# Patent

## Title
Heterocyclic kinase inhibitors

## Abstract

Provided herein are compounds of formula (I-A), (I-B), (I-C), or (I-D), pharmaceutical compositions comprising the compounds, and methods of use thereof. The compounds provided herein modulate kinase activity, including PI3 kinase activity, and are useful for treating diseases and conditions associated with kinase activity, including diseases and conditions associated with PI3 kinase activity.

## Background
This application is a continuation application of U.S. application Ser. No. 13/121,157, which is a national phase entry pursuant to 35 U.S.C. 371 of International Patent Application No. PCT/US2009/005380, filed on Sep. 28, 2009, which claims the benefit of U.S. Provisional Application Ser. No. 61/194,310, filed on Sep. 26, 2008, each of which is hereby incorporated by reference in its entirety for all purposes.


BACKGROUND OF THE INVENTION
The activity of cells can be regulated by external signals that stimulate or inhibit intracellular events. The process by which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response is referred to as signal transduction. Over the past decades, cascades of signal transduction events have been elucidated and found to play a central role in a variety of biological responses. Defects in various components of signal transduction pathways have been found to account for a vast number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al. Current Medicinal Chemistry (2007) 14:2214-2234).
Kinases represent a class of important signaling molecules. Kinases can generally be classified into protein kinases and lipid kinases, and certain kinases exhibit dual specificities. Protein kinases are enzymes that phosphorylate other proteins and/or themselves (i.e., autophosphorylation). Protein kinases can be generally classified into three major groups based upon their substrate utilization: tyrosine kinases which predominantly phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl), serine/threonine kinases which predominantly phosphorylate substrates on serine and/or threonine residues (e.g., mTorC1, mTorC2, ATM, ATR, DNA-PK, Akt), and dual-specificity kinases which phosphorylate substrates on tyrosine, serine and/or threonine residues.
Lipid kinases are enzymes that catalyze the phosphorylation of lipids. These enzymes, and the resulting phosphorylated lipids and lipid-derived biologically active organic molecules, play a role in many different physiological processes, including cell proliferation, migration, adhesion, and differentiation. Certain lipid kinases are membrane associated and they catalyze the phosphorylation of lipids contained in or associated with cell membranes. Examples of such enzymes include phosphoinositide(s) kinases (such as PI3-kinases, PI4-Kinases), diacylglycerol kinases, and sphingosine kinases.
The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of the most highly mutated systems in human cancers. PI3K signaling is also a key factor in many other diseases in humans. PI3K signaling is involved in many disease states including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory complications of the cardiovascular system such as acute coronary syndrome.
PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3′-OH group on phosphatidylinositols or phosphoinositides. The PI3K family comprises 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation (Katso et al., 2001). The class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3, which engages downstream effectors such as those in the Akt/PDK1 pathway, mTOR, the Tec family kinases, and the Rho family GTPases. The class II and III PI3-Ks play a key role in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2. The PIKKs are protein kinases that control cell growth (mTORC1) or monitor genomic integrity (ATM, ATR, DNA-PK, and hSmg-1).
The delta (δ) isoform of class I PI3K has been implicated, in particular, in a number of diseases and biological processes. PI3K δ is expressed primarily in hematopoietic cells including leukocytes such as T-cells, dendritic cells, neutrophils, mast cells, B-cells, and macrophages. PI3K δ is integrally involved in mammalian immune system functions such as T-cell function, B-cell activation, mast cell activation, dendritic cell function, and neutrophil activity. Due to its integral role in immune system function, PI3K δ is also involved in a number of diseases related to undesirable immune response such as allergic reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis, auto-immune diseases such as lupus, asthma, emphysema and other respiratory diseases. Other class I PI3K involved in immune system function includes PI3K γ, which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus.
Downstream mediators of the PI3K signal transduction pathway include Akt and mammalian target of rapamycin (mTOR). Akt possesses a plckstrin homology (PH) domain that binds PIP3, leading to Akt kinase activation. Akt phosphorylates many substrates and is a central downstream effector of PI3K for diverse cellular responses. One important function of Akt is to augment the activity of mTOR, through phosphorylation of TSC2 and other mechanisms. mTOR is a serine-threonine kinase related to the lipid kinases of the PI3K family. mTOR has been implicated in a wide range of biological processes including cell growth, cell proliferation, cell motility and survival. Disregulation of the mTOR pathway has been reported in various types of cancer. mTOR is a multifunctional kinase that integrates growth factor and nutrient signals to regulate protein translation, nutrient uptake, autophagy, and mitochondrial function.
As such, kinases, particularly PI3Ks are prime targets for drug development. There remains a need for PI3K inhibitors suitable for drug development. The present invention addresses this need and provides related advantages as well by providing new classes of kinase inhibitors.
SUMMARY OF THE INVENTION
The present invention provides a compound having a structure of one of the following formulae:




or a pharmaceutically acceptable salt thereof, wherein:
X5 and X6 are C—R6, N, C-L1-R1, or N-L1-R1 wherein one of X5 and X6 is C-L1-R1 or N-L1-R1; X1 is C or N; and X2 and X8 are independently N or C—R6; X3 and X7 are C or N, and at least one of X3 and X7 is C;
X4 in Formula I-A or I-C is C or N; and X4 in Formula I-B or I-D is C—R6, NH, or N;
and wherein no more than two adjacent ring atoms are N or NH;
R1 is hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and n is an integer from 0 to 2;
L1 is a bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
R2 and R3 are independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R4 and R5 are independently hydrogen or R6, or R4 and R5 are taken together to form a 5, 6 or 7 membered ring, wherein the 5, 6, or 7 membered ring is optionally substituted with (R6)q;
L is —NH—CR7R8—, —(CR7R8)z—, —C═O—, or —CR7R8(C═O)—, —O—, —SO—, or —SO2—;
z is an integer from 0 to 10;
q is an integer from 0 to 5;
each of R6 is independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R7 and R8 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyalkyl, or R7 and R8 taken together form a cycloalkyl, heterocycloalkyl or aryl ring;
R9 is hydrogen, halogen, —CN, —OR10, —S(O)nR11, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R10 is independently hydrogen, —C(O)R15, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R11 is independently —NR16R17, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R12 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R13 is independently hydrogen, —S(O)nR18, —C(O)R19, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R12 and R13 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR12R13; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R14 is independently —NR20R21, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R15 is independently —NR22R23, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R16 and R17 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R16 and R17 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR16R17; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R18 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R19 is independently —NR24R25, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R20 and R21 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R20 and R21 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR20R21; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R22 and R23 are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R22 and R23 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR22R23; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R24 and R25 are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R24 and R25 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR24R25; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted; and
W is CR6 or N.
In some embodiments, the compound of Formula I-A or I-C is a compound having a structure of one of the following formulae:




In some embodiments, the compound of Formula I-E is a compound of Formula I-J or Formula I-J-1:




In some embodiments, the compound of Formula I-A is a compound having a structure of one of the following formulae:




In some embodiments, the compound of Formula I-B or I-D, having a structure of one of the following formulae:




In another aspect, the invention provides for a compound having is a compound having a structure of the formula




or a pharmaceutically acceptable salt thereof, wherein:
X5 and X5 are C—R6, N, C-L1-R1, or N-L1-R1 wherein one and no more than one of X5 and X6 is C-L1-R1 or N-L1-R1; X1 is C or N; and X2 and X8 are independently N, or C—R6; X3 and X7 are C or N, at least one of X3 and X7 is C;
X4 in Formula V-A and Formula V-C is C or N; and X4 in Formula V-B and Formula V-D is C—R6, NH, or N;
and wherein no more than two adjacent ring atoms are N or NH;
R1 is hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and n is an integer from 0 to 2;
L1 is a bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each of R2 and R3 is independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R4 and R5 is independently hydrogen or R6, or R4 and R5 are taken together to form a 5, 6 or 7 membered ring, wherein the 5, 6, or 7 membered ring is optionally substituted with (R6)q;
L is —NH—CR7R8—, —(CR7R8)z—, —C═O—, or —CR7R8(C═O)—, —O—, —SO—, or —SO2—;
z is an integer from 0 to 10;
q is an integer from 0 to 5;
each R6 is independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein n is independently an integer from 0 to 2;
each of R7 and R8 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyalkyl, or R7 and R8 taken together form a cycloalkyl, heterocycloalkyl or aryl ring;
R9 is hydrogen, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R10 is independently hydrogen, —C(O)R15, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R11 is independently —NR16R17, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R12 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R13 is independently hydrogen, —S(O)nR18, —C(O)R19, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R12 and R13 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR12R13, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R14 is independently —NR20R21, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R15 is independently —NR22R23, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R16 and R17 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R16 and R17 are taken together to form a 5, 6, 7 or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR16R17, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R18 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R19 is independently —NR24R25, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R20 and R21 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R20 and R21 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR20R21, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each of R22 and R23 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R22 and R23 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR22R23, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted; and
each of R24 and R25 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R24 and R25 are taken together to form a 5, 6, 7, or 8 membered ring wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR24R25, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted.
In some embodiments, the compound of Formula V-A is a compound having a structure of Formula VI-A1:




In another aspect, the invention provides for a compound having a structure of one of the following formulae




or a pharmaceutically acceptable salt thereof, wherein:
X5 and X6 are C—R6, N, C-L1-R1, or N-L1-R1 wherein one and no more than one of X5 and X6 is C-L1-R1 or N-L1-R1;
X1 is C or N; and X2 and X8 are independently N, or C—R6;
X3 and X7 are C or N, at least one of X3 and X7 is C;
X4 in Formula VII-A and Formula VII-C is C or N; and X4 in Formula VII-B and Formula VII-D is C—R6, NH, or N; and wherein no more than two adjacent ring atoms are N or NH;
R1 is hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and n is an integer from 0 to 2;
L1 is a bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each of R2 and R3 is independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R4 and R5 is independently hydrogen or R6, or R4 and R5 are taken together to form a 5, 6 or 7 membered ring, wherein the 5, 6, 7, or 8 membered ring is optionally substituted with (R6)q;
L is —NH—CR7R8—, —(CR7R8)z—, —C═O—, or —CR7R8(C═O)—, —O—, —SO—, or —SO2—;
z is an integer from 0 to 10;
q is an integer from 0 to 5;
each R6 is independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein n is independently an integer from 0 to 2;
each of R7 and R8 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyalkyl, or R7 and R8 taken together form a cycloalkyl, heterocycloalkyl or aryl ring;
R9 is hydrogen, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R10 is independently hydrogen, —C(O)R15, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R11 is independently —NR16R17, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R12 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R13 is independently hydrogen, —S(O)nR18, —C(O)R19, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R12 and R13 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR12R13, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R14 is independently —NR20R21, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R15 is independently —NR22R23, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R16 and R17 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R16 and R17 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 additional ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR16R17, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R18 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R19 is independently —NR24R25, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R20 and R21 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R20 and R21 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 additional ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR20R21, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each of R22 and R23 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R22 and R23 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR22R23, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted; and
each of R24 and R25 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R24 and R25 are taken together to form a 5, 6, 7, or 8 membered ring wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR24R25, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 additional ring heteroatoms selected from N, S, or O, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted.
In some embodiments, compound of Formula VII-A is a compound having a structure of Formula VII-A1:




In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, when L is —(CR7R8)z— and z is 1, then R1 is alkynyl, aryl, or heteroaryl. In some other embodiments, when L is —(CR7R8)z— and z is 1, then L1 is a bond, and R1 is alkynyl, aryl, or heteroaryl.
In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, R9 is −OR10, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, when R9 is aryl, then R9 is substituted with halogen, alkyl or heteroalkyl. In other embodiments, wherein when R9 is —NR12R13, then R12 and R13 are taken together to form a 5, 6, 7 or 8 membered ring.
In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, R1 is bicyclic heteroaryl.
In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, R4 and R5 are taken together to form a 6-membered ring.
In some embodiments of a compound of Formula I-A, I-C, I-E, I-G, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-C, VI-A, VI-A1, VI-A2, VI-C, VII-A, VII-A1, VII-A2, or VII-C, R2 is —NH2.
In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A2, VII-B, VII-C, or VII-D, R7 is alkyl.
In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-B, VI-C, VI-D, VII-A, VII-B, VII-C, or VII-D, R7 and R8 are hydrogen.
In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, or VI-D, W is CH.
In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VII-A, VII-B, VII-C, or VII-D, W is N.
In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, R3 is hydrogen.
In some embodiments of the invention, a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided, wherein R9 is halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and wherein n is independently an integer from 0 to 2. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided, wherein R9 is =substituted heterocycloalkyl. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided, wherein R9 is substituted heterocycloalkyl. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A2, VII-B, VII-C, or VII-D is provided, wherein R9 is unsubstituted aryl or substituted aryl. In some embodiments, R9 is aryl substituted with halogen, aryl substituted with alkyl, or aryl substituted with heteroalkyl. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided, wherein R9 is —NR12R13. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided, wherein R12 is —H and R13 is unsubstituted alkyl or cycloalkyl. Alternatively, R12 and R15 are unsubstituted alkyl or cycloalkyl. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-B, VII-C, or VII-DD is provided, wherein L1 is a bond.
In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided, wherein R1 is monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, or bicyclic heteroaryl. In some embodiments, R1 is unsubstituted aryl, or substituted aryl. In some embodiments, R1 is aryl substituted with halogen or hydroxy. In other embodiments, R1 is aryl substituted with halogen and hydroxy. In yet other embodiments, R1 is unsubstituted heteroaryl or substituted heteroaryl. Alternatively, R1 is unsubstituted alkynyl or substituted alkynyl. In some embodiments, R1 is alkynyl substituted with hydroxy. In further embodiments, R1 is halogen, —CN, —C(═O)R14, alkyl, or alkenyl.
In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided wherein R4 and R5 taken together form a 6-membered ring. The 6-membered ring can be substituted with R6. In some embodiments, R6 in a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A1, VII-B, VII-C, or VII-D, is alkyl. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided wherein R2 is —NR12R13. In some embodiments, R2 in a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, is —NH2. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided wherein R7 is alkyl. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A2, VII-B, VII-C, or VII-D is provided wherein R7 and R8 are hydrogen. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided wherein W is CH. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided wherein z is 1. In some embodiments of the invention a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D is provided wherein R3 is hydrogen.
In some embodiments of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, the compound selectively inhibits one or more members of type I phosphatidylinositol 3-kinases (PI3-kinase) relative to other members of type I PI3-kinase, ascertained by an in vitro kinase assay. In some embodiments, the compound selectively inhibits PI3-kinase γ and PI3-kinase δ as compared to PI3-kinase β and PI3-kinase α. In other embodiments, the compound selectively inhibits PI3-kinase δ and PI3-kinase β as compared to PI3-kinase α and PI3-kinase γ.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, VII-D or a pharmaceutically acceptable salt of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, and a pharmaceutically acceptable excipient.
The invention also provides a method of treating a medical condition mediated by a type I-PI3 kinase (e.g. mediated by p110δ, p110γ, p110α, or p110β kinase), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, or a pharmaceutically acceptable salt of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D. In some embodiments, the medical condition is selected from the group consisting of hematologic malignancy, inflammation, autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, asthma, and cardiovascular disease. In other embodiments, the medical condition is selected from the group consisting of acute myelogenous leukemia, chronic myelogenous leukemia, mastocytosis, chronic lymphocytic leukemia, multiple myeloma, and myelodysplastic syndrome. In other embodiments, the method of treating a medical condition further comprises administering an anti-cancer agent.
The present invention also provides a method of inhibiting activity of a protein kinase and/or a lipid kinase present in a cell, comprising contacting said cell with an effective amount of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D or a pharmaceutically acceptable salt of a compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.


DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures wherein hydrogen is replaced by deuterium or tritium, or wherein carbon atom is replaced by 13C- or 14C-enriched carbon, are within the scope of this invention.
The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) includes those embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, that “consist of” or “consist essentially of” the described features.
As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.
As used herein, “agent” or “biologically active agent” refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound. Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts, and the like. A skilled artisan can readily recognize that there is no limit as to the structural nature of the agents of the present invention.
The term “agonist” as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term “agonist” is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g. bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.
The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the terms “antagonist” and “inhibitors” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g. bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease.
An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent” refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents comprises chemotherapeutic agents. “Chemotherapy” means the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.
The term “cell proliferation” refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.
The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g. reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” is used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
“Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
“Signal transduction” is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response. A modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.
“Radiation therapy” means exposing a patient, using routine methods and compositions known to the practitioner, to radiation emitters such as alpha-particle emitting radionucleotides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (i.e. beta emitters), conversion electron emitters (e.g. strontium-89 and samarium-153-EDTMP, or high-energy radiation, including without limitation x-rays, gamma rays, and neutrons.
“Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
“Acyl” refers to a —(C═O)R radical wherein “R” is alkyl, aryl, heteroaryl, heteroalkyl, or heterocyclyl, which are as described herein. In some embodiments, it is a C1-C10 acyl radical which refers to the total number of chain or ring atoms of the alkyl, aryl, heteroaryl or heterocyclyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e three other ring or chain atoms plus carbonyl. If the R radical is heteroaryl or heterocyclyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the “R” of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —OC(O)N(Ra)2, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. “Acyloxy” refers to a R(C═O)O— radical wherein “R” is alkyl, aryl, heteroaryl or heterocyclyl, which are as described herein. In some embodiments, it is a C1-C4 acyloxy radical which refers to the total number of chain or ring atoms of the alkyl, aryl, heteroaryl or heterocyclyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e three other ring or chain atoms plus carbonyl. If the R radical is heteroaryl or heterocyclyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the “R” of an acyloxy group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
“Alkoxy” refers to a (alkyl)O— radical, where alkyl is as described herein and contains 1 to 10 carbons (e.g., C1-C10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C1-C4 alkoxy group. A alkoxy moiety may be substituted by one or more of the substituents described as suitable substituents for an alkyl radical.
“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C1-C10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, it is a C1-C4 alkyl group. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and the like. The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
“Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (ie. C2-C10 alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to five carbon atoms (e.g., C2-C5 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (ie. C2-C10 alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to five carbon atoms (e.g., C2-C5 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Amino” or “amine” refers to a —N(Ra)2 radical group, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Amide” or “amido” refers to a chemical moiety with formula —C(O)NHR or —NHC(O)R, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). In some embodiments it is a C1-C4 amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical. Unless stated otherwise specifically in the specification, an amino group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl. An amide may be an amino acid or a peptide molecule attached to a compound of Formula (I), thereby forming a prodrug. Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be amidified. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
“Aromatic” or “aryl” refers to an aromatic radical with six to ten ring atoms (e.g., C6-C10 aromatic or C6-C10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Carboxaldehyde” refers to a —(C═O)H radical.
“Carboxyl” refers to a —(C═O)OH radical.
“Cyano” refers to a —CN radical.
“Cycloalkyl” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (ie. C2-C10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C3-C5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Ester” refers to a chemical radical of formula —COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
“Halo”, “halide”, or, alternatively, “halogen” means fluoro, chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
“Heteroalkyl” “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given, e.g. C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long. For example, a —CH2OCH2CH3 radical is referred to as a “C4” heteroalkyl, which includes the heteroatom center in the atom chain length description. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain. A heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Heteroaryl” or, alternatively, “heteroaromatic” refers to a 5- to 18-membered aromatic radical (e.g., C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range; e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteraryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Heteroarylalkyl” or “hetarylalkyl” refers to an (heteroaryl)alkyl-radical where heteroaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
“Heterocyclyl” or “heterocycloalkyl” refers to a stable 3- to 18-membered non-aromatic ring (e.g., C3-C18 heterocyclyl) radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range; e.g., “3 to 18 ring atoms” means that the heteroaryl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. In some embodiments, it is a C5-C10 heterocyclyl. In some embodiments, it is a C4-C10 heterocyclyl. In some embodiments, it is a C3-C10 heterocyclyl. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to 6,7-dihydro-5H-cyclopenta[b]pyridine, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocylyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Heteroalicyclic” refers to a cycloalkyl radical that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless stated otherwise specifically in the specification, a heteroalicyclic group is optionally substituted by one or more of substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —ORa, —SRa, —OC(O)—Ra, —N(Ra)2, —C(O)Ra, —C(O)ORa, —C(O)N(Ra)2, —N(Ra)C(O)ORa, —N(Ra)C(O)Ra, —N(Ra)S(O)tRa (where t is 1 or 2), —S(O)tORa (where t is 1 or 2), —S(O)tN(Ra)2 (where t is 1 or 2), —OPO3WY (where W and Y are hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO3Z (where Z is calcium, magnesium or iron) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Imino” refers to the ═N—H radical.
“Isocyanato” refers to a —NCO radical.
“Isothiocyanato” refers to a —NCS radical.
“Mercaptyl” refers to a (alkyl)S— or (H)S— radical.
“Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
“Nitro” refers to the —NO2 radical.
“Oxa” refers to the —O— radical.
“Oxo” refers to the ═O radical.
“Sulfinyl” refers to a —S(═O)—R radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
“Sulfonyl” refers to a —S(═O)2—R radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
“Sulfonamidyl” or “sulfonamido” refers to a —S(═O)2—NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). In some embodiments, it is a C1-C4 sulfonamido, wherein each R in sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4 carbons total. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl respectively
“Sulfoxyl” refers to a —S(═O)2OH radical.
“Sulfonate” refers to a —S(═O)2—OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl respectively.
“Thiocyanato” refers to a —CNS radical.
“Thioxo” refers to the ═S radical.
“Substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, heteroaryl, heterocyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloakyl substituent may have a halide substituted at one or more ring carbons, and the like. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, above.
The compounds presented herein may possess one or more chiral centers and each center may exist in the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns.
The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds having the same type of activity. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
The term “selective inhibition” or “selectively inhibit” as referred to a biologically active agent refers to the agent's ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.
Compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. All formulae disclosed here are shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of the shown formulae and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
“Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space, i.e. having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(.±.)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (−) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
“Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
A “leaving group or atom” is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless otherwise specified are halogen atoms, mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy groups.
“Protecting group” has the meaning conventionally associated with it in organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a hydroxy protected form is where at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group. Likewise, amines and other reactive groups may similarly be protected
A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
The term “co-administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
The term “in vivo” refers to an event that takes place in a subject's body.
The term “in vitro” refers to an event that takes places outside of a subject's body. For example, an in vitro assay encompasses any assay run outside of a subject assay. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.
A “subject,” “individual” or “patient” is used interchangeably herein, which refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells and their progeny of a biological entity obtained in vitro or cultured in vitro are also encompassed.
II. Compositions
In one aspect, the present invention provides a compound of the formula:




or a pharmaceutically acceptable salt thereof, wherein:
X5 and X6 are C—R6, N, C-L1-R1, or N-L1-R1 wherein one of X5 and X6 is C-L1-R1 or N-L1-R1;
X1 is C or N; and X2 and X8 are independently N or C—R6;
X3 and X7 are C or N, and at least one of X3 and X7 is C;
X4 in Formula I-A or I-C is C or N; and X4 in Formula I-B or I-D is C—R6, NH, or N; and no more than two adjacent ring atoms are N or NH;
R1 is hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and n is an integer from 0 to 2;
L1 is a bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
R2 and R3 are independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, heteroalkyl, cycloalkyl, heterocyclyalkyl, aryl, or heteroaryl;
R4 and R5 are independently hydrogen or R6, or R4 and R5 are taken together to form a 5, 6 or 7-membered ring, wherein the 5, 6, or 7 membered ring is optionally substituted with (R6)q;
L is —NH—CR7R8—, —(CR7R8)z—, —C═O—, or —CR7R8(C═O)—, —O—, —SO—, or —SO2—;
z is an integer from 0 to 10;
q is an integer from 0 to 5;
each of R6 is independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R7 and R8 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyalkyl, or R7 and R8 taken together form a cycloalkyl, heterocycloalkyl or aryl ring;
R9 is hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R10 is independently hydrogen, —C(O)R15, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R11 is independently —NR16R17, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R12 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R13 is independently hydrogen, —S(O)nR18, —C(O)R19, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R12 and R13 are taken together to form a 5, 6 or 7-membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR12R13; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R14 is independently —NR20R21, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R15 is independently —NR22R23, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R16 and R17 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R16 and R17 are taken together to form a 5, 6 or 7-membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR16R17; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R18 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R19 is independently —NR24R25, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R20 and R21 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R20 and R21 are taken together to form a 5, 6 or 7-membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR20R21; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each of R22 and R23 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R22 and R23 are taken together to form a 5, 6 or 7-membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR22R23; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each of R24 and R25 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R24 and R25 are taken together to form a 5, 6 or 7-membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR24R25; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted; and
W is C—R6 or N.
In some embodiments, a compound of one of Formula I-A, I-B, I-C, or I-D has a structure of one of the following formulae:




In some embodiments of the invention, the compound of Formula I-E has a structure of Formula I-J or Formula I-K:




In some embodiments, the compound of Formula I-J is a compound of Formula I-J-1:




In some embodiments, the compound of Formula I-E is a compound of Formula II-A, Formula II-A1 or Formula II-A2:




In other embodiments, a compound of Formula I-E has a structure of Formula III-A:




In other embodiments, a compound of Formula I-E has a structure of Formula IV-A:




In some embodiments, W is C—R6. In other embodiments, W is CH. In yet other embodiments W is N.
In another aspect, a compound of the invention has a structure of one of the following formulae:




or a pharmaceutically acceptable salt thereof, wherein:
W is C—R6 or N;
X5 and X6 are C—R6, N, C-L1-R1, or N-L1-R1 wherein one and no more than one of X5 and X6 is C-L1-R1 or N-L1-R1;
X1 is C or N; and X2 and X8 are independently N, or C—R6;
X3 and X7 are C or N, at least one of X3 and X7 is C;
X4 in Formula V-A and Formula V-C is C or N; and X4 in Formula V-B and Formula V-D is C—R6, NH, or N;
and wherein no more than two adjacent ring atoms are N or NH;
R1 is hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and n is an integer from 0 to 2;
L1 is a bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each of R2 and R3 is independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R4 and R5 is independently hydrogen or R6, or R4 and R5 are taken together to form a 5, 6 or 7 membered ring, wherein the 5, 6, or 7 membered ring is optionally substituted with (R6)q;
L is —NH—CR7R8—, —(CR7R8)z—, —C═O—, or —CR7R8(C═O)—, —O—, —SO—, or —SO2—;
z is an integer from 0 to 10;
q is an integer from 0 to 5;
each R6 is independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein n is independently an integer from 0 to 2;
each of R7 and R8 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyalkyl, or R7 and R8 taken together form a cycloalkyl, heterocycloalkyl or aryl ring;
R9 is hydrogen, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R10 is independently hydrogen, —C(O)R15, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R11 is independently —NR16R17, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R12 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R13 is independently hydrogen, —S(O)nR18, —C(O)R19, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
or R12 and R13 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR12R13, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R14 is independently —NR20R21, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R15 is independently —NR22R23, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R16 and R17 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R16 and R17 are taken together to form a 5, 6, 7 or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR16R17, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R18 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R19 is independently —NR24R25, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R20 and R21 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R20 and R21 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR20R21, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each of R22 and R23 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R22 and R23 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR22R23, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted; and
each of R24 and R25 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R24 and R25 are taken together to form a 5, 6, 7, or 8 membered ring wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR24R25, and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted.
In some embodiments, the compound of Formula V-A is a compound having the structure of Formula V-A1:




In some embodiments, the compound of Formula V-A, Formula V-B, Formula V-C or Formula V-D is a compound having a structure of one of the following formulae:




In some embodiments, a compound of Formula VI-A is a compound having a structure of Formula VI-A1 or Formula VI-A2:




In some other embodiments, the compound of Formula V-A, Formula V-B, Formula V-C or Formula V-D is a compound having a structure of one of the following formulae:




In some embodiments, a compound of Formula VI-A is a compound having a structure of Formula VI-A1 or Formula VI-A2:




In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A1, VII-A2, VII-B, VII-C, or VII-D, L is a group of the formula —(CR7R8)z—, where z is an integer from 0 to 10. In some embodiments, z is 1, 2 or 3. For example, z may be 1. Each R7 and R8 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyalkyl, or R7 and R8 taken together form a cycloalkyl, heterocycloalkyl or aryl ring. In some embodiments, L is methylene or ethylene. In other embodiments, L is methylene or ethylene substituted with additional alkyl groups such as methyl, ethyl or isopropyl.
In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, R1 is halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein n is independently an integer from 0 to 2. For example, R1 may be an monocyclic aryl group, that can be substituted or is unsubstituted; a bicyclic aryl group, that can be substituted or unsubstituted; a monocyclic heteroaryl group, that can be substituted or is unsubstituted; or a bicyclic heteroaryl group, that can be substituted or is unsubstituted. In other embodiments, R1 may be a monocyclic heterocycloalkyl group, that can be substituted or is unsubstituted; a bicyclic heterocycloalkyl group, that can be substituted or is unsubstituted; a heteroalkyl group, that can be substituted or is unsubstituted; or an alkyl group, that can be substituted or is unsubstituted. In some embodiments, R1 is substituted with halogen, —CN, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, R1 is an aryl group substituted with —C(O)R14. In other embodiments, R1 is a heteroaryl group substituted with halogen or —NR12R13. When R1 is a monocyclic aromatic or heteroaryl group, substitutions on R1 may be effected, for example, at the ortho, meta and/or para positions. In some embodiments, R1 is monocyclic aryl. In other embodiments, R1 is bicyclic aryl.
Additional examples of R1 groups are illustrated below:










In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, L1 may be a bond or a linker connecting R1 to a heterocyclic moiety of the compounds of the invention. In some embodiments, L1 is a bond. In other embodiments, L1 is an alkylene group.
In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, R4 and R5 are independently hydrogen. Alternatively, R4 and R5 taken together form a 5, 6 or 7-membered ring, unsubstituted or substituted with (R6)q. In some embodiments, R4 and R5 taken together form a 5 or 6-membered unsubstituted or substituted with (R6)q. The ring may be saturated, unsaturated, or partially unsaturated, and may be aromatic or nonaromatic. In some embodiments, the ring is aromatic and substituted by R6. In some embodiments, R4 and R5 taken together form a group having a structure of one of the following formulae:




In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, R6 may be any substituent such as halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein n is independently an integer from 0 to 2. In some embodiments, R6 is halogen. Alternatively, R6 is an alkyl group such as methyl. In further embodiments, R6 is a substituted alkyl group such as CF3.
In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-K, II-A, II-A1, II-A2, III-A, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, R9 may be any cyclic, linear or branched substituent. In some embodiments, R9 is halogen, —CN, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein n is independently an integer from 0 to 2. For example, R9 may be an monocyclic aryl group, substituted or unsubstituted; a bicyclic aryl group, substituted or unsubstituted; a monocyclic heteroaryl group, substituted or unsubstituted; a bicyclic heteroaryl group, substituted or unsubstituted; a monocyclic heterocycloalkyl group, substituted or unsubstituted; a bicyclic heterocycloalkyl group, substituted or unsubstituted; a heteroalkyl group, substituted or unsubstituted; an alkyl group, substituted or unsubstituted. In some embodiments, R9 is substituted with halogen, —CN, OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
In some embodiments, R9 is any of the groups shown below:
















In some embodiments of the compound of Formula I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-J, I-J-1, I-K, II-A, II-A1, II-A2, IV-A, V-A, V-A1, V-B, V-C, V-D, VI-A, VI-A1, VI-A2, VI-B, VI-C, VI-D, VII-A, VII-A1, VII-A2, VII-B, VII-C, or VII-D, R12 and R13 in —NR12R13, R16 and R17 in —NR16R17, R20 and R21 in —NR20R21, R22 and R23 in —NR22R23, or R24 and R25 in —NR24R25, are taken together with the nitrogen atom to which they are attached to form a 5-8 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR12R13, hydroxyl, halogen, oxo, aryl, hetaryl, C1-6alkyl, —C(═O)OC1-6alkyl, —OPO3H2 or —O-aryl, and wherein said 5-8 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms selected from N, O, or S in addition to the nitrogen.
In some embodiments, R12 and R13 in —NR12R13, R16 and R17 in —NR16R17, R20 and R21 in —NR20R21, R22 and R23 in —NR22R23, or R24 and R25 in —NR24R25, are taken together with the nitrogen atom to which they are attached to form a moiety of one of the following formulae:




In some embodiments, the compound of the invention comprises a heterocyclic subunit of the formulas Za or Zb shown below. The symbol  represents the point of attachment to the linker L. In specific embodiments, the point of attachment to the linker L is X4 or the exocyclic amine moiety. Additional substituents may be present at any or several of the X1, X2, X4, X5, and X6 positions. For example, an R1 group as defined above may be connected to X6.







TABLE 1







Heterocyclic subunits of the compounds of the invention


Formula Za








 


Formula Zb








 














Core
X1
X2
X3
X4
X5
X6
X7





Z-1
C
C
C
C
C
C
C


Z-2
C
C
C
N
C
C
C


Z-3
C
C
C
C
C
N
C


Z-4
C
C
C
C
N
C
C


Z-5
C
C
N
C
C
C
C


Z-6
C
C
C
C
C
C
N


Z-7
C
N
C
N
C
C
C


Z-8
C
N
C
C
C
N
C


Z-9
C
N
C
C
N
C
C


Z-10
C
N
N
C
C
C
C


Z-11
C
N
C
C
C
C
N


Z-12
N
C
C
N
C
C
C


Z-13
N
C
C
C
C
N
C


Z-14
N
C
C
C
N
C
C


Z-15
N
C
N
C
C
C
C


Z-16
N
C
C
C
C
C
N


Z-17
C
C
C
C
N
N
C


Z-18
C
C
C
N
N
C
C


Z-19
C
N
C
C
N
N
C


Z-20
C
N
C
N
N
C
C


Z-21
N
C
C
C
N
N
C


Z-22
N
C
C
N
N
C
C


Z-23
N
C
C
C
N
C
N


Z-24
C
N
C
C
N
C
N


Z-25
C
C
C
C
N
C
N


Z-26
C
C
N
C
N
C
C


Z-27
N
C
N
C
N
C
C


Z-28
C
C
N
N
C
C
C





“C” represents —CH═ or >C═, and “N” and represents


—N═, < or —N< or —NH— as required for proper valency. Any illustrated subunit Z may be combined with the embodiments disclosed for R1 through R9, L and W to design a compound of the invention






Non-limiting examples of compounds of the invention are described in more detail in Tables 2-5 below.







TABLE 2







Formula II-A








 


Exemplary compounds of Formula II-A, wherein X represents Cl, Br, or F.













