40 (dd, J=8.4, 1.9 Hz, 1H), 4.77 (dd, J=14.4, 1.0 Hz, 1H), 4.70 (p, J=6.1 Hz, 1H), 4.66-4.59 (m, 1H), 3.95 (s, 3H), 3.74 (s, 3H), 3.58-3.46 (m, 1H), 2.98 (d, J=11.0 Hz, 2H), 2.48-2.38 (m, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H), 2.19-2.06 (m, 2H), 1.78 (d, J=12.7 Hz, 2H), 1.68 (qd, J=12.3, 3.7 Hz, 2H), 1.36 (s, 3H), 1.34 (s, 3H), 1.31 (s, 2H), 1.11 (dd, J=6.1, 1.4 Hz, 3H). MS m/z: 637.4 [M+1].

##STR00209##

[0334] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (s, 1H), 7.44 (s, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.10 (d, J=8.3 Hz, 4H), 6.65 (d, J=2.6 Hz, 1H), 6.56 (dd, J=8.6, 2.6 Hz, 1H), 6.47 (d, J=2.5 Hz, 1H), 5.99 (d, J=8.5 Hz, 1H), 4.60 (dd, J=14.3, 1.0 Hz, 1H), 4.50-4.40 (m, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.60 (s, 3H), 2.97 (dd, J=6.3, 3.7 Hz, 4H), 2.30 (q, J=7.2 Hz, 2H), 2.17 (d, J=11.6 Hz, 6H), 0.97 (t, J=7.2 Hz, 3H). MS m/z: 624.3 [M+1].

##STR00210##

[0335] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 8.29 (d, J=3.5 Hz, 1H), 8.14 (s, 1H), 7.61 (s, 1H), 7.57 (dd, J.sub.1=8.5 Hz, J.sub.2=3.0 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.15-7.18 (m, 4H), 6.53 (d, J=2.5 Hz, 1H), 6.04 (s, 1H), 4.62 (s, 2H), 3.92 (s, 3H), 3.77 (s, 3H), 3.04 (t, J=5.0 Hz, 4H), 2.45 (t, J=5.0 Hz, 4H), 2.25 (s, 6H), 2.22 (s, 3H) ppm. MS m/z: 581.3 [M+1].

##STR00211##

[0336] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.24 (dd, J=3.2, 0.5 Hz, 1H), 8.09 (s, 1H), 7.53 (dd, J=8.7, 3.1 Hz, 1H), 7.42 (s, 1H), 7.34 (dd, J=8.6, 0.5 Hz, 1H), 7.15-7.01 (m, 4H), 6.49 (d, J=2.6 Hz, 1H), 5.92 (d, J=8.8 Hz, 1H), 4.62-4.48 (m, 3H), 3.87 (s, 3H), 3.01-2.89 (m, 4H), 2.41-2.35 (m, 4H), 2.19 (s, 6H), 2.16 (s, 3H), 1.18 (s, 3H), 1.17 (s, 3H). MS m/z: 609.3 [M+1].

##STR00212##

[0337] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.24 (dd, J=3.2, 0.5 Hz, 1H), 8.13 (d, J=0.9 Hz, 1H), 7.62 (s, 1H), 7.52 (dd, J=8.7, 3.1 Hz, 1H), 7.35 (dd, J=8.7, 0.5 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.15-7.06 (m, 3H), 6.74 (d, J=1.9 Hz, 1H), 6.36-6.24 (m, 1H), 4.58 (d, J=0.9 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.84 (d, J=11.1 Hz, 2H), 2.30 (tt, J=11.5, 4.0 Hz, 1H), 2.19 (s, 6H), 2.17 (s, 3H), 2.02-1.91 (m, 2H), 1.69-1.61 (m, 2H), 1.56 (qd, J=12.2, 3.7 Hz, 2H). MS m/z: 580.3 [M+1].

##STR00213##

[0338] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.26 (dd, J=3.1, 0.6 Hz, 1H), 8.13 (d, J=0.9 Hz, 1H), 7.59-7.49 (m, 2H), 7.39-7.33 (m, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.14-7.05 (m, 3H), 6.74 (d, J=1.9 Hz, 1H), 6.23 (dd, J=8.4, 1.8 Hz, 1H), 4.62-4.50 (m, 3H), 3.88 (s, 3H), 2.81 (d, J=10.8 Hz, 2H), 2.27 (tt, J=11.6, 3.8 Hz, 1H), 2.19 (s, 6H), 2.15 (s, 3H), 1.93 (t, J=11.4 Hz, 2H), 1.63 (d, J=12.2 Hz, 2H), 1.52 (qd, J=12.3, 3.7 Hz, 2H), 1.21 (s, 3H), 1.19 (s, 3H). MS m/z: 608.3 [M+1].

##STR00214##

[0339] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.24 (d, J=3.3 Hz, 1H), 8.14 (d, J=1.0 Hz, 1H), 7.65 (s, 1H), 7.52 (dd, J=8.7, 3.1 Hz, 1H), 7.36 (d, J=8.9 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.16-7.06 (m, 3H), 6.77 (d, J=1.7 Hz, 1H), 6.37 (dd, J=8.3, 1.7 Hz, 1H), 4.62-4.54 (m, 2H), 3.88 (s, 3H), 3.73 (s, 3H), 3.24 (s, 3H), 2.19 (s, 6H), 2.09 (s, 3H). MS m/z: 595.3 [M+1].

##STR00215##

[0340] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.26 (d, J=3.1 Hz, 1H), 8.15 (s, 1H), 7.57 (s, 1H), 7.54 (dd, J=8.7, 3.1 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.15-7.06 (m, 3H), 6.79 (d, J=1.7 Hz, 1H), 6.30 (dd, J=8.3, 1.7 Hz, 1H), 4.59 (s, 2H), 4.52 (p, J=6.1 Hz, 1H), 3.89 (s, 3H), 3.24 (s, 3H), 2.19 (s, 6H), 2.10 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H). MS m/z: 623.4 [M+1].

##STR00216##

[0341] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.16 (s, 1H), 8.09 (s, 1H), 7.14-7.06 (m, 4H), 7.00-6.91 (m, 1H), 6.86 (s, 1H), 6.68-6.60 (m, 2H), 6.55 (dd, J=8.6, 2.7 Hz, 1H), 4.60 (dd, J=14.3, 1.0 Hz, 1H), 4.52-4.42 (m, 1H), 3.78 (s, 3H), 3.60 (s, 3H), 3.54 (s, 3H), 2.86-2.75 (m, 2H), 2.61 (tt, J=11.5, 4.1 Hz, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H), 1.92 (td, J=11.4, 3.0 Hz, 2H), 1.59-1.41 (m, 4H). MS m/z: 609.3 [M+1].

##STR00217##

[0342] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.20 (s, 1H), 8.23 (d, J=3.1 Hz, 1H), 8.14 (s, 1H), 7.51 (dd, J=8.7, 3.1 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.14-7.05 (m, 3H), 6.89-6.76 (m, 2H), 6.62 (d, J=8.3 Hz, 1H), 4.57 (s, 2H), 3.86 (s, 3H), 3.55 (s, 3H), 2.89-2.73 (m, 2H), 2.61 (tt, J=11.7, 4.4 Hz, 1H), 2.19 (s, 6H), 2.14 (s, 3H), 1.91 (td, J=11.4, 3.0 Hz, 2H), 1.60-1.38 (m, 4H). MS m/z: 580.3 [M+1].

##STR00218##

[0343] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.29 (s, 1H), 8.32 (d, J=3.0 Hz, 1H), 8.20 (s, 1H), 7.61 (dd, J.sub.1=7.5 Hz, J.sub.2=3.0 Hz, 1H), 7.46 (dd, J.sub.1=7.0 Hz, J.sub.2=1.5 Hz, 1H), 7.40 (d, J=10.5 Hz, 1H), 7.31-7.36 (m, 2H), 7.06 (s, 2H), 6.56 (d, J=6.5 Hz, 2H), 4.64-4.71 (m, 2H), 3.94 (s, 3H), 2.98 (t, J=5.0 Hz, 4H), 2.44 (t, J=5.0 Hz, 4H), 2.32 (s, 3H), 2.21 (s, 3H) ppm. MS m/z: 571.3 [M+1].

##STR00219##

[0344] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 8.29 (d, J=3.0 Hz, 1H), 8.17 (s, 1H), 7.67 (s, 1H), 7.58 (dd, J.sub.1=8.5 Hz, J.sub.2=3.0 Hz, 1H), 7.46 (dd, J.sub.1=7.5 Hz, J.sub.2=2.0 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.31-7.35 (m, 2H), 7.12 (bs, 1H), 6.54 (d, J=2.5 Hz, 1H), 6.04 (bs, 1H), 4.64-4.71 (m, 2H), 3.92 (s, 3H), 3.76 (s, 3H), 3.05 (s, 4H), 2.48 (s, 4H), 2.32 (s, 3H), 2.24 (s, 3H) ppm. MS m/z: 601.3 [M+1].

##STR00220##

[0345] .sup.1H NMR (DMSO-d.sub.6, 500 MHz): δ 9.52 (s, 1H), 8.33 (d, J=3.0 Hz, 1H), 8.25 (s, 1H), 7.61 (dd, J.sub.1=8.5 Hz, J.sub.2=3.0 Hz, 1H), 7.46 (dd, J.sub.1=7.0 Hz, J.sub.2=2.0 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 7.32-7.36 (m, 2H), 7.15 (d, J=6.5 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H), 4.67-4.74 (m, 2H), 3.96 (s, 3H), 3.34 (s, 4H), 2.25-2.46 (bs, 8H), 2.18 (s, 4H) ppm. MS m/z: 585.3 [M+1].

##STR00221##

[0346] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.39 (s, 1H), 8.37 (d, J=3.1 Hz, 1H), 8.30 (s, 1H), 7.65 (dd, J=8.7, 3.1 Hz, 1H), 7.52 (dd, J=7.1, 2.4 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.43-7.34 (m, 2H), 7.04-6.89 (m, 2H), 6.76-6.66 (m, 1H), 4.83-4.70 (m, 2H), 3.99 (s, 3H), 3.83-3.76 (m, 1H), 3.69 (s, 3H), 3.24 (d, J=11.3 Hz, 2H), 2.95-2.81 (m, 1H), 2.38 (s, 3H), 1.86-1.65 (m, 4H). MS m/z: 600.3 [M+1].

##STR00222##

[0347] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.25 (d, J=3.1 Hz, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 7.53 (dd, J=8.7, 3.1 Hz, 1H), 7.39 (dd, J=7.1, 2.3 Hz, 1H), 7.33 (d, =8.6 Hz, 1H), 7.30-7.22 (m, 2H), 7.19 (d, J=8.1 Hz, 1H), 6.74 (d, J=1.9 Hz, 1H), 6.30 (d, J=8.4 Hz, 1H), 4.69-4.57 (m, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.87 (d, J=11.0 Hz, 2H), 2.37-2.28 (m, 1H), 2.26 (s, 3H), 2.21 (s, 3H), 2.09-1.95 (m, 2H), 1.71-1.62 (m, 2H), 1.57 (qd, J=12.3, 3.7 Hz, 2H). MS m/z: 600.3 [M+1].

##STR00223##

[0348] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23 (d, J=3.1 Hz, 1H), 8.10 (s, 1H), 7.58-7.47 (m, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.11 (d, J=3.5 Hz, 4H), 6.51 (d, J=2.6 Hz, 1H), 5.96 (d, J=8.1 Hz, 1H), 4.56 (s, 2H), 3.98 (q, J=7.0 Hz, 2H), 3.86 (s, 3H), 3.16-3.00 (m, 4H), 2.93-2.75 (m, 4H), 2.55-2.45 (m, 3H), 2.19 (s, 6H), 1.25 (t, J=7.0 Hz, 3H). MS m/z: 595.3 [M+1].

##STR00224##

[0349] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.24 (d, J=3.1 Hz, 1H), 8.12 (s, 1H), 7.55-7.50 (m, 2H), 7.39 (dd, J=6.7, 2.8 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.30-7.20 (m, 2H), 7.06 (d, J=8.8 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H), 5.95 (d, J=9.5 Hz, 1H), 4.71-4.54 (m, 2H), 3.97 (q, J=7.0 Hz, 2H), 3.86 (s, 3H), 3.10-2.94 (m, 4H), 2.67-2.49 (m, 4H), 2.30 (s, 3H), 2.25 (s, 3H), 1.25 (t, J=7.0 Hz, 3H). MS m/z: 615.3 [M+1].

##STR00225##

[0350] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.29 (s, 1H), 8.22 (d, J=3.2 Hz, 1H), 8.10 (s, 1H), 7.48 (dd, J=8.7, 3.1 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.15-7.12 (m, 3H), 6.89 (d, J=2.8 Hz, 1H), 6.63-6.58 (m, 1H), 4.59 (d, J=0.9 Hz, 2H), 3.86 (s, 3H), 3.21-3.03 (m, 4H), 2.71-2.54 (m, 4H), 2.43-2.27 (m, 3H), 2.23 (s, 6H). MS m/z: 585.3 [M+1].

##STR00226##

[0351] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.33 (s, 1H), 8.22 (d, J=3.1 Hz, 1H), 8.13 (s, 1H), 7.49 (dd, J=8.7, 3.1 Hz, 1H), 7.45-7.40 (m, 1H), 7.35-7.27 (m, 3H), 7.12 (d, J=9.0 Hz, 1H), 6.88 (d, J=2.8 Hz, 1H), 6.60 (d, J=9.0 Hz, 1H), 4.71-4.58 (m, 2H), 3.86 (s, 3H), 3.20-3.03 (m, 4H), 2.70-2.51 (m, 4H), 2.37-2.30 (m, 4H), 2.29 (s, 3H). MS m/z: 605.2 [M+1].

##STR00227##

[0352] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.22 (d, J=3.2 Hz, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.48 (dd, J=8.7, 3.1 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 7.17-7.10 (m, 4H), 7.04 (d, J=2.8 Hz, 1H), 6.66 (d, J=9.0 Hz, 1H), 4.59 (d, J=0.9 Hz, 2H), 3.86 (s, 3H), 3.19-3.01 (m, 4H), 2.70-2.55 (m, 4H), 2.42-2.30 (m, 3H), 2.22 (s, 6H). MS m/z: 629.2 [M+1].

##STR00228##

[0353] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.24 (s, 1H), 8.22 (d, J=3.1 Hz, 1H), 8.12 (s, 1H), 7.48 (dd, J=8.7, 3.1 Hz, 1H), 7.45-7.40 (m, 1H), 7.34-7.27 (m, 3H), 7.10 (d, J=8.9 Hz, 1H), 7.02 (d, J=2.8 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H), 4.73-4.58 (m, 2H), 3.86 (s, 3H), 3.17-3.00 (m, 4H), 2.57-2.49 (m, 4H), 2.29 (s, 3H), 2.28-2.23 (m, 3H). MS m/z: 649.2 [M+1].

##STR00229##

[0354] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.29-8.23 (m, 1H), 8.14 (s, 1H), 7.62 (s, 1H), 7.54 (dd, J=8.7, 3.1 Hz, 1H), 7.37 (dd, J=8.6, 0.5 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.15-7.07 (m, 3H), 6.73 (d, J=1.8 Hz, 1H), 6.25 (dd, J=8.2, 1.8 Hz, 1H), 4.59 (d, J=0.9 Hz, 2H), 4.00 (q, J=6.9 Hz, 2H), 3.88 (s, 3H), 3.28-3.20 (m, 4H), 2.78-2.46 (m, 5H), 2.19 (s, 6H), 1.81 (d, J=13.4 Hz, 2H), 1.74-1.57 (m, 2H), 1.28 (t, J=6.9 Hz, 3H). MS m/z: 594.3 [M+1].