R1
R6
W
R7
R9























No












H
Me
X
C
N
H
Me
Et

























2-1
X


X


X

X


X






2-2
X


X


X

X



X





2-3
X


X


X

X




X




2-4
X


X


X

X





X



2-5
X


X


X

X






X


2-6
X


X


X


X

X






2-7
X


X


X


X


X





2-8
X


X


X


X



X




2-9
X


X


X


X




X



2-10
X


X


X


X





X


2-11
X


X


X



X
X






2-12
X


X


X



X

X





2-13
X


X


X



X


X




2-14
X


X


X



X



X



2-15
X


X


X



X




X


2-16
X


X



X
X


X






2-17
X


X



X
X



X





2-18
X


X



X
X




X




2-19
X


X



X
X





X



2-20
X


X



X
X






X


2-21
X


X



X

X

X






2-22
X


X



X

X


X





2-23
X


X



X

X



X




2-24
X


X



X

X




X



2-25
X


X



X

X





X


2-26
X


X



X


X
X






2-27
X


X



X


X

X





2-28
X


X



X


X


X




2-29
X


X



X


X



X



2-30
X


X



X


X




X


2-31
X



X

X

X


X






2-32
X



X

X

X



X





2-33
X



X

X

X




X




2-34
X



X

X

X





X



2-35
X



X

X

X






X


2-36
X



X

X


X

X






2-37
X



X

X


X


X





2-38
X



X

X


X



X




2-39
X



X

X


X




X



2-40
X



X

X


X





X


2-41
X



X

X



X
X






2-42
X



X

X



X

X





2-43
X



X

X



X


X




2-44
X



X

X



X



X



2-45
X



X

X



X




X


2-46
X



X


X
X


X






2-47
X



X


X
X



X





2-48
X



X


X
X




X




2-49
X



X


X
X





X



2-50
X



X


X
X






X


2-51
X



X


X

X

X






2-52
X



X


X

X


X





2-53
X



X


X

X



X




2-54
X



X


X

X




X



2-55
X



X


X

X





X


2-56
X



X


X


X
X






2-57
X



X


X


X

X





2-58
X



X


X


X


X




2-59
X



X


X


X



X



2-60
X



X


X


X




X


2-61
X




X
X

X


X






2-62
X




X
X

X



X





2-63
X




X
X

X




X




2-64
X




X
X

X





X



2-65
X




X
X

X






X


2-66
X




X
X


X

X






2-67
X




X
X


X


X





2-68
X




X
X


X



X




2-69
X




X
X


X




X



2-70
X




X
X


X





X


2-71
X




X
X



X
X






2-72
X




X
X



X

X





2-73
X




X
X



X


X




2-74
X




X
X



X



X



2-75
X




X
X



X




X


2-76
X




X

X
X


X






2-77
X




X

X
X



X





2-78
X




X

X
X




X




2-79
X




X

X
X





X



2-80
X




X

X
X






X


2-81
X




X

X

X

X






2-82
X




X

X

X


X





2-83
X




X

X

X



X




2-84
X




X

X

X




X



2-85
X




X

X

X





X


2-86
X




X

X


X
X






2-87
X




X

X


X

X





2-88
X




X

X


X


X




2-89
X




X

X


X



X



2-90
X




X

X


X




X


2-91

X

X


X

X


X






2-92

X

X


X

X



X





2-93

X

X


X

X




X




2-94

X

X


X

X





X



2-95

X

X


X

X






X


2-96

X

X


X


X

X






2-97

X

X


X


X


X





2-98

X

X


X


X



X




2-99

X

X


X


X




X



2-100

X

X


X


X





X


2-101

X

X


X



X
X






2-102

X

X


X



X

X





2-103

X

X


X



X


X




2-104

X

X


X



X



X



2-105

X

X


X



X




X


2-106

X

X



X
X


X






2-107

X

X



X
X



X





2-108

X

X



X
X




X




2-109

X

X



X
X





X



2-110

X

X



X
X






X


2-111

X

X



X

X

X






2-112

X

X



X

X


X





2-113

X

X



X

X



X




2-114

X

X



X

X




X



2-115

X

X



X

X





X


2-116

X

X



X


X
X






2-117

X

X



X


X

X





2-118

X

X



X


X


X




2-119

X

X



X


X



X



2-120

X

X



X


X




X


2-121

X


X

X

X


X






2-122

X


X

X

X



X





2-123

X


X

X

X




X




2-124

X


X

X

X





X



2-125

X


X

X

X






X


2-126

X


X

X


X

X






2-127

X


X

X


X


X





2-128

X


X

X


X



X




2-129

X


X

X


X




X



2-130

X


X

X


X





X


2-131

X


X

X



X
X






2-132

X


X

X



X

X





2-133

X


X

X



X


X




2-134

X


X

X



X



X



2-135

X


X

X



X




X


2-136

X


X


X
X


X






2-137

X


X


X
X



X





2-138

X


X


X
X




X




2-139

X


X


X
X





X



2-140

X


X


X
X






X


2-141

X


X


X

X

X






2-142

X


X


X

X


X





2-143

X


X


X

X



X




2-144

X


X


X

X




X



2-145

X


X


X

X





X


2-146

X


X


X


X
X






2-147

X


X


X


X

X





2-148

X


X


X


X


X




2-149

X


X


X


X



X



2-150

X


X


X


X




X


2-151

X



X
X

X


X






2-152

X



X
X

X



X





2-153

X



X
X

X




X




2-154

X



X
X

X





X



2-155

X



X
X

X






X


2-156

X



X
X


X

X






2-157

X



X
X


X


X





2-158

X



X
X


X



X




2-159

X



X
X


X




X



2-160

X



X
X


X





X


2-161

X



X
X



X
X






2-162

X



X
X



X

X





2-163

X



X
X



X


X




2-164

X



X
X



X



X



2-165

X



X
X



X




X


2-166

X



X

X
X


X






2-167

X



X

X
X



X





2-168

X



X

X
X




X




2-169

X



X

X
X





X



2-170

X



X

X
X






X


2-171

X



X

X

X

X






2-172

X



X

X

X


X





2-173

X



X

X

X



X




2-174

X



X

X

X




X



2-175

X



X

X

X





X


2-176

X



X

X


X
X






2-177

X



X

X


X

X





2-178

X



X

X


X


X




2-179

X



X

X


X



X



2-180

X



X

X


X




X


2-181


X
X


X

X


X






2-182


X
X


X

X



X





2-183


X
X


X

X




X




2-184


X
X


X

X





X



2-185


X
X


X

X






X


2-186


X
X


X


X

X






2-187


X
X


X


X


X





2-188


X
X


X


X



X




2-189


X
X


X


X




X



2-190


X
X


X


X





X


2-191


X
X


X



X
X






2-192


X
X


X



X

X





2-193


X
X


X



X


X




2-194


X
X


X



X



X



2-195


X
X


X



X




X


2-196


X
X



X
X


X






2-197


X
X



X
X



X





2-198


X
X



X
X




X




2-199


X
X



X
X





X



2-200


X
X



X
X






X


2-201


X
X



X

X

X






2-202


X
X



X

X


X





2-203


X
X



X

X



X




2-204


X
X



X

X




X



2-205


X
X



X

X





X


2-206


X
X



X


X
X






2-207


X
X



X


X

X





2-208


X
X



X


X


X




2-209


X
X



X


X



X



2-210


X
X



X


X




X


2-211


X

X

X

X


X






2-212


X

X

X

X



X





2-213


X

X

X

X




X




2-214


X

X

X

X





X



2-215


X

X

X

X






X


2-216


X

X

X


X

X






2-217


X

X

X


X


X





2-218


X

X

X


X



X




2-219


X

X

X


X




X



2-220


X

X

X


X





X


2-221


X

X

X



X
X






2-222


X

X

X



X

X





2-223


X

X

X



X


X




2-224


X

X

X



X



X



2-225


X

X

X



X




X


2-226


X

X


X
X


X






2-227


X

X


X
X



X





2-228


X

X


X
X




X




2-229


X

X


X
X





X



2-230


X

X


X
X






X


2-231


X

X


X

X

X






2-232


X

X


X

X


X





2-233


X

X


X

X



X




2-234


X

X


X

X




X



2-235


X

X


X

X





X


2-236


X

X


X


X
X






2-237


X

X


X


X

X





2-238


X

X


X


X


X




2-239


X

X


X


X



X



2-240


X

X


X


X




X


2-241


X


X
X

X


X






2-242


X


X
X

X



X





2-243


X


X
X

X




X




2-244


X


X
X

X





X



2-245


X


X
X

X






X


2-246


X


X
X


X

X






2-247


X


X
X


X


X





2-248


X


X
X


X



X




2-249


X


X
X


X




X



2-250


X


X
X


X





X


2-251


X


X
X



X
X






2-252


X


X
X



X

X





2-253


X


X
X



X


X




2-254


X


X
X



X



X



2-255


X


X
X



X




X


2-256


X


X
X
X



X






2-257


X


X
X
X




X





2-258


X


X
X
X





X




2-259


X


X
X
X






X



2-260


X


X
X
X







X


2-261


X


X
X

X


X






2-262


X


X
X

X



X





2-263


X


X
X

X




X




2-264


X


X
X

X





X



2-265


X


X
X

X






X


2-266


X


X
X


X

X






2-267


X


X
X


X


X





2-268


X


X
X


X



X




2-269


X


X
X


X




X



2-270


X


X
X


X





X
















R1
R6
W
R7
R9























No












H
Me
X
C
N
H
Me
Et

























2-271
X


X


X

X


X






2-272
X


X


X

X



X





2-273
X


X


X

X




X




2-274
X


X


X

X





X



2-275
X


X


X

X






X


2-276
X


X


X


X

X






2-277
X


X


X


X


X





2-278
X


X


X


X



X




2-279
X


X


X


X




X



2-280
X


X


X


X





X


2-281
X


X


X



X
X






2-282
X


X


X



X

X





2-283
X


X


X



X


X




2-284
X


X


X



X



X



2-285
X


X


X



X




X


2-286
X


X



X
X


X






2-287
X


X



X
X



X





2-288
X


X



X
X




X




2-289
X


X



X
X





X



2-290
X


X



X
X






X


2-291
X


X



X

X

X






2-292
X


X



X

X


X





2-293
X


X



X

X



X




2-294
X


X



X

X




X



2-295
X


X



X

X





X


2-296
X


X



X


X
X






2-297
X


X



X


X

X





2-298
X


X



X


X


X




2-299
X


X



X


X



X



2-300
X


X



X


X




X


2-301
X



X

X

X


X






2-302
X



X

X

X



X





2-303
X



X

X

X




X




2-304
X



X

X

X





X



2-305
X



X

X

X






X


2-306
X



X

X


X

X






2-307
X



X

X


X


X





2-308
X



X

X


X



X




2-309
X



X

X


X




X



2-310
X



X

X


X





X


2-311
X



X

X



X
X






2-312
X



X

X



X

X





2-313
X



X

X



X


X




2-314
X



X

X



X



X



2-315
X



X

X



X




X


2-316
X



X


X
X


X






2-317
X



X


X
X



X





2-318
X



X


X
X




X




2-319
X



X


X
X





X



2-320
X



X


X
X






X


2-321
X



X


X

X

X






2-322
X



X


X

X


X





2-323
X



X


X

X



X




2-324
X



X


X

X




X



2-325
X



X


X

X





X


2-326
X



X


X


X
X






2-327
X



X


X


X

X





2-328
X



X


X


X


X




2-329
X



X


X


X



X



2-330
X



X


X


X




X


2-331
X




X
X

X


X






2-332
X




X
X

X



X





2-333
X




X
X

X




X




2-334
X




X
X

X





X



2-335
X




X
X

X






X


2-336
X




X
X


X

X






2-337
X




X
X


X


X





2-338
X




X
X


X



X




2-339
X




X
X


X




X



2-340
X




X
X


X





X


2-341
X




X
X



X
X






2-342
X




X
X



X

X





2-343
X




X
X



X


X




2-344
X




X
X



X



X



2-345
X




X
X



X




X


2-346
X




X

X
X


X






2-347
X




X

X
X



X





2-348
X




X

X
X




X




2-349
X




X

X
X





X



2-350
X




X

X
X






X


2-351
X




X

X

X

X






2-352
X




X

X

X


X





2-353
X




X

X

X



X




2-354
X




X

X

X




X



2-355
X




X

X

X





X


2-356
X




X

X


X
X






2-357
X




X

X


X

X





2-358
X




X

X


X


X




2-359
X




X

X


X



X



2-360
X




X

X


X




X


2-361

X

X


X

X


X






2-362

X

X


X

X



X





2-363

X

X


X

X




X




2-364

X

X


X

X





X



2-365

X

X


X

X






X


2-366

X

X


X


X

X






2-367

X

X


X


X


X





2-368

X

X


X


X



X




2-369

X

X


X


X




X



2-370

X

X


X


X





X


2-371

X

X


X



X
X






2-372

X

X


X



X

X





2-373

X

X


X



X


X




2-374

X

X


X



X



X



2-375

X

X


X



X




X


2-376

X

X



X
X


X






2-377

X

X



X
X



X





2-378

X

X



X
X




X




2-379

X

X



X
X





X



2-380

X

X



X
X






X


2-381

X

X



X

X

X






2-382

X

X



X

X


X





2-383

X

X



X

X



X




2-384

X

X



X

X




X



2-385

X

X



X

X





X


2-386

X

X



X


X
X






2-387

X

X



X


X

X





2-388

X

X



X


X


X




2-389

X

X



X


X



X



2-390

X

X



X


X




X


2-391

X


X