##STR00230##

[0355] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.34-8.27 (m, 1H), 8.21 (d, J=0.9 Hz, 1H), 7.67 (s, 1H), 7.59 (dd, J=8.7, 3.1 Hz, 1H), 7.47-7.42 (m, 1H), 7.41-7.36 (m, 1H), 7.35-7.28 (m, 2H), 7.21 (d, J=8.3 Hz, 1H), 6.77 (d, J=1.9 Hz, 1H), 6.34-6.26 (m, 1H), 4.75-4.62 (m, 2H), 4.04 (q, J=7.0 Hz, 2H), 3.92 (s, 3H), 2.86 (d, J=10.9 Hz, 2H), 2.38-2.31 (m, 1H), 2.31 (s, 3H), 2.20 (s, 3H), 2.03-1.90 (m, 2H), 1.73-1.64 (m, 2H), 1.58 (qd, J=12.4, 3.8 Hz, 2H), 1.32 (t, J=6.9 Hz, 3H). MS m/z: 614.3 [M+1].

##STR00231##

[0356] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.54 (s, 1H), 8.33 (dd, J=3.1, 0.6 Hz, 1H), 8.25 (d, J=0.9 Hz, 1H), 8.08-8.00 (m, 1H), 7.61 (dd, J=8.7, 3.1 Hz, 1H), 7.43 (dd, J=8.7, 0.6 Hz, 1H), 7.21-7.12 (m, 4H), 7.07 (dd, J=8.7, 2.5 Hz, 1H), 4.66 (d, J=0.9 Hz, 2H), 3.93 (s, 3H), 3.00-2.85 (m, 2H), 2.46-2.35 (m, 1H), 2.25 (s, 6H), 2.15-1.95 (m, 2H), 1.70 (d, J=12.7 Hz, 2H), 1.63-1.54 (m, 2H). MS m/z: 551.3 [M+1].

##STR00232##

[0357] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.57 (s, 1H), 8.34 (d, J=3.1 Hz, 1H), 8.27 (d, J=1.0 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.61 (dd, J=8.7, 3.2 Hz, 1H), 7.47-7.43 (m, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.36-7.28 (m, 2H), 7.16 (d, J=8.6 Hz, 1H), 7.07 (dd, J=8.7, 2.5 Hz, 1H), 4.79-4.64 (m, 2H), 3.93 (s, 3H), 3.00-2.82 (m, 2H), 2.45-2.34 (m, 1H), 2.31 (s, 3H), 2.29-2.19 (m, 2H), 1.69 (d, J=12.7 Hz, 3H), 1.64-1.53 (m, 2H). MS m/z: 571.3 [M+1].

##STR00233##

[0358] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.28 (s, 1H), 8.20 (d, J=3.1 Hz, 1H), 8.06 (s, 1H), 7.45 (dd, J=8.7, 3.2 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.19-7.10 (m, 3H), 6.93 (d, J=8.8 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.49-6.39 (m, 1H), 4.56 (s, 2H), 3.85 (s, 3H), 3.09-2.96 (m, 4H), 2.29-2.23 (m, 3H), 2.22 (s, 6H), 2.04 (s, 3H). MS m/z: 565.3 [M+1].

##STR00234##

[0359] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.32 (s, 1H), 8.20 (d, J=3.1 Hz, 1H), 8.08 (s, 1H), 7.45 (dd, J=8.7, 3.1 Hz, 1H), 7.43 (dd, J=7.4, 2.1 Hz, 1H), 7.35-7.26 (m, 3H), 6.92 (d, J=8.8 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.48-6.40 (m, 1H), 4.70-4.54 (m, 2H), 3.85 (s, 4H), 3.08-2.96 (m, 4H), 2.29 (s, 3H), 2.27-2.22 (m, 4H), 2.04 (s, 3H). MS m/z: 585.3 [M+1].

##STR00235##

[0360] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.32 (s, 1H), 8.75 (s, 2H), 8.27 (d, J=3.1 Hz, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.55 (dd, J=8.7, 3.1 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.20-7.12 (m, 3H), 6.60 (s, 1H), 4.62 (s, 2H), 3.90 (s, 3H), 3.22-3.13 (m, 4H), 2.24 (s, 6H). MS m/z: 538.3 [M+1].

##STR00236##

[0361] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.33 (s, 1H), 8.77 (s, 2H), 8.28 (d, J=3.1 Hz, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.55 (dd, J=8.7, 3.1 Hz, 1H), 7.48 (s, 1H), 7.44 (dd, J=7.4, 2.1 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.36-7.27 (m, 2H), 6.59 (s, 1H), 4.72-4.62 (m, 2H), 3.90 (s, 3H), 3.18 (s, 4H), 2.30 (s, 3H). MS m/z: 558.2 [M+1].

##STR00237##

[0362] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.33 (s, 1H), 8.32 (d, J=3.2 Hz, 1H), 8.21 (s, 1H), 7.87 (d, J=3.1 Hz, 1H), 7.60 (dd, J=8.7, 3.1 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.21-7.12 (m, 3H), 7.07 (d, J=9.1 Hz, 1H), 6.81 (dd, J=9.3, 3.1 Hz, 1H), 4.66 (d, J=4.2 Hz, 1H), 4.64 (s, 2H), 3.92 (s, 3H), 3.60 (tq, J=8.4, 4.0 Hz, 1H), 3.37 (dt, J=12.5, 4.4 Hz, 2H), 2.75 (ddd, J=12.8, 10.0, 3.0 Hz, 2H), 2.24 (s, 6H), 1.86-1.74 (m, 2H), 1.46 (dtd, J=12.9, 9.4, 3.8 Hz, 2H). MS m/z: 553.3 [M+1].

##STR00238##

[0363] .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 9.37 (s, 1H), 8.33 (d, J=3.1 Hz, 1H), 8.24 (s, 1H), 7.87 (d, J=3.0 Hz, 1H), 7.60 (dd, J=8.7, 3.1 Hz, 1H), 7.44 (dd, J=7.4, 2.1 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.36-7.28 (m, 2H), 7.06 (d, J=9.1 Hz, 1H), 6.81 (d, J=8.9 Hz, 1H), 4.75-4.62 (m, 3H), 3.92 (s, 3H), 3.60 (tt, J=8.9, 4.2 Hz, 1H), 3.37 (dt, J=12.6, 4.6 Hz, 2H), 2.76 (ddd, J=12.8, 10.1, 3.0 Hz, 2H), 2.31 (s, 3H), 1.86-1.75 (m, 2H), 1.46 (dtd, J=12.9, 9.3, 3.8 Hz, 2H). MS m/z: 573.2 [M+1].

##STR00239##

[0364] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 9.31 (s, 1H), 8.08 (d, J=1.0 Hz, 1H), 7.59 (d, J=9.1 Hz, 2H), 7.26-7.08 (m, 3H), 6.89 (d, J=9.1 Hz, 2H), 4.55-4.40 (m, 2H), 3.14-2.96 (m, 4H), 2.49-2.41 (m, 4H), 2.23 (s, 3H), 2.18 (s, 6H). MS m/z: 458.3 [M+1].

##STR00240##

[0365] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.04 (s, 1H), 7.86 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.23-7.10 (m, 3H), 6.64 (d, J=2.6 Hz, 1H), 6.50 (dd, J=8.8, 2.6 Hz, 1H), 4.53-4.41 (m, 2H), 3.83 (s, 3H), 3.27 (s, 3H), 3.18-3.06 (m, 4H), 2.49-2.42 (m, 4H), 2.23 (s, 3H), 2.17 (s, 6H). MS m/z: 488.3 [M+1].

##STR00241##

[0366] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.09 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.91 (s, 1H), 7.26-7.11 (m, 3H), 6.93 (d, J=1.8 Hz, 1H), 6.82 (dd, J=8.3, 1.8 Hz, 1H), 4.49 (s, 2H), 3.87 (s, 3H), 3.31 (s, 3H), 2.88 (dt, J=11.8, 3.2 Hz, 2H), 2.51 (p, J=1.9 Hz, 6H), 2.44 (tt, J=11.6, 4.1 Hz, 1H), 2.21 (s, 3H), 2.17 (s, 6H), 1.98 (td, =11.6, 2.8 Hz, 2H), 1.81-1.62 (m, 4H). MS m/z: 487.3 [M+1].

##STR00242##

[0367] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.12 (s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.91 (s, 1H), 7.47-7.34 (m, 4H), 7.27 (td, J=7.1, 1.5 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 6.82 (dd, J=8.3, 1.9 Hz, 1H), 4.72 (s, 2H), 3.87 (s, 3H), 2.89 (dt, J=12.0, 3.1 Hz, 2H), 2.44 (ddt, J=11.7, 8.1, 4.1 Hz, 1H), 2.22 (s, 3H), 2.00 (t, J=11.4 Hz, 2H), 1.82-1.63 (m, 4H). MS m/z: 459.3 [M+1].

##STR00243##

[0368] .sup.1H NMR (CDCl.sub.3, 400 MHz): δ 8.36 (d, J=2.1 Hz, 1H), 8.04 (s, 1H), 7.32-7.38 (m, 2H), 7.08-7.15 (m, 5H), 6.93 (s, 1H), 6.70 (d, J=8.8 Hz, 1H), 4.73 (q, J=6.4 Hz, 1H), 3.93 (s, 1H), 3.12 (t, J=5.2 Hz, 4H), 2.58 (t, J=5.2 Hz, 4H), 2.35 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 1.51 (d, J=6.4 Hz, 3H) ppm. MS m/z: 565.3 [M+1].

##STR00244##

[0369] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.37 (d, J=2.8 Hz, 1H), 8.06 (s, 1H), 7.34-7.43 (m, 4H), 7.10-7.16 (m, 3H), 6.45 (d, J=2.4 Hz, 1H), 6.13 (d, J=6.4 Hz, 1H), 4.71-4.76 (q, J=6.4 Hz, 1H), 3.95 (s, 3H), 3.81 (s, 3H), 3.22 (t, J=5.2 Hz, 4H), 2.82 (s, 4H), 2.52 (s, 3H), 2.33 (s, 3H), 2.28 (s, 3H), 1.51 (d, J=6.4 Hz, 3H). MS m/z: 595.3 [M+1].

##STR00245##

[0370] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.31 (d, J=3.1 Hz, 1H), 8.29 (s, 1H), 7.73 (s, 1H), 7.61 (dd, J=8.7, 3.1 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.23-7.14 (m, 3H), 6.81 (d, J=1.9 Hz, 1H), 6.38 (d, J=8.3 Hz, 1H), 4.86 (q, J=6.5 Hz, 1H), 3.95 (s, 3H), 3.81 (s, 3H), 3.04-2.89 (m, 2H), 2.47-2.36 (m, 1H), 2.35-2.27 (m, 2H), 2.20-2.05 (m, 1H), 1.80-1.71 (m, 2H), 1.65 (qd, J=12.5, 3.7 Hz, 2H), 1.41 (d, J=6.5 Hz, 3H). MS m/z: 594.3 [M+1].

##STR00246##

[0371] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.22 (s, 1H), 7.98 (s, 1H), 7.10-7.02 (m, 5H), 6.87 (d, J=2.2 Hz, 1H), 6.71 (dd, J=8.2, 2.2 Hz, 1H), 6.56 (d, J=2.7 Hz, 1H), 6.46 (dd, J=8.6, 2.6 Hz, 1H), 4.55 (d, J=14.5 Hz, 1H), 4.43 (d, J=14.5 Hz, 1H), 3.74 (s, 3H), 3.59 (s, 3H), 3.04-2.90 (m, 2H), 2.35-2.26 (m, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 1.74-1.66 (m, 2H), 1.65-1.53 (m, 2H), 0.98 (t, J=7.5 Hz, 3H). MS m/z: 607.4 [M+1].

##STR00247##

[0372] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.35 (s, 1H), 8.16 (d, J=3.1 Hz, 1H), 8.05 (s, 1H), 7.41 (dd, J=8.7, 3.1 Hz, 1H), 7.38 (dd, J=7.2, 2.3 Hz, 1H), 7.29-7.21 (m, 4H), 6.97 (d, J=8.3 Hz, 1H), 6.87 (d, J=2.1 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 4.64-4.51 (m, 2H), 3.81 (s, 3H), 2.86 (d, J=11.0 Hz, 2H), 2.35-2.26 (m, 1H), 2.24 (s, 3H), 2.19 (s, 3H), 2.07-1.92 (m, 2H), 1.63 (t, J=7.7 Hz, 2H), 1.55 (qd, J=12.4, 3.7 Hz, 2H), 0.97 (t, J=7.5 Hz, 3H). MS m/z: 598.3 [M+1].

##STR00248##

[0373] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.54 (s, 1H), 7.90 (s, 1H), 7.27 (d, J=8.2 Hz, 1H), 7.12-7.05 (m, 3H), 7.02 (d, J=2.1 Hz, 1H), 6.96 (dd, J=8.2, 2.2 Hz, 1H), 4.43-4.32 (m, 2H), 3.16 (s, 3H), 2.85 (d, J=11.0 Hz, 2H), 2.54 (q, J=7.6 Hz, 2H), 2.40-2.34 (m, 1H), 2.18 (s, 3H), 2.09 (s, 6H), 2.04-1.93 (m, 2H), 1.73-1.66 (m, 2H), 1.60 (qd, J=12.3, 3.8 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H). MS m/z: 485.3 [M+1].

##STR00249##

[0374] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.04 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.16-7.02 (m, 3H), 6.85 (d, J=1.8 Hz, 1H), 6.76 (dd, J=8.3, 1.8 Hz, 1H), 4.80-4.64 (m, 1H), 4.33 (s, 2H), 3.78 (s, 3H), 3.10-2.92 (m, 2H), 2.53-2.45 (m, 2H), 2.39-2.16 (m, 5H), 2.07 (s, 6H), 1.77 (d, J=11.7 Hz, 2H), 1.68 (qd, J=12.5, 3.3 Hz, 2H), 1.59 (tt, J=10.0, 4.3 Hz, 2H). MS m/z: 527.3 [M+1].

##STR00250##

[0375] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.05 (s, 1H), 7.97 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.16-7.01 (m, 3H), 6.86 (d, J=1.9 Hz, 1H), 6.75 (dd, J=8.3, 1.9 Hz, 1H), 4.69 (tt, J=12.0, 3.9 Hz, 1H), 4.35 (s, 2H), 3.87 (dd, J=11.2, 4.4 Hz, 2H), 3.79 (s, 3H), 3.01-2.84 (m, 2H), 2.56 (qd, J=12.3, 4.6 Hz, 2H), 2.25 (s, 3H), 2.08 (s, 6H), 1.79-1.61 (m, 4H), 1.57-1.45 (m, 2H). MS m/z: 557.3 [M+1].

##STR00251##

[0376] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.35 (d, J=2.0 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.33-7.38 (m, 2H), 7.24 (d, J=6.8 Hz, 1H), 7.07-7.14 (m, 3H), 6.96 (s, 1H), 6.69 (d, J=8.2 Hz, 2H), 4.79 (d, J=13.6 Hz, 1H), 4.57 (d, J=14 Hz, 1H), 3.93 (s, 3H), 3.11 (t, J=5.2 Hz, 4H), 2.58 (t, J=5.2 Hz, 4H), 2.38 (s, 3H), 2.35 (s, 3H), 1.80 (s, 3H). MS m/z: 615.2 [M+1].