X

X


X






2-392

X


X

X

X



X





2-393

X


X

X

X




X




2-394

X


X

X

X





X



2-395

X


X

X

X






X


2-396

X


X

X


X

X






2-397

X


X

X


X


X





2-398

X


X

X


X



X




2-399

X


X

X


X




X



2-400

X


X

X


X





X


2-401

X


X

X



X
X






2-402

X


X

X



X

X





2-403

X


X

X



X


X




2-404

X


X

X



X



X



2-405

X


X

X



X




X


2-406

X


X


X
X


X






2-407

X


X


X
X



X





2-408

X


X


X
X




X




2-409

X


X


X
X





X



2-410

X


X


X
X






X


2-411

X


X


X

X

X






2-412

X


X


X

X


X





2-413

X


X


X

X



X




2-414

X


X


X

X




X



2-415

X


X


X

X





X


2-416

X


X


X


X
X






2-417

X


X


X


X

X





2-418

X


X


X


X


X




2-419

X


X


X


X



X



2-420

X


X


X


X




X


2-421

X



X
X

X


X






2-422

X



X
X

X



X





2-423

X



X
X

X




X




2-424

X



X
X

X





X



2-425

X



X
X

X






X


2-426

X



X
X


X

X






2-427

X



X
X


X


X





2-428

X



X
X


X



X




2-429

X



X
X


X




X



2-430

X



X
X


X





X


2-431

X



X
X



X
X






2-432

X



X
X



X

X





2-433

X



X
X



X


X




2-434

X



X
X



X



X



2-435

X



X
X



X




X


2-436

X



X

X
X


X






2-437

X



X

X
X



X





2-438

X



X

X
X




X




2-439

X



X

X
X





X



2-440

X



X

X
X






X


2-441

X



X

X

X

X






2-442

X



X

X

X


X





2-443

X



X

X

X



X




2-444

X



X

X

X




X



2-445

X



X

X

X





X


2-446

X



X

X


X
X






2-447

X



X

X


X

X





2-448

X



X

X


X


X




2-449

X



X

X


X



X



2-450

X



X

X


X




X


2-451


X
X


X

X


X






2-452


X
X


X

X



X





2-453


X
X


X

X




X




2-454


X
X


X

X





X



2-455


X
X


X

X






X


2-456


X
X


X


X

X






2-457


X
X


X


X


X





2-458


X
X


X


X



X




2-459


X
X


X


X




X



2-460


X
X


X


X





X


2-461


X
X


X



X
X






2-462


X
X


X



X

X





2-463


X
X


X



X


X




2-464


X
X


X



X



X



2-465


X
X


X



X




X


2-466


X
X



X
X


X






2-467


X
X



X
X



X





2-468


X
X



X
X




X




2-469


X
X



X
X





X



2-470


X
X



X
X






X


2-471


X
X



X

X

X






2-472


X
X



X

X


X





2-473


X
X



X

X



X




2-474


X
X



X

X




X



2-475


X
X



X

X





X


2-476


X
X



X


X
X






2-477


X
X



X


X

X





2-478


X
X



X


X


X




2-479


X
X



X


X



X



2-480


X
X



X


X




X


2-481


X

X

X

X


X






2-482


X

X

X

X



X





2-483


X

X

X

X




X




2-484


X

X

X

X





X



2-485


X

X

X

X






X


2-486


X

X

X


X

X






2-487


X

X

X


X


X





2-488


X

X

X


X



X




2-489


X

X

X


X




X



2-490


X

X

X


X





X


2-491


X

X

X



X
X






2-492


X

X

X



X

X





2-493


X

X

X



X


X




2-494


X

X

X



X



X



2-495


X

X

X



X




X


2-496


X

X


X
X


X






2-497


X

X


X
X



X





2-498


X

X


X
X




X




2-499


X

X


X
X





X



2-500


X

X


X
X






X


2-501


X

X


X

X

X






2-502


X

X


X

X


X





2-503


X

X


X

X



X




2-504


X

X


X

X




X



2-505


X

X


X

X





X


2-506


X

X


X


X
X






2-507


X

X


X


X

X





2-508


X

X


X


X


X




2-509


X

X


X


X



X



2-510


X

X


X


X




X


2-511


X


X
X

X


X






2-512


X


X
X

X



X





2-513


X


X
X

X




X




2-514


X


X
X

X





X



2-515


X


X
X

X






X


2-516


X


X
X


X

X






2-517


X


X
X


X


X





2-518


X


X
X


X



X




2-519


X


X
X


X




X



2-520


X


X
X


X





X


2-521


X


X
X



X
X






2-522


X


X
X



X

X





2-523


X


X
X



X


X




2-524


X


X
X



X



X



2-525


X


X
X



X




X


2-526


X


X

X
X


X






2-527


X


X

X
X



X





2-528


X


X

X
X




X




2-529


X


X

X
X





X



2-530


X


X

X
X






X


2-531


X


X

X

X

X






2-532


X


X

X

X


X





2-533


X


X

X

X



X




2-534


X


X

X

X




X



2-535


X


X

X

X





X


2-536


X


X

X


X
X






2-537


X


X

X


X

X





2-538


X


X

X


X


X




2-539


X


X

X


X



X



2-540


X


X

X


X




X
















TABLE 3





Exemplary compounds of the invention of Formula III-A, wherein X represents a halo group (Cl, Br, I or F).


Formula III-A


























R1
W
R7
R9




















              No








        



              C
              N
              H
              Me
              Et
      







      



      












3-1
X


X

X


X






3-2
X


X

X



X





3-3
X


X

X




X




3-4
X


X

X





X



3-5
X


X

X






X


3-6
X


X


X

X






3-7
X


X


X


X





3-8
X


X


X



X




3-9
X


X


X




X



3-10
X


X


X





X


3-11
X


X



X
X






3-12
X


X



X

X





3-13
X


X



X


X




3-14
X


X



X



X



3-15
X


X



X




X


3-16
X



X
X


X






3-17
X



X
X



X





3-18
X



X
X




X




3-19
X



X
X





X



3-20
X



X
X






X


3-21
X



X

X

X






3-22
X



X

X


X





3-23
X



X

X



X




3-24
X



X

X




X



3-25
X



X

X





X


3-26
X



X


X
X






3-27
X



X


X

X





3-28
X



X


X


X




3-29
X



X


X



X



3-30
X



X


X




X


3-31
X


X

X


X






3-32
X


X

X



X





3-33
X


X

X




X




3-34
X


X

X





X



3-35
X


X

X






X


3-36
X


X


X

X






3-37
X


X


X


X





3-38
X


X


X



X




3-39
X


X


X




X



3-40
X


X


X





X


3-41
X


X



X
X






3-42
X


X



X

X





3-43
X


X



X


X




3-44
X


X



X



X



3-45
X


X



X




X


3-46
X



X
X


X






3-47
X



X
X



X





3-48
X



X
X




X




3-49
X



X
X





X



3-50
X



X
X






X


3-51
X



X

X

X






3-52
X



X

X


X





3-53
X



X

X



X




3-54
X



X

X




X



3-55
X



X

X





X


3-56
X



X


X
X






3-57
X



X


X

X





3-58
X



X


X


X




3-59
X



X


X



X



3-60
X



X


X




X


3-61
X


X

X


X






3-62
X


X

X



X





3-63
X


X

X




X




3-64
X


X

X





X



3-65
X


X

X






X


3-66
X


X


X

X






3-67
X


X


X


X





3-68
X


X


X



X




3-69
X


X


X




X



3-70
X


X


X





X


3-71
X


X



X
X






3-72
X


X



X

X





3-73
X


X



X


X




3-74
X


X



X



X



3-75
X


X



X




X


3-76
X



X
X


X






3-77
X



X
X



X





3-78
X



X
X




X




3-79
X



X
X





X



3-80
X



X
X






X


3-81
X



X

X

X






3-82
X



X

X


X





3-83
X



X

X



X




3-84
X



X

X




X



3-85
X



X

X





X


3-86
X



X


X
X






3-87
X



X


X

X





3-88
X



X


X


X




3-89
X



X


X



X



3-90
X



X


X




X


3-91

X

X

X


X






3-92

X

X

X



X





3-93

X

X

X




X




3-94

X

X

X





X



3-95

X

X

X






X


3-96

X

X


X

X






3-97

X

X


X


X





3-98

X

X


X



X




3-99

X

X


X




X



3-100

X

X


X





X


3-101

X

X



X
X






3-102

X

X



X

X





3-103

X

X



X


X




3-104

X

X



X



X



3-105

X

X



X




X


3-106

X


X
X


X






3-107

X


X
X



X





3-108

X


X
X




X




3-109

X


X
X





X



3-110

X


X
X






X


3-111

X


X

X

X






3-112

X


X

X


X





3-113

X


X

X



X




3-114

X


X

X




X



3-115

X


X

X





X


3-116

X


X


X
X






3-117

X


X


X

X





3-118

X


X


X


X




3-119

X


X


X



X



3-120

X


X


X




X


3-121

X

X

X


X






3-122

X

X

X



X





3-123

X

X

X




X




3-124

X

X

X





X



3-125

X

X

X






X


3-126

X

X


X

X






3-127

X

X


X


X





3-128

X

X


X



X




3-129

X

X


X




X



3-130

X

X


X





X


3-131

X

X



X
X






3-132

X

X



X

X





3-133

X

X



X


X




3-134

X

X



X



X



3-135

X

X



X




X


3-136

X


X
X


X






3-137

X


X
X



X





3-138

X


X
X




X




3-139

X


X
X





X



3-140

X


X
X






X


3-141

X


X

X

X






3-142

X


X

X


X





3-143

X


X

X



X




3-144

X


X

X




X



3-145

X


X

X





X


3-146

X


X


X
X






3-147

X


X


X

X





3-148

X


X


X


X




3-149

X


X


X



X



3-150

X


X


X




X


3-151

X

X

X


X






3-152

X

X

X



X





3-153

X

X

X




X




3-154

X

X

X





X



3-155

X

X

X






X


3-156

X

X


X

X






3-157

X

X


X


X





3-158

X

X


X



X




3-159

X

X


X




X



3-160

X

X


X





X


3-161

X

X



X
X






3-162

X

X



X

X





3-163

X

X



X


X




3-164

X

X



X



X



3-165

X

X



X




X


3-166

X


X
X


X






3-167

X


X
X



X





3-168

X


X
X




X




3-169

X


X
X





X



3-170

X


X
X






X


3-171

X


X

X

X






3-172

X


X

X


X





3-173

X


X

X



X




3-174

X


X

X




X



3-175

X


X

X





X


3-176

X


X


X
X






3-177

X


X


X

X





3-178

X


X


X


X




3-179

X


X


X



X



3-180

X


X


X




X


3-181


X
X

X


X






3-182


X
X

X



X





3-183


X
X

X




X




3-184


X
X

X





X



3-185


X
X

X






X


3-186


X
X


X

X






3-187


X
X


X


X





3-188


X
X


X



X




3-189


X
X


X




X



3-190


X
X


X





X


3-191


X
X



X
X






3-192


X
X



X

X





3-193


X
X



X


X




3-194


X
X



X



X



3-195


X
X



X




X


3-196


X

X
X


X






3-197


X

X
X



X





3-198


X

X
X




X




3-199


X

X
X





X



3-200


X

X
X






X


3-201


X

X

X

X






3-202


X

X

X


X





3-203


X

X

X



X




3-204


X

X

X




X



3-205


X

X

X





X


3-206


X

X


X
X






3-207


X

X


X

X





3-208


X

X


X


X




3-209


X

X


X



X



3-210


X

X


X




X


3-211


X
X

X


X






3-212


X
X

X



X





3-213


X
X

X




X




3-214


X
X

X





X



3-215


X
X

X






X


3-216


X
X


X

X






3-217


X
X


X


X





3-218


X
X


X



X




3-219


X
X


X




X



3-220


X
X


X





X


3-221


X
X




X






3-222


X
X





X





3-223


X
X






X




3-224


X
X







X



3-225


X
X








X


3-226


X

X
X


X






3-227


X

X
X



X





3-228


X

X
X




X




3-229


X

X
X





X



3-230


X

X
X






X


3-231


X

X

X

X






3-232


X

X

X


X





3-233


X

X

X



X




3-234


X

X

X




X



3-235


X

X

X





X


3-236


X

X


X
X






3-237


X

X


X

X





3-238


X

X


X


X




3-239


X

X


X



X



3-240


X

X


X




X


3-241


X
X

X


X






3-242


X
X

X



X





3-243


X
X

X




X




3-244


X
X

X





X



3-245


X
X

X






X


3-246


X
X


X

X






3-247


X
X


X


X





3-248


X
X


X



X




3-249


X
X


X




X



3-250


X
X


X





X


3-251


X
X



X
X






3-252


X
X



X

X





3-253


X
X



X


X




3-254


X
X



X



X



3-255


X
X



X




X


3-256


X

X
X


X






3-257


X

X
X



X





3-258


X

X
X




X




3-259


X

X
X





X



3-260


X

X
X






X


3-261


X

X

X

X






3-262


X

X

X


X





3-263


X

X

X



X




3-264


X

X

X




X



3-265


X

X

X





X


3-266


X

X


X
X






3-267


X

X


X

X





3-268


X

X


X


X




3-269


X

X


X



X



3-270


X

X


X




X















R1
W
R7
R9




















              No








        