##STR00252##

[0377] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.37 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.35-7.40 (m, 2H), 7.23 (d, J=7.2 Hz, 1H), 7.13 (t, J=7.2 Hz, 3H), 6.46 (d, J=2.0 Hz, 1H), 6.13 (d, J=6 Hz 2H), 4.79 (d, J=14.0 Hz, 1H), 4.58 (d, J=13.6 Hz, 1H), 3.95 (s, 3H), 3.81 (s, 3H), 3.12 (t, J=4.8 Hz, 4H), 2.59 (t, J=4.8 Hz, 4H), 2.39 (s, 3H), 2.36 (s, 3H). MS m/z: 645.2 [M+1].

##STR00253##

[0378] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.92 (s, 1H), 7.44-7.48 (m, 2H), 7.08-7.15 (m, 3H), 7.02 (s, 1H), 6.92-6.96 (m, 2H), 5.02-5.13 (m, 1H), 4.37 (d, J=0.4 Hz, 2H), 3.19 (t, J=5.2 Hz, 4H), 2.60 (t, J=5.2 Hz, 4H), 2.36 (s, 3H), 2.23 (s, 6H), 1.55 (s, 3H), 1.53 (s, 3H). MS m/z: 486.3 [M+1].

##STR00254##

[0379] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.22 (d, J=9.6 Hz, 1H), 7.94 (s, 1H), 7.39 (s, 1H), 7.09-7.15 (m, 3H), 6.55-6.58 (m, 2H), 5.06-5.17 (m, 1H), 4.38 (s, 2H), 3.90 (s, 3H), 3.20 (t, J=5.2 Hz, 4H), 2.62 (t, J=5.2 Hz, 4H), 2.37 (s, 3H), 2.23 (s, 6H), 1.58 (s, 3H), 1.56 (s, 3H). MS m/z: 516.3 [M+1].

##STR00255##

[0380] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.93 (s, 1H), 7.44-7.48 (m, 2H), 7.09-7.16 (m, 3H), 6.93-6.97 (m, 3H), 4.84-4.93 (m, 1H), 4.36 (s, 2H), 3.19 (t, J=4.8 Hz, 4H), 2.55-2.65 (m, 6H), 2.42-2.50 (m, 2H), 2.36 (s, 3H), 2.22 (s, 6H), 1.71-1.85 (m, 2H). MS m/z: 498.3 [M+1].

##STR00256##

[0381] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.22 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.36 (s, 1H), 7.09-7.15 (m, 3H), 6.56-6.60 (m, 2H), 4.90-4.98 (m, 1H), 4.36 (s, 2H), 3.90 (s, 3H), 3.20 (t, J=5.2 Hz, 4H), 2.57-2.67 (m, 6H), 2.46-2.53 (m, 2H), 2.38 (s, 3H), 2.23 (s, 6H), 1.74-1.88 (m, 2H). MS m/z: 528.3 [M+1].

##STR00257##

[0382] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.92 (s, 1H), 7.46-7.50 (m, 2H), 7.08-7.15 (m, 3H), 7.01 (s, 1H), 6.92-6.96 (m, 2H), 4.61-4.69 (m, 1H), 4.37 (s, 2H), 3.18 (t, J=5.2 Hz, 4H), 2.60 (t, J=5.2 Hz, 4H), 2.43-2.53 (m, 2H), 2.36 (s, 3H), 2.22 (s, 6H), 1.76-1.85 (m, 4H), 1.65 (d, J=12.4 Hz, 1H), 1.31-1.43 (m, 2H), 1.13-1.23 (m, 1H). MS m/z: 526.3 [M+1].

##STR00258##

[0383] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.24 (d, J=8.4 Hz, 1H), 7.93 (s, 1H), 7.42 (s, 1H), 7.08-7.15 (m, 3H), 7.54-7.57 (m, 2H), 4.65-4.73 (m, 1H), 4.37 (s, 2H), 3.90 (m, 3H), 3.19 (t, J=5.2 Hz, 4H), 2.61 (t, J=5.2 Hz, 4H), 2.45-2.54 (m, 2H), 2.37 (s, 3H), 2.22 (s, 6H), 1.80-1.88 (m, 4H), 1.69 (d, 1H), 1.35-1.45 (m, 2H), 1.17-1.27 (m, 1H). MS m/z: 556.3 [M+1].

##STR00259##

[0384] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 8.08 (s, 1H), 8.05 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.19-7.10 (m, 3H), 6.93 (d, J=1.9 Hz, 1H), 6.81 (dd, J=8.2, 1.9 Hz, 1H), 4.48 (tt, J=11.9, 3.5 Hz, 1H), 4.40 (s, 2H), 3.84 (s, 3H), 2.91 (d, J=10.8 Hz, 2H), 2.49-2.41 (m, 1H), 2.32 (qd, J=12.6, 3.7 Hz, 2H), 2.24 (s, 3H), 2.14 (s, 6H), 2.08-1.94 (m, 2H), 1.81-1.67 (m, 6H), 1.67-1.61 (m, 2H), 1.58 (d, J=12.9 Hz, 1H), 1.25 (d, J=12.8 Hz, 4H), 1.07-0.95 (m, 2H). MS m/z: 555.3 [M+1].

##STR00260##

[0385] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.92 (s, 1H), 7.44-7.47 (m, 2H), 7.08-7.15 (m, 3H), 6.99 (m, 3H), 6.91-6.95 (m, 2H), 5.17-5.26 (m, 1H), 4.38 (s, 2H), 3.19 (t, J=5.2 Hz, 4H), 2.60 (t, J=5.2 Hz, 4H), 2.36 (s, 3H), 2.23 (s, 6H), 2.17-2.21 (m, 2H), 1.88-1.91 (m, 4H), 1.52-1.57 (m, 2H). MS m/z: 512.3 [M+1].

##STR00261##

[0386] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.20 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.38 (s, 1H), 7.08-7.15 (m, 3H), 6.56 (t, 2H), 5.22-5.31 (m, 1H), 4.39 (s, 2H), 3.90 (s, 3H), 3.19 (t, J=5.2 Hz, 4H), 2.60 (t, J=5.2 Hz, 4H), 2.36 (s, 3H), 2.23 (s, 6H), 2.19-2.27 (m, 2H), 1.92-2.00 (m, 4H), 1.74-1.88 (m, 2H). MS m/z: 542.3 [M+1].

##STR00262##

[0387] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.95 (s, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.10-7.16 (m, 4H), 6.95 (d, J=8.8 Hz, 2H), 4.87-4.95 (m, 1H), 4.39 (s, 2H), 4.07-4.11 (q, 2H), 3.50 (t, J=11.2 Hz, 2H), 3.19 (t, J=4.8 Hz, 4H), 2.90-3.00 (m, 2H), 2.60 (t, J=4.8 Hz, 4H), 2.36 (s, 3H), 2.22 (s, 6H), 1.67 (d, J=10.4 Hz, 2H). MS m/z: 528.3 [M+1].

##STR00263##

[0388] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.23 (t, 1H), 7.96 (s, 1H), 7.44 (s, 1H), 7.09-7.16 (m, 3H), 6.58 (t, 2H), 4.90-4.98 (m, 1H), 4.39 (s, 2H), 4.11 (dd, J=4.0 Hz, J=11.2 Hz, 2H), 3.91 (s, 3H), 3.53 (t, J=11.2 Hz, 2H), 3.19 (t, J=5.2 Hz, 4H), 2.90-3.01 (m, 2H), 2.61 (t, J=5.2 Hz, 4H), 2.37 (s, 3H), 2.23 (s, 6H), 1.68-1.72 (m, 2H). MS m/z: 558.3 [M+1].

##STR00264##

[0389] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.35 (d, J=2.8 Hz, 1H), 8.06 (d, 1H), 7.32-7.38 (m, 3H), 7.19-7.21 (m, 2H), 7.09 (d, J=8.0 Hz, 2H), 6.94 (s, 1H), 6.69 (d, J=8.8 Hz, 2H), 4.97-5.02 (q, J=6.8 Hz, 0.73H), 4.76-4.81 (q, J=6.8 Hz, 0.27H), 3.93 (s, 3H), 3.12 (t, J=4.8 Hz, 4H), 2.60 (t, J=4.8 Hz, 4H), 2.35 (t, 6H), 1.56 (d, J=6.4 Hz, 1H), 1.50 (d, J=6.8 Hz, 2H). MS m/z: 585.3 [M+1].

##STR00265##

[0390] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.37 (d, J=2.8 Hz, 1H), 8.07 (s, 1H), 7.32-7.41 (m, 5H), 7.19-7.22 (m, 2H), 6.46 (d, J=2.4 Hz, 1H), 6.13 (d, J=6.4 Hz, 1H), 4.98-5.03 (q, J=6.4 Hz, 1H), 3.95 (s, 3H), 3.81 (s, 3H), 3.11 (t, J=4.8 Hz, 4H), 2.59 (t, J=4.8 Hz, 4H), 2.38 (s, 3H), 2.36 (s, 3H), 1.51 (d, J=6.8 Hz, 3H). MS m/z: 615.3 [M+1].

##STR00266##

[0391] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.37 (d, J=2.4 Hz, 1H), 8.06 (s, 1H), 7.32-7.41 (m, 5H), 7.19-7.22 (m, 2H), 6.46 (d, J=2.4 Hz, 1H), 6.13 (d, J=6.0 Hz, 1H), 4.80 (q, J=6.4 Hz, 1H), 3.95 (s, 3H), 3.81 (s, 3H), 3.11 (t, J=4.8 Hz, 4H), 2.59 (t, J=4.8 Hz, 4H), 2.36 (s, 3H), 2.34 (s, 3H), 1.57 (d, J=6.4 Hz, 3H). MS m/z: 615.3

##STR00267##

[0392] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.38 (d, J=2.4 Hz, 1H), 8.07 (s, 1H), 7.31-7.40 (m, 5H), 7.20 (t, 2H), 6.46 (d, J=2.4 Hz, 1H), 6.13 (d, J=6.8 Hz, 1H), 4.98-5.03 (q, J=6.4 Hz, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 3.12 (t, J=4.8 Hz, 4H), 2.59 (t, J=4.8 Hz, 4H), 2.38 (s, 3H), 2.36 (s, 3H), 1.51 (d, J=6.8 Hz, 3H). MS m/z: 615.3 [M+1].

##STR00268##

[0393] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.36 (d, J=2.8 Hz, 1H), 7.99 (s, 1H), 7.29-7.36 (m, 2H), 7.11-7.17 (m, 5H), 6.98 (s, 1H), 6.71 (d, J=8.4 Hz, 2H), 4.28 (d, J=2.8 Hz, 1H), 3.92 (s, 3H), 3.11 (t, J=4.8 Hz, 4H), 2.57 (t, J=4.8 Hz, 4H), 2.39 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H), 2.16-2.20 (m, 1H), 1.17 (d, J=6.4 Hz, 3H), 0.90 (d, J=7.2 Hz, 3H). MS m/z: 592.4 [M+1].

##STR00269##

[0394] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.38 (d, J=2.8 Hz, 1H), 8.00 (s, 1H), 7.30-7.41 (m, 4H), 7.11-7.17 (m, 3H), 6.46 (d, J=2.4 Hz, 1H), 6.14 (s, 1H), 4.28 (d, J=3.2 Hz, 1H), 3.94 (s, 3H), 3.82 (s, 3H), 3.11 (t, J=4.8 Hz, 4H), 2.59 (t, J=4.8 Hz, 4H), 2.40 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H), 2.14-2.22 (m, 1H), 1.17 (d, J=6.4 Hz, 3H), 0.91 (d, J=7.2 Hz, 3H). MS m/z: 622.4 [M+1].

##STR00270##

[0395] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.94 (s, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.33 (d, J=4.8 Hz, 1H), 7.19 (t, 3H), 6.95 (d, J=8.8 Hz, 2H), 4.69 (d, J=13.6 Hz, 1H), 4.35 (d, J=13.6 Hz, 1H), 3.44 (s, 3H), 3.19 (t, J=4.8 Hz, 4H), 2.60 (t, J=4.8 Hz, 4H), 2.36 (s, 3H), 2.29 (s, 3H). MS m/z: 478.2 [M+1].

##STR00271##

[0396] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.26 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.47 (s, 1H), 7.31-7.35 (m, 1H), 7.20 (d, J=4.8 Hz, 2H), 6.58 (t, 2H), 4.70 (d, J=14 Hz, 1H), 4.36 (d, J=14.0 Hz, 1H), 3.90 (s, 3H), 3.47 (s, 3H), 3.19 (t, J=4.8 Hz, 4H), 2.61 (t, J=4.8 Hz, 4H), 2.36 (s, 3H), 2.29 (s, 3H). MS m/z: 508.2 [M+1].

##STR00272##

[0397] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.94 (s, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.30-7.33 (m, 1H), 7.18 (d, 2H), 6.95 (t, 3H), 5.04-5.150 (m, 1H), 4.62 (d, J=13.6 Hz, 1H), 4.27 (d, J=13.6 Hz, 1H), 3.19 (t, J=4.8 Hz, 4H), 2.60 (t, J=4.8 Hz, 4H), 2.36 (s, 3H), 2.27 (s, 3H), 1.53-1.56 (m, 6H). MS m/z: 506.2 [M+1].

##STR00273##

[0398] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.21 (t, 1H), 7.95 (s, 1H), 7.39 (s, 1H), 7.30-7.33 (q, 1H), 7.18 (t, 2H), 6.57 (t, 2H), 5.09-5.19 (m, 1H), 4.62 (d, J=13.6 Hz, 1H), 4.27 (d, J=13.6 Hz, 1H), 3.90 (m, 3H), 3.19 (t, J=4.8 Hz, 4H), 2.61 (t, J=4.8 Hz, 4H), 2.37 (s, 3H), 2.27 (s, 3H), 1.56-1.59 (m, 6H). MS m/z: 536.3 [M+1].

##STR00274##

[0399] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.95 (s, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.30-7.34 (m, 1H), 7.18 (q, 2H), 6.96 (t, 3H), 4.86-4.95 (m, 1H), 4.61 (d, J=13.6 Hz, 1H), 4.25 (d, J=14 Hz, 1H), 3.19 (t, J=4.8 Hz, 4H), 2.55-2.68 (m, 6H), 2.42-2.48 (m, 2H), 2.36 (s, 3H), 2.26 (s, 3H), 1.68-1.85 (m, 2H). MS m/z: 518.3 [M+1].

##STR00275##

[0400] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.21 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 7.36 (s, 1H), 7.30-7.34 (m, 1H), 7.17 (q, 2H), 6.59 (t, 2H), 4.91-5.00 (m, 1H), 4.62 (d, J=13.6 Hz, 1H), 4.25 (d, J=14.0 Hz, 1H), 3.90 (s, 3H), 3.20 (t, J=4.8 Hz, 4H), 2.60-2.71 (m, 6H), 2.46-2.53 (m, 2H), 2.37 (s, 3H), 2.26 (s, 3H), 1.72-1.86 (m, 2H). MS m/z: 548.3 [M+1].

##STR00276##

[0401] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 7.93 (s, 1H), 7.48 (d, J=9.2 Hz, 2H), 7.30-7.33 (m, 1H), 7.18 (d, 2H), 7.04 (s, 1H), 6.94 (d, J=9.2 Hz, 2H), 4.60-4.71 (m, 2H), 4.27 (d, J=14 Hz, 1H), 3.19 (t, J=4.8 Hz, 4H), 2.61 (t, J=4.8 Hz, 4H), 2.40-2.53 (m, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 1.77-1.85 (m, 4H), 1.65 (d, 1H), 1.30-1.42 (m, 2H), 1.13-1.23 (m, 1H). MS m/z: 546.3 [M+1].