              C
              N
              H
              Me
              Et
    



      







    



      








3-271
X


X

X


X






3-272
X


X

X



X





3-273
X


X

X




X




3-274
X


X

X





X



3-275
X


X

X






X


3-276
X


X


X

X






3-277
X


X


X


X





3-278
X


X


X



X




3-279
X


X


X




X



3-280
X


X


X





X


3-281
X


X



X
X






3-282
X


X



X

X





3-283
X


X



X


X




3-284
X


X



X



X



3-285
X


X



X




X


3-286
X



X
X


X






3-287
X



X
X



X





3-288
X



X
X




X




3-289
X



X
X





X



3-290
X



X
X






X


3-291
X



X

X

X






3-292
X



X

X


X





3-293
X



X

X



X




3-294
X



X

X




X



3-295
X



X

X





X


3-296
X



X


X
X






3-297
X



X


X

X





3-298
X



X


X


X




3-299
X



X


X



X



3-300
X



X


X




X


3-301
X


X

X


X






3-302
X


X

X



X





3-303
X


X

X




X




3-304
X


X

X





X



3-305
X


X

X






X


3-306
X


X


X

X






3-307
X


X


X


X





3-308
X


X


X



X




3-309
X


X


X




X



3-310
X


X


X





X


3-311
X


X



X
X






3-312
X


X



X

X





3-313
X


X



X


X




3-314
X


X



X



X



3-315
X


X



X




X


3-316
X



X
X


X






3-317
X



X
X



X





3-318
X



X
X




X




3-319
X



X
X





X



3-320
X



X
X






X


3-321
X



X

X

X






3-322
X



X

X


X





3-323
X



X

X



X




3-324
X



X

X




X



3-325
X



X

X





X


3-326
X



X


X
X






3-327
X



X


X

X





3-328
X



X


X


X




3-329
X



X


X



X



3-330
X



X


X




X


3-331
X


X

X


X






3-332
X


X

X



X





3-333
X


X

X




X




3-334
X


X

X





X



3-335
X


X

X






X


3-336
X


X


X

X






3-337
X


X


X


X





3-338
X


X


X



X




3-339
X


X


X




X



3-340
X


X


X





X


3-341
X


X



X
X






3-342
X


X



X

X





3-343
X


X



X


X




3-344
X


X



X



X



3-345
X


X



X




X


3-346
X



X
X


X






3-347
X



X
X



X





3-348
X



X
X




X




3-349
X



X
X





X



3-350
X



X
X






X


3-351
X



X

X

X






3-352
X



X

X


X





3-353
X



X

X



X




3-354
X



X

X




X



3-355
X



X

X





X


3-356
X



X


X
X






3-357
X



X


X

X





3-358
X



X


X


X




3-359
X



X


X



X



3-360
X



X


X




X


3-361

X

X

X


X






3-362

X

X

X



X





3-363

X

X

X




X




3-364

X

X

X





X



3-365

X

X

X






X


3-366

X

X


X

X






3-367

X

X


X


X





3-368

X

X


X



X




3-369

X

X


X




X



3-370

X

X


X





X


3-371

X

X



X
X






3-372

X

X



X

X





3-373

X

X



X


X




3-374

X

X



X



X



3-375

X

X



X




X


3-376

X


X
X


X






3-377

X


X
X



X





3-378

X


X
X




X




3-379

X


X
X





X



3-380

X


X
X






X


3-381

X


X

X

X






3-382

X


X

X


X





3-383

X


X

X



X




3-384

X


X

X




X



3-385

X


X

X





X


3-386

X


X


X
X






3-387

X


X


X

X





3-388

X


X


X


X




3-389

X


X


X



X



3-390

X


X


X




X


3-391

X

X

X


X






3-392

X

X

X



X





3-393

X

X

X




X




3-394

X

X

X





X



3-395

X

X

X






X


3-396

X

X


X

X






3-397

X

X


X


X





3-398

X

X


X



X




3-399

X

X


X




X



3-400

X

X


X





X


3-401

X

X



X
X






3-402

X

X



X

X





3-403

X

X



X


X




3-404

X

X



X



X



3-405

X

X



X




X


3-406

X


X
X


X






3-407

X


X
X



X





3-408

X


X
X




X




3-409

X


X
X





X



3-410

X


X
X






X


3-411

X


X

X

X






3-412

X


X

X


X





3-413

X


X

X



X




3-414

X


X

X




X



3-415

X


X

X





X


3-416

X


X


X
X






3-417

X


X


X

X





3-418

X


X


X


X




3-419

X


X


X



X



3-420

X


X


X




X


3-421

X

X

X


X






3-422

X

X

X



X





3-423

X

X

X




X




3-424

X

X

X





X



3-425

X

X

X






X


3-426

X

X


X

X






3-427

X

X


X


X





3-428

X

X


X



X




3-429

X

X


X




X



3-430

X

X


X





X


3-431

X

X



X
X






3-432

X

X



X

X





3-433

X

X



X


X




3-434

X

X



X



X



3-435

X

X



X




X


3-436

X


X
X


X






3-437

X


X
X



X





3-438

X


X
X




X




3-439

X


X
X





X



3-440

X


X
X






X


3-441

X


X

X

X






3-442

X


X

X


X





3-443

X


X

X



X




3-444

X


X

X




X



3-445

X


X

X





X


3-446

X


X


X
X






3-447

X


X


X

X





3-448

X


X


X


X




3-449

X


X


X



X



3-450

X


X


X




X


3-451


X
X

X


X






3-452


X
X

X



X





3-453


X
X

X




X




3-454


X
X

X





X



3-455


X
X

X






X


3-456


X
X


X

X






3-457


X
X


X


X





3-458


X
X


X



X




3-459


X
X


X




X



3-460


X
X


X





X


3-461


X
X



X
X






3-462


X
X



X

X





3-463


X
X



X


X




3-464


X
X



X



X



3-465


X
X



X




X


3-466


X

X
X


X






3-467


X

X
X



X





3-468


X

X
X




X




3-469


X

X
X





X



3-470


X

X
X






X


3-471


X

X

X

X






3-472


X

X

X


X





3-473


X

X

X



X




3-474


X

X

X




X



3-475


X

X

X





X


3-476


X

X


X
X






3-477


X

X


X

X





3-478


X

X


X


X




3-479


X

X


X



X



3-480


X

X


X




X


3-481


X
X

X


X






3-482


X
X

X



X





3-483


X
X

X




X




3-484


X
X

X





X



3-485


X
X

X






X


3-486


X
X


X

X






3-487


X
X


X


X





3-488


X
X


X



X




3-489


X
X


X




X



3-490


X
X


X





X


3-491


X
X



X
X






3-492


X
X



X

X





3-493


X
X



X


X




3-494


X
X



X



X



3-495


X
X



X




X


3-496


X

X
X


X






3-497


X

X
X



X





3-498


X

X
X




X




3-499


X

X
X





X



3-500


X

X
X






X


3-501


X

X

X

X






3-502


X

X

X


X





3-503


X

X

X



X




3-504


X

X

X




X



3-505


X

X

X





X


3-506


X

X


X
X






3-507


X

X


X

X





3-508


X

X


X


X




3-509


X

X


X



X



3-510


X

X


X




X


3-511


X
X

X


X






3-512


X
X

X



X





3-513


X
X

X




X




3-514


X
X

X





X



3-515


X
X

X






X


3-516


X
X


X

X






3-517


X
X


X


X





3-518


X
X


X



X




3-519


X
X


X




X



3-520


X
X


X





X


3-521


X
X



X
X






3-522


X
X



X

X





3-523


X
X



X


X




3-524


X
X



X



X



3-525


X
X



X




X


3-526


X

X
X


X






3-527


X

X
X



X





3-528


X

X
X




X




3-529


X

X
X





X



3-530


X

X
X






X


3-531


X

X

X

X






3-532


X

X

X


X





3-533


X

X

X



X




3-534


X

X

X




X



3-535


X

X

X





X


3-536


X

X


X
X






3-537


X

X


X

X





3-538


X

X


X


X




3-539


X

X


X



X



3-540


X

X


X




X
















TABLE 4





Exemplary compounds of the invention of Formula IV-A. X represents a halo group (Cl, Br, I or F).