##STR00277##

[0402] .sup.1H-NMR (CDCl.sub.3, 400 MHz): δ 8.22 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.42 (s, 1H), 7.30-7.33 (m, 1H), 7.17 (d, 2H), 6.56 (d, 2H), 4.68-4.75 (m, 1H), 4.62 (d, J=13.6 Hz, 1H), 4.27 (d, J=13.6 Hz, 1H), 3.90 (s, 3H), 3.19 (t, J=4.8 Hz, 4H), 2.61 (t, J=4.8 Hz, 4H), 2.42-2.56 (m, 2H), 2.37 (s, 3H), 2.27 (s, 3H), 1.80-1.88 (m, 4H), 1.68 (d, 1H), 1.34-1.46 (m, 2H), 1.18-1.27 (m, 1H). MS m/z: 576.3 [M+1].

TABLE-US-00002 TABLE 2 Percent activity of selected compounds against SIK1, SIK2, and SIK3 (all compounds assayed at 1 μM; all assays conducted at approximate K.sub.m for ATP) SIK1 SIK2 % % COMPOUND ACTIVITY S.D. ACTIVITY S.D. HG-11-143-01 7.9 7.9 4.3 4.3 HG-11-23-01 12.5 10.5 7.0 1.5 HG-11-139-02 36.0 5.5 32.8 3.0 HG-11-139-01 15.3 13.0 2.1 0.6 HG-11-137-01 12.9 10.1 1.4 0.7 HG-11-136-01 19.1 18.2 2.8 1.4 GNF-7 12.0 9.7 27.4 0.7 SIK3 % COMPOUND ACTIVITY S.D. HG-11-143-01 9.3 0.2 HG-11-139-01 7.5 1.1 HG-11-137-01 8.6 1.8 HG-11-136-01 9 0.5

TABLE-US-00003 TABLE 3 Selectivity of selected compounds against different classes of kinases HG-11-136-01 KINOMEscan Gene Symbol GRAY779 Compound Concentration (uM) 1 uM AAK1 13 ABL1(E255K)-phosphorylated 0.4 ABL1(F317I)-nonphosphorylated 0 ABL1(F317I)-phosphorylated 1.3 ABL1(F317L)-nonphosphorylated 0 ABL1(F317L)-phosphorylated 1.8 ABL1(H396P)-nonphosphorylated 0 ABL1(H396P)-phosphorylated 0 ABL1(M351T)-phosphorylated 0.55 ABL1(Q252H)-nonphosphorylated 0 ABL1(Q252H)-phosphorylated 0.25 ABL1(T315I)-nonphosphorylated 0 ABL1(T315I)-phosphorylated 1.2 ABL1(Y253F)-phosphorylated 0.15 ABL1-nonphosphorylated 0 ABL1-phosphorylated 0 ABL2 0.35 ACVR1 2.8 ACVR1B 9.6 ACVR2A 5 ACVR2B 3.2 ACVRL1 16 ADCK3 38 ADCK4 44 AKT1 100 AKT2 100 AKT3 100 ALK 1.6 ALK(C1156Y) 12 ALK(L1196M) 8.2 AMPK-alpha1 33 AMPK-alpha2 30 ANKK1 68 ARK5 8.2 ASK1 100 ASK2 46 AURKA 0 AURKB 26 AURKC 33 AXL 25 BIKE 8.8 BLK 0.1 BMPR1A 4.6 BMPR1B 0 BMPR2 77 BMX 3 BRAF 26 BRAF(V600E) 13 BRK 0.45 BRSK1 100 BRSK2 91 BTK 0.05 BUB1 100 CAMK1 82 CAMK1D 68 CAMK1G 95 CAMK2A 93 CAMK2B 90 CAMK2D 100 CAMK2G 100 CAMK4 100 CAMKK1 94 CAMKK2 100 CASK 54 CDC2L1 79 CDC2L2 83 CDC2L5 65 CDK11 89 CDK2 97 CDK3 100 CDK4-cyclinD1 9 CDK4-cyclinD3 26 CDK5 100 CDK7 60 CDK8 100 CDK9 91 CDKL1 84 CDKL2 14 CDKL3 58 CDKL5 98 CHEK1 82 CHEK2 46 CIT 58 CLK1 19 CLK2 35 CLK3 78 CLK4 33 CSF1R 0.35 CSF1R-autoinhibited 1 CSK 0.3 CSNK1A1 100 CSNK1A1L 97 CSNK1D 100 CSNK1E 59 CSNK1G1 92 CSNK1G2 100 CSNK1G3 84 CSNK2A1 1.9 CSNK2A2 0.05 CTK 33 DAPK1 63 DAPK2 88 DAPK3 63 DCAMKL1 51 DCAMKL2 88 DCAMKL3 77 DDR1 0.3 DDR2 1.6 DLK 6.6 DMPK 88 DMPK2 1.6 DRAK1 96 DRAK2 100 DYRK1A 30 DYRK1B 60 DYRK2 5 EGFR 0.7 EGFR(E746-A750del) 1.8 EGFR(G719C) 0.1 EGFR(G719S) 0.2 EGFR(L747-E749del, A750P) 0.35 EGFR(L747-S752del, P753S) 0.95 EGFR(L747-T751del, Sins) 0.3 EGFR(L858R) 0.1 EGFR(L858R, T790M) 1.7 EGFR(L861Q) 0 EGFR(S752-I759del) 4.2 EGFR(T790M) 0.7 EIF2AK1 93 EPHA1 0 EPHA2 0.6 EPHA3 0.8 EPHA4 0 EPHA5 0.6 EPHA6 0.2 EPHA7 72 EPHA8 0.9 EPHB1 0.3 EPHB2 0 EPHB3 0 EPHB4 0 EPHB6 0.7 ERBB2 0 ERBB3 0 ERBB4 0.2 ERK1 100 ERK2 96 ERK3 81 ERK4 95 ERK5 84 ERK8 88 ERN1 13 FAK 24 FER 0.1 FES 0 FGFR1 0.15 FGFR2 0.8 FGFR3 0.95 FGFR3(G697C) 1.4 FGFR4 2 FGR 0 FLT1 5.2 FLT3 34 FLT3(D835H) 16 FLT3(D835Y) 14 FLT3(ITD) 57 FLT3(K663Q) 31 FLT3(N841I) 11 FLT3(R834Q) 48 FLT3-autoinhibited 66 FLT4 6.6 FRK 0.05 FYN 0.35 GAK 6.8 GCN2(Kin.Dom.2, S808G) 0.75 GRK1 77 GRK4 26 GRK7 96 αK3A 100 GSK3B 100 HASPIN 92 HCK 0.05 HIPK1 3.8 HIPK2 0.95 HIPK3 2.6 HIPK4 51 HPK1 0.95 HUNK 28 ICK 61 IGF1R 100 IKK-alpha 99 IKK-beta 80 IKK-epsilon 47 INSR 48 INSRR 100 IRAK1 4.4 IRAK3 38 IRAK4 49 ITK 66 JAK1(JH1domain-catalytic) 57 JAK1(JH2domain-pseudokinase) 8.1 JAK2(JH1domain-catalytic) 0.75 JAK3(JH1domain-catalytic) 0 JNK1 23 JNK2 20 JNK3 32 KIT 0 KIT(A829P) 3.6 KIT(D816H) 6 KIT(D816V) 0.2 KIT(L576P) 0 KIT(V559D) 0 KIT(V559D, T670I) 55 KIT(V559D, V654A) 2.2 KIT-autoinhibited 0.35 LATS1 100 LATS2 60 LCK 0.05 LIMK1 0.05 LIMK2 0 LKB1 69 LOK 0 LRRK2 21 LRRK2(G2019S) 6.6 LTK 18 LYN 0 LZK 4 MAK 100 MAP3K1 73 MAP3K15 40 MAP3K2 0.05 MAP3K3 0.1 MAP3K4 16 MAP4K2 0.3 MAP4K3 1.8 MAP4K4 17 MAP4K5 0.3 MAPKAPK2 100 MAPKAPK5 96 MARK1 5.1 MARK2 3.7 MARK3 1.6 MARK4 32 MAST1 62 MEK1 0.55 MEK2 0.2 MEK3 6.4 MEK4 48 MEK5 0.1 MEK6 30 MELK 36 MERTK 5.6 MET 66 MET(M1250T) 46 MET(Y1235D) 61 MINK 2.8 MKK7 80 MKNK1 85 MKNK2 99 MLCK 100 MLK1 6 MLK2 11 MLK3 28 MRCKA 99 MRCKB 38 MST1 2.1 MST1R 100 MST2 0.75 MST3 4.6 MST4 2.8 MTOR 83 MUSK 86 MYLK 86 MYLK2 81 MYLK4 60 MYO3A 40 MYO3B 29 NDR1 46 NDR2 28 NEK1 88 NEK10 9.6 NEK11 21 NEK2 75 NEK3 39 NEK4 100 NEK5 98 NEK6 100 NEK7 100 NEK9 81 NIK 36 NIM1 42 NLK 7.6 OSR1 49 p38-alpha 1 p38-beta 3.1 p38-delta 100 p38-gamma 91 PAK1 3.7 PAK2 61 PAK3 11 PAK4 34 PAK6 37 PAK7 1.3 PCTK1 73 PCTK2 91 PCTK3 100 PDGFRA 0.5 PDGFRB 0 PDPK1 100 PFCDPK1(P. falciparum) 0.1 PFPK5(P. falciparum) 96 PFTAIRE2 78 PFTK1 100 PHKG1 100 PHKG2 93 PIK3C2B 0.55 PIK3C2G 87 PIK3CA 100 PIK3CA(C420R) 69 PIK3CA(E542K) 88 PIK3CA(E545A) 69 PIK3CA(E545K) 98 PIK3CA(H1047L) 96 PIK3CA(H1047Y) 63 PIK3CA(I800L) 94 PIK3CA(M1043I) 64 PIK3CA(Q546K) 94 PIK3CB 92 PIK3CD 72 PIK3CG 77 PIK4CB 63 PIM1 100 PIM2 100 PIM3 90 PIP5K1A 14 PIP5K1C 70 PIP5K2B 27 PIP5K2C 100 PKAC-alpha 85 PKAC-beta 66 PKMYT1 42 PKN1 95 PKN2 94 PKNB(M. tuberculosis) 6.6 PLK1 60 PLK2 21 PLK3 31 PLK4 18 PRKCD 94 PRKCE 61 PRKCH 100 PRKCI 63 PRKCQ 80 PRKD1 3.6 PRKD2 3.6 PRKD3 5.4 PRKG1 100 PRKG2 92 PRKR 73 PRKX 100 PRP4 100 PYK2 15 QSK 0.25 RAF1 93 RET 0 RET(M918T) 0.05 RET(V804L) 24 RET(V804M) 7.6 RIOK1 9.2 RIOK2 87 RIOK3 25 RIPK1 35 RIPK2 0.1 RIPK4 55 RIPK5 2.8 ROCK1 81 ROCK2 89 ROS1 63 RPS6KA4(Kin.Dom.1-N-terminal) 79 RPS6KA4(Kin.Dom.2-C-terminal) 90 RPS6KA5(Kin.Dom.1-N-terminal) 100 RPS6KA5(Kin.Dom.2-C-terminal) 80 RSK1(Kin.Dom.1-N-terminal) 48 RSK1(Kin.Dom.2-C-terminal) 9.7 RSK2(Kin.Dom.1-N-terminal) 12 RSK2(Kin.Dom.2-C-terminal) 51 RSK3(Kin.Dom.1-N-terminal) 40 RSK3(Kin.Dom.2-C-terminal) 67 RSK4(Kin.Dom.1-N-terminal) 39 RSK4(Kin.Dom.2-C-terminal) 4 S6K1 72 SBK1 6.6 SGK 63 SgK110 8.6 SGK2 76 SGK3 77 SIK 0.9 SIK2 6.1 SLK 0.1 SNARK 0.4 SNRK 91 SRC 0.15 SRMS 0 SRPK1 16 SRPK2 93 SRPK3 70 STK16 5.6 STK33 24 STK35 49 STK36 0 STK39 28 SYK 1.2 TAK1 11 TAOK1 1 TAOK2 0 TAOK3 1.8 TBK1 37 TEC 2.6 TESK1 0 TGFBR1 33 TGFBR2 38 TIE1 30 TIE2 0.75 TLK1 76 TLK2 92 TNIK 2.8 TNK1 0.9 TNK2 0.15 TNNI3K 3.6 TRKA 41 TRKB 63 TRKC 71 TRPM6 69 TSSK1B 50 TTK 47 TXK 0.25 TYK2(JH1domain-catalytic) 5.6 TYK2(JH2domain-pseudokinase) 1.2 TYRO3 1.6 ULK1 3.2 ULK2 2.2 ULK3 2 VEGFR2 1.8 VRK2 86 WEE1 69 WEE2 82 WNK1 89 WNK3 50 YANK1 0.2 YANK2 1.8 YANK3 32 YES 0.05 YSK1 19 YSK4 0.4 ZAK 1.2 ZAP70 25