Formula IV-A


























R1
W
R7
R9




















No












C
N
H
Me
Et

























4-1
X


X

X


X






4-2
X


X

X



X





4-3
X


X

X




X




4-4
X


X

X





X



4-5
X


X

X






X


4-6
X


X


X

X






4-7
X


X


X


X





4-8
X


X


X



X




4-9
X


X


X




X



4-10
X


X


X





X


4-11
X


X



X
X






4-12
X


X



X

X





4-13
X


X



X


X




4-14
X


X



X



X



4-15
X


X



X




X


4-16
X



X
X


X






4-17
X



X
X



X





4-18
X



X
X




X




4-19
X



X
X





X



4-20
X



X
X






X


4-21
X



X

X

X






4-22
X



X

X


X





4-23
X



X

X



X




4-24
X



X

X




X



4-25
X



X

X





X


4-26
X



X


X
X






4-27
X



X


X

X





4-28
X



X


X


X




4-29
X



X


X



X



4-30
X



X


X




X


4-31
X


X

X


X






4-32
X


X

X



X





4-33
X


X

X




X




4-34
X


X

X





X



4-35
X


X

X






X


4-36
X


X


X

X






4-37
X


X


X


X





4-38
X


X


X



X




4-39
X


X


X




X



4-40
X


X


X





X


4-41
X


X



X
X






4-42
X


X



X

X





4-43
X


X



X


X




4-44
X


X



X



X



4-45
X


X



X




X


4-46
X



X
X


X






4-47
X



X
X



X





4-48
X



X
X




X




4-49
X



X
X





X



4-50
X



X
X






X


4-51
X



X

X

X






4-52
X



X

X


X





4-53
X



X

X



X




4-54
X



X

X




X



4-55
X



X

X





X


4-56
X



X


X
X






4-57
X



X


X

X





4-58
X



X


X


X




4-59
X



X


X



X



4-60
X



X


X




X


4-61
X


X

X


X






4-62
X


X

X



X





4-63
X


X

X




X




4-64
X


X

X





X



4-65
X


X

X






X


4-66
X


X


X

X






4-67
X


X


X


X





4-68
X


X


X



X




4-69
X


X


X




X



4-70
X


X


X





X


4-71
X


X



X
X






4-72
X


X



X

X





4-73
X


X



X


X




4-74
X


X



X



X



4-75
X


X



X




X


4-76
X



X
X


X






4-77
X



X
X



X





4-78
X



X
X




X




4-79
X



X
X





X



4-80
X



X
X






X


4-81
X



X

X

X






4-82
X



X

X


X





4-83
X



X

X



X




4-84
X



X

X




X



4-85
X



X

X





X


4-86
X



X


X
X






4-87
X



X


X

X





4-88
X



X


X


X




4-89
X



X


X



X



4-90
X



X


X




X


4-91

X

X

X


X






4-92

X

X

X



X





4-93

X

X

X




X




4-94

X

X

X





X



4-95

X

X

X






X


4-96

X

X


X

X






4-97

X

X


X


X





4-98

X

X


X



X




4-99

X

X


X




X



4-100

X

X


X





X


4-101

X

X



X
X






4-102

X

X



X

X





4-103

X

X



X


X




4-104

X

X



X



X



4-105

X

X



X




X


4-106

X


X
X


X






4-107

X


X
X



X





4-108

X


X
X




X




4-109

X


X
X





X



4-110

X


X
X






X


4-111

X


X

X

X






4-112

X


X

X


X





4-113

X


X

X



X




4-114

X


X

X




X



4-115

X


X

X





X


4-116

X


X


X
X






4-117

X


X


X

X





4-118

X


X


X


X




4-119

X


X


X



X



4-120

X


X


X




X


4-121

X

X

X


X






4-122

X

X

X



X





4-123

X

X

X




X




4-124

X

X

X





X



4-125

X

X

X






X


4-126

X

X


X

X






4-127

X

X


X


X





4-128

X

X


X



X




4-129

X

X


X




X



4-130

X

X


X





X


4-131

X

X



X
X






4-132

X

X



X

X





4-133

X

X



X


X




4-134

X

X



X



X



4-135

X

X



X




X


4-136

X


X
X


X






4-137

X


X
X



X





4-138

X


X
X




X




4-139

X


X
X





X



4-140

X


X
X






X


4-141

X


X

X

X






4-142

X


X

X


X





4-143

X


X

X



X




4-144

X


X

X




X



4-145

X


X

X





X


4-146

X


X


X
X






4-147

X


X


X

X





4-148

X


X


X


X




4-149

X


X


X



X



4-150

X


X


X




X


4-151

X

X

X


X






4-152

X

X

X



X





4-153

X

X

X




X




4-154

X

X

X





X



4-155

X

X

X






X


4-156

X

X


X

X






4-157

X

X


X


X





4-158

X

X


X



X




4-159

X

X


X




X



4-160

X

X


X





X


4-161

X

X



X
X






4-162

X

X



X

X





4-163

X

X



X


X




4-164

X

X



X



X



4-165

X

X



X




X


4-166

X


X
X


X






4-167

X


X
X



X





4-168

X


X
X




X




4-169

X


X
X





X



4-170

X


X
X






X


4-171

X


X

X

X






4-172

X


X

X


X





4-173

X


X

X



X




4-174

X


X

X




X



4-175

X


X

X





X


4-176

X


X


X
X






4-177

X


X


X

X





4-178

X


X


X


X




4-179

X


X


X



X



4-180

X


X


X




X


4-181


X
X

X


X






4-182


X
X

X



X





4-183


X
X

X




X




4-184


X
X

X





X



4-185


X
X

X






X


4-186


X
X


X

X






4-187


X
X


X


X





4-188


X
X


X



X




4-189


X
X


X




X



4-190


X
X


X





X


4-191


X
X



X
X






4-192


X
X



X

X





4-193


X
X



X


X




4-194


X
X



X



X



4-195


X
X



X




X


4-196


X

X
X


X






4-197


X

X
X



X





4-198


X

X
X




X




4-199


X

X
X





X



4-200


X

X
X






X


4-201


X

X

X

X






4-202


X

X

X


X





4-203


X

X

X



X




4-204


X

X

X




X



4-205


X

X

X





X


4-206


X

X


X
X






4-207


X

X


X

X





4-208


X

X


X


X




4-209


X

X


X



X



4-210


X

X


X




X


4-211


X
X

X


X






4-212


X
X

X



X





4-213


X
X

X




X




4-214


X
X

X





X



4-215


X
X

X






X


4-216


X
X


X

X






4-217


X
X


X


X





4-218


X
X


X



X




4-219


X
X


X




X



4-220


X
X


X





X


4-221


X
X



X
X






4-222


X
X



X

X





4-223


X
X



X


X




4-224


X
X



X



X



4-225


X
X



X




X


4-226


X

X
X


X






4-227


X

X
X



X





4-228


X

X
X




X




4-229


X

X
X





X



4-230


X

X
X






X


4-231


X

X

X

X






4-232


X

X

X


X





4-233


X

X

X



X




4-234


X

X

X




X



4-235


X

X

X





X


4-236


X

X


X
X






4-237


X

X


X

X





4-238


X

X


X


X




4-239


X

X


X



X



4-240


X

X


X




X


4-241


X
X

X


X






4-242


X
X

X



X





4-243


X
X

X




X




4-244


X
X

X





X



4-245


X
X

X






X


4-246


X
X


X

X






4-247


X
X


X


X





4-248


X
X


X



X




4-249


X
X


X




X



4-250


X
X


X





X


4-251


X
X



X
X






4-252


X
X



X

X





4-253


X
X



X


X




4-254


X
X



X



X



4-255


X
X



X




X


4-256


X

X
X


X






4-257


X

X
X



X





4-258


X

X
X




X




4-259


X

X
X





X



4-260


X

X
X






X


4-261


X

X

X

X






4-262


X

X

X


X





4-263


X

X

X



X




4-264


X

X

X




X



4-265


X

X

X





X


4-266


X

X


X
X






4-267


X

X


X

X





4-268


X

X


X


X




4-269


X

X


X



X



4-270


X

X


X




X















R1
W
R7
R9




















No












C
N
H
Me
Et

























4-271
X


X

X


X






4-272
X


X

X



X





4-273
X


X

X




X




4-274
X


X

X





X



4-275
X


X

X






X


4-276
X


X


X

X






4-277
X


X


X


X





4-278
X


X


X



X




4-279
X


X


X




X



4-280
X


X


X





X


4-281
X


X



X
X






4-282
X


X



X

X





4-283
X


X



X


X




4-284
X


X



X



X



4-285
X


X



X




X


4-286
X



X
X


X






4-287
X



X
X



X





4-288
X



X
X




X




4-289
X



X
X





X



4-290
X



X
X






X


4-291
X



X

X

X






4-292
X



X

X


x





4-293
X



X

X



X




4-294
X



X

X




X



4-295
X



X

X





X


4-296
X



X


X
X






4-297
X



X


X

X





4-298
X



X


X


X




4-299
X



X


X



X



4-300
X



X


X




X


4-301
X


X

X


X






4-302
X


X

X



X





4-303
X


X

X




X




4-304
X


X

X





X



4-305
X


X

X






X


4-306
X


X


X

X






4-307
X


X


X


X





4-308
X


X


X



X




4-309
X


X


X




X



4-310
X


X


X





X


4-311
X


X



X
X






4-312
X


X



X

X





4-313
X


X



X


X




4-314
X


X



X



X



4-315
X


X



X




X


4-316
X



X
X


X






4-317
X



X
X



X





4-318
X



X
X




X




4-319
X



X
X





X



4-320
X



X
X






X


4-321
X



X

X

X






4-322
X



X

X


X





4-323
X



X

X



X




4-324
X



X

X




X



4-325
X



X

X





X


4-326
X



X


X
X






4-327
X



X


X

X





4-328
X



X


X


X




4-329
X



X


X



X



4-330
X



X


X




X


4-331
X


X

X


X






4-332
X


X

X



X





4-333
X


X

X




X




4-334
X


X

X





X



4-335
X


X

X






X


4-336
X


X


X

X






4-337
X


X


X


X





4-338
X


X


X



X




4-339
X


X


X




X



4-340
X


X


X





X


4-341
X


X



X
X






4-342
X


X



X

X





4-343
X


X



X


X




4-344
X


X



X



X



4-345
X


X



X




X


4-346
X



X
X


X






4-347
X



X
X



X





4-348
X



X
X




X




4-349
X



X
X





X



4-350
X



X
X






X


4-351
X



X

X

X






4-352
X



X

X


X





4-353
X



X

X



X




4-354
X



X

X




X



4-355
X



X

X





X


4-356
X



X


X
X






4-357
X



X


X

X





4-358
X



X


X


X




4-359
X



X


X



X



4-360
X



X


X




X


4-361

X

X

X


X






4-362

X

X

X



X





4-363

X

X

X




X




4-364

X

X

X





X



4-365

X

X

X






X


4-366

X

X


X

X






4-367

X

X


X


X





4-368

X

X


X



X




4-369

X

X


X




X



4-370

X

X


X





X


4-371

X

X



X
X






4-372

X

X



X

X





4-373

X

X



X


X




4-374

X

X



X



X



4-375

X

X



X




X


4-376

X


X
X


X






4-377

X


X
X



X





4-378

X


X
X




X




4-379

X


X
X





X



4-380

X


X
X






X


4-381

X


X

X

X






4-382

X


X

X


X





4-383

X


X

X



X




4-384

X


X

X




X



4-385

X


X

X





X


4-386

X


X


X
X






4-387

X


X


X

X





4-388

X


X


X


X




4-389

X


X


X



X



4-390

X


X


X




X


4-391

X

X

X


X






4-392

X

X

X



X





4-393

X

X

X




X




4-394

X

X

X





X



4-395

X

X

X






X


4-396

X

X


X

X






4-397

X

X


X


X





4-398

X

X


X



X




4-399

X

X


X




X



4-400

X

X


X





X


4-401

X

X



X
X






4-402

X

X



X

X





4-403

X

X



X


X




4-404

X

X



X



X



4-405

X

X



X




X


4-406

X


X
X


X






4-407

X


X
X



X





4-408

X


X
X




X




4-409

X


X
X





X



4-410

X


X
X






X


4-411

X


X

X

X






4-412

X


X

X


X





4-413

X


X

X



X




4-414

X


X

X




X



4-415

X


X

X





X


4-416

X


X


X
X






4-417

X


X


X

X





4-418

X


X


X


X




4-419

X


X


X



X



4-420

X


X


X




X


4-421

X

X

X


X






4-422

X

X

X



X





4-423

X

X

X




X




4-424

X

X

X





X



4-425

X

X

X






X


4-426

X

X


X

X






4-427

X

X


X


X





4-428

X

X


X



X




4-429

X

X


X




X



4-430

X

X


X





X


4-431

X

X



X
X






4-432

X

X



X

X





4-433

X

X



X


X




4-434

X

X



X



X



4-435

X

X



X




X


4-436

X


X
X


X






4-437

X


X
X



X





4-438

X


X
X




X




4-439

X


X
X





X



4-440

X


X
X






X


4-441

X


X

X

X






4-442

X


X

X


X





4-143

X


X

X



X




4-444

X


X

X




X



4-445

X


X

X





X


4-446

X


X


X
X






4-447

X


X


X

X





4-448

X


X


X


X




4-449

X


X


X



X



4-450

X


X


X




X


4-451


X
X

X


X






4-452


X
X

X



X





4-453


X
X

X




X




4-454


X
X

X





X



4-455


X
X

X






X


4-456


X
X


X

X






4-457


X
X


X


X





4-458


X
X


X



X




4-459


X
X


X




X



4-460


X
X


X





X


4-461


X
X



X
X






4-462


X
X



X

X





4-463


X
X



X


X




4-464


X
X



X



X



4-465


X
X



X




X


4-466


X

X
X


X






4-467


X

X
X



X





4-468


X

X
X




X




4-469


X

X
X





X



4-470


X

X
X






X


4-471


X

X

X

X






4-472


X

X

X


X





4-473


X

X

X



X




4-474


X

X

X




X



4-475


X

X

X





X


4-476


X

X


X
X






4-477


X

X


X

X





4-478


X

X


X


X




4-479


X

X


X



X



4-480


X

X


X




X


4-481


X
X

X


X






4-482


X
X

X



X





4-483


X
X

X




X




4-484


X
X

X





X



4-485


X
X

X






X


4-486


X
X


X

X






4-487


X
X


X


X





4-488


X
X


X



X




4-489


X
X


X




X



4-490


X
X


X





X


4-491


X
X



X
X






4-492


X
X



X

X





4-493


X
X



X


X




4-494


X
X



X



X



4-495


X
X



X




X


4-496


X

X
X


X






4-497


X

X
X



X





4-498


X

X
X




X




4-499


X

X
X





X



4-500


X

X
X






X


4-501


X

X

X

X






4-502


X

X

X


X





4-503


X

X

X



X




4-504


X

X

X




X



4-505


X

X

X





X


4-506


X

X


X
X






4-507


X

X


X

X





4-508


X

X


X


X




4-509


X

X


X



X



4-510


X

X


X




X


4-511


X
X

X


X






4-512


X
X

X



X





4-513


X
X

X




X




4-514


X
X

X





X



4-515


X
X

X






X


4-516


X
X


X

X






4-517


X
X


X


X





4-518


X
X


X



X




4-519


X
X


X




X



4-520


X
X


X





X


4-521


X
X



X
X






4-522


X
x



X

X





4-523


X
X



X


X




4-524


X
X



X



X



4-525


X
X



X




X


4-526


X

X
X


X






4-527


X

X
X



X





4-528


X

X
X




X




4-529


X

X
X





X



4-530


X

X
X






X


4-531


X

X

X

X






4-532


X

X

X


X





4-533


X

X

X



X




4-534


X

X

X




X



4-535


X

X

X





X


4-536


X

X


X
X






4-537


X

X


X

X





4-538


X

X


X


X




4-539


X

X


X



X



4-540


X

X


X




X
















TABLE 5







Exemplary compounds of the invention of Formula V-Al. 