TABLE-US-00004 TABLE 4 Selected Compounds and Biological Assay Data Viability Viability Enzyme Viability loss loss Enzyme (μM) at 1 μM (%) Com- qAC50 qAC50 loss data AC50 AC40 SIK SIK SIK activity pound Data Mode Mode (M) mode mode (M) 1 2 3 SIK1 SIK2 SIK3 HG- decreasing < 5.00E−08 decreasing = 1.06E−07 12.5 7 11-23- (super- 01 active) HG- decreasing − 1.71E−07 decreasing − 9.70E−08 19.1 2.8 9 11- 136-01 HG- increasing = 4.66E−07 decreasing = 6.96E−06 12.9 1.4 8.6 11- 137-01 HG- increasing < 5.00E−08 decreasing − 8.91E−06 15.3 2.1 7.5 11- (super- 139-01 active) HG- increasing > 2.60E−05 inactive > 1.00E−05 11- (weakly 139-02 active) HG- decreasing = 4.69E−07 undefined − − 7.9 4.3 9.3 11- 143-01

TABLE-US-00005 TABLE 5 IC.sub.50 values of exemplary compounds described herein in the SIK2 inhibition assay Compound SIK2 IC.sub.50 (nM) YKL-05-95 6 ± 3 YKL-05-96 34 ± 14 YKL-05-99 40 ± 25

REFERENCES

[0403] 1. Altarejos, J. Y., and Montminy, M. (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat. Rev. Mol. Cell Biol. 12, 141-151. [0404] 2. Patel, K., Foretz, M., Marion, A., Campbell, D. G., Gourlay, R., Boudaba, N., Tournier, E., Titchenell, P., Peggie, M., Deak, M., Wan, M., Kaestner, K. H., Goransson, O., Viollet, B., Gray, N. S., Birnbaum, M. J., Sutherland, C., and Sakamoto, K. (2014) The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver, Nat. Commun., 5. [0405] 3. Park, J., Yoon, Y. S., Han, H. S., Kim, Y. H., Ogawa, Y., Park, K. G., Lee, C. H., Kim, S. T., and Koo, S. H. (2014) SIK2 Is Critical in the Regulation of Lipid Homeostasis and Adipogenesis In Vivo. Diabetes, 63, 3659-3673. [0406] 4. Henriksson, E., Sall, J., Gormand, A., Wasserstrom, S., Morrice, N. A., Fritzen, A. M., Foretz, M., Campbell, D. G., Sakamoto, K., Ekelund, M., Degerman, E., Stenkula, K. G., and Goransson, O. (2015) SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes. J. Cell Sci., 128, 472-486.

EQUIVALENTS AND SCOPE

[0407] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0408] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0409] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0410] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

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Abstract

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