Formula V-A1








 













R1


















              No








          



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                R7     H Me Et
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5-1
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5-2
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5-3
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5-4
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5-5
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5-6
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5-7
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5-8
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5-9
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5-10
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5-11
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5-12
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5-13
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5-14
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5-15
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5-16
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5-17
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5-18
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5-19
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5-20
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X
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5-21
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5-22
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X

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5-23
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5-24
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5-25
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5-26
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5-27
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5-28
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5-29
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5-30
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5-31
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5-32
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5-33
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5-34
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5-35
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5-36
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5-37
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5-38
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5-39
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5-40
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5-41
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5-42
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5-43
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5-44
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5-45
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5-46
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5-47
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5-48
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5-49
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5-50
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5-51
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5-52
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5-53
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5-54
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5-55
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5-56
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X


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5-57
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5-58
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X


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5-59
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X


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5-60
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X


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5-61
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X
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5-62
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X
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5-63
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X
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5-64
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X
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5-65
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X
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5-66
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X
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5-67
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X
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5-68
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X
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5-69
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X
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5-70
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X
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5-71
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X
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X
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5-72
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X
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5-73
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X
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5-74
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X
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5-75
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X
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5-76
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X

X
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5-77
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X

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5-78
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X

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5-79
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X

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5-80
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X

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5-81
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X

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5-82
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X

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5-83
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X

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5-84
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X

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X


5-85
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X

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5-86
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X

X


X
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5-87
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X

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5-88
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X

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5-89
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X

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5-90
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X

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5-91

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X


X

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5-92

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5-93

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X


X

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5-94

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X

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X


5-95

X

X


X

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5-96

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5-97

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X


X


X


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5-98

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5-99

X

X


X


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5-100

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X


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5-101

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X
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5-102

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X


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5-103

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5-104

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X


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5-105

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5-106

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X
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5-107

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X
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5-108

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X
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5-109

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X
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5-110

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X
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5-111

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X

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5-112

X

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X

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5-113

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X

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5-114

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X

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X


5-115

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5-116

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X
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5-117

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5-118

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5-119

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X


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5-120

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X


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5-121

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X

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5-122

X


X

X

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5-123

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X

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5-124

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X

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X


5-125

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X

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5-126

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X

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5-127

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X


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5-128

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X

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5-129

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X

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5-130

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X

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5-131

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X
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5-132

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X

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5-133

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X


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5-134

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X

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5-135

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5-136

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X
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5-137

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X
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5-138

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X


X
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5-139

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X


X
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X


5-140

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X


X
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5-141

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5-142

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X


X

X


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5-143

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X


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5-144

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X


X

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X


5-145

X


X


X

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5-146

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X


X


X
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5-147

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X


X


X

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5-148

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X


X


X


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5-149

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X


X


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X


5-150

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5-151

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X
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5-152

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5-153

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X
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5-154

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X
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5-155

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X
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5-156

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X
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X

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5-157

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X
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5-158

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X
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5-159

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X
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5-160

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X
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5-161

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X
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X
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5-162

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X
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X

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5-163

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X
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5-164

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5-165

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X
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5-166

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X

X
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5-167

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X

X
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5-168

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X

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5-169

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X

X
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X


5-170

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X

X
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5-171

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X

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5-172

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X

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5-173

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X

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5-174

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X

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X


5-175

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X

X

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5-176

X



X

X


X
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5-177

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X

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X

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5-178

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X

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5-179

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X

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5-180

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X

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5-181


X
X


X

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5-182


X
X


X

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5-183


X
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X

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5-184


X
X


X

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X


5-185


X
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X

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5-186


X
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5-187


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5-188


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5-189


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5-190


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5-191


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5-192


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5-193


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5-194


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5-195


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5-196


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5-197


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5-198


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5-199


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5-200


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5-201


X
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5-202


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5-203


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5-204


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X

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5-205


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5-206


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X


X
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5-207


X
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X


X

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5-208


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X


X


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5-209


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X


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5-210


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X


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5-211


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5-212


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5-213


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5-214


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5-215


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5-216


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X

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5-217


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5-218


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5-219


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5-220


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5-221


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X
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5-222


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5-223


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5-224


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5-225


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X

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5-226


X

X


X
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5-227


X

X


X
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5-228


X

X


X
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5-229


X

X


X
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X


5-230


X

X


X
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5-231


X

X


X

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5-232


X

X


X

X


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5-233


X

X


X

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5-234


X

X


X

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X


5-235


X

X


X

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5-236


X

X


X


X
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5-237


X

X


X


X

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5-238


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X


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5-239


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X


X


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5-240


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5-241


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X
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5-242


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X
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5-243


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X
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5-244


X


X
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X


5-245


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X
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5-246


X


X
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X

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5-247


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X
X


X


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5-248


X


X
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5-249


X


X
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X




X


5-250


X


X
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5-251


X


X
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X
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5-252


X


X
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X

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5-253


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X
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X


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5-254


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X
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X



X


5-255


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X
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5-256


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X

X
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5-257


X


X

X
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5-258


X


X

X
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X



5-259


X


X

X
X





X


5-260


X


X

X
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5-261


X


X

X

X

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5-262


X


X

X

X


X




5-263


X


X

X

X



X



5-264


X


X

X

X




X


5-265


X


X

X

X







5-266


X


X

X


X
X





5-267


X


X

X


X

X




5-268


X


X

X


X


X



5-269


X


X

X


X



X


5-270


X


X

X


X






5-271
X


X


X

X


X





5-272
X


X


X

X



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5-273
X


X


X

X




X



5-274
X


X


X

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X


5-275
X


X


X

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5-276
X


X


X


X

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5-277
X


X


X


X


X




5-278
X


X


X


X



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5-279
X


X


X


X




X


5-280
X


X


X


X







5-281
X


X


X



X
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5-282
X


X


X



X

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5-283
X


X


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X


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5-284
X


X


X



X



X


5-285
X


X


X



X






5-286
X


X



X
X


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5-287
X


X



X
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X




5-288
X


X



X
X




X



5-289
X


X



X
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X


5-290
X


X



X
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5-291
X


X



X

X

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5-292
X


X



X

X


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5-293
X


X



X

X



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5-294
X


X



X

X




X


5-295
X


X



X

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5-296
X


X



X


X
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5-297
X


X



X


X

X




5-298
X


X



X


X


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5-299
X


X



X


X



X


5-300
X


X



X


X






5-301
X



X

X

X


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5-302
X



X

X

X



X




5-303
X



X

X

X




X



5-304
X



X

X

X





X


5-305
X



X

X

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5-306
X



X

X


X

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5-307
X



X

X


X


X




5-308
X



X

X


X



X



5-309
X



X

X


X




X


5-310
X



X

X


X







5-311
X



X

X



X
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5-312
X



X

X



X

X




5-313
X



X

X



X


X



5-314
X



X

X



X



X


5-315
X



X

X



X






5-316
X



X


X
X


X





5-317
X



X


X
X



X




5-318
X



X


X
X




X



5-319
X



X


X
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X


5-320
X



X


X
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5-321
X



X


X

X

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5-322
X



X


X

X


X




5-323
X



X


X

X



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5-324
X



X


X

X




X


5-325
X



X


X

X







5-326
X



X


X


X
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5-327
X



X


X


X

X




5-328
X



X


X


X


X



5-329
X



X


X


X



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5-330
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X


X


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5-331
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X
X

X


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5-332
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X
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5-333
X




X
X

X




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5-334
X




X
X

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5-335
X




X
X

X








5-336
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X
X


X

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5-337
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X
X


X


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5-338
X




X
X


X



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5-339
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X
X


X




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5-340
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X
X


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5-341
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X
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X
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5-342
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X
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5-343
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5-344
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5-345
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X
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5-346
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X

X
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5-347
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X

X
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5-348
X




X

X
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5-349
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X

X
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5-350
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X

X
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5-351
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X

X

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5-352
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X

X

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5-353
X




X

X

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5-354
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X

X

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5-355
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X

X

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5-356
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X

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X
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5-357
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X

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5-358
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X

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5-359
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5-360
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5-361

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5-362

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5-363

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5-364

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5-365

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5-366

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5-367

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5-368

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5-371

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5-372

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5-373

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5-375

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5-376

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5-377

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5-378

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5-379

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5-380

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5-381

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5-382

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5-383

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5-384

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5-385

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5-386

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5-387

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5-389

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5-390

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5-391

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5-392

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5-394

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5-395

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5-396

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5-397

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X

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5-398

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5-399

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5-400

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5-401

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5-402

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5-403

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5-404

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5-405

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5-406

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X


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5-407

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5-408

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X


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5-409

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5-410

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5-411

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5-412

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5-413

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X


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5-414

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X




X


5-415

X


X


X

X







5-416

X


X


X


X
X





5-417

X


X


X


X

X




5-418

X


X


X


X


X



5-419

X


X


X


X



X


5-420

X


X


X


X






5-421

X



X
X

X


X





5-422

X



X
X

X



X




5-423

X



X
X

X




X



5-424

X



X
X

X





X


5-425

X



X
X

X








5-426

X



X
X


X

X





5-427

X



X
X


X


X




5-428

X



X
X


X



X



5-429

X



X
X


X




X


5-430

X



X
X


X







5-431

X



X
X



X
X





5-432

X



X
X



X

X




5-433

X



X
X



X


X



5-434

X



X
X



X



X


5-435

X



X
X



X






5-436

X



X

X
X


X





5-437

X



X

X
X



X




5-438

X



X

X
X




X



5-439

X



X

X
X





X


5-440

X



X

X
X








5-441

X



X

X

X

X





5-442

X



X

X

X


X




5-443

X



X

X

X



X



5-444

X



X

X

X




X


5-445

X



X

X

X







5-446

X



X

X


X
X





5-447

X



X

X


X

X




5-448

X



X

X


X


X



5-449

X



X

X


X



X


5-450

X



X

X


X






5-451


X
X


X

X


X





5-452


X
X


X

X



X




5-453


X
X


X

X




X



5-454


X
X


X

X





X


5-455


X
X


X

X








5-456


X
X


X


X

X





5-457


X
X


X


X


X




5-458


X
X


X


X



X



5-459


X
X


X


X




X


5-460


X
X


X


X







5-461


X
X


X



X
X





5-462


X
X


X



X

X




5-463


X
X


X



X


X



5-464


X
X


X



X



X


5-465


X
X


X



X






5-466


X
X



X
X


X





5-467


X
X



X
X



X




5-468


X
X



X
X




X



5-469


X
X



X
X





X


5-470


X
X



X
X








5-471


X
X



X

X

X





5-472


X
X



X

X


X




5-473


X
X



X

X



X



5-474


X
X



X

X




X


5-475


X
X



X

X







5-476


X
X



X


X
X





5-477


X
X



X


X

X




5-478


X
X



X


X


X



5-479


X
X



X


X



X


5-480


X
X



X


X






5-481


X

X

X

X


X





5-482


X

X

X

X



X




5-483


X

X

X

X




X



5-484


X

X

X

X





X


5-485


X

X

X

X








5-486


X

X

X


X

X





5-487


X

X

X


X


X




5-488


X

X

X


X



X



5-489


X

X

X


X




X


5-490


X

X

X


X







5-491


X

X

X



X
X





5-492


X

X

X



X

X




5-493


X

X

X



X


X



5-494


X

X

X



X



X


5-495


X

X

X



X






5-496


X

X


X
X


X





5-497


X

X


X
X



X




5-498


X

X


X
X




X



5-499


X

X


X
X





X


5-500


X

X


X
X








5-501


X

X


X

X

X





5-502


X

X


X

X


X




5-503


X

X


X

X



X



5-504


X

X


X

X




X


5-505


X

X


X

X







5-506


X

X


X


X
X





5-507


X

X


X


X

X




5-508


X

X


X


X


X



5-509


X

X


X


X



X


5-510


X

X


X


X






5-511


X


X
X

X


X





5-512


X


X
X

X



X




5-513


X


X
X

X




X



5-514


X


X
X

X





X


5-515


X


X
X

X








5-516


X


X
X


X

X





5-517


X


X
X


X


X




5-518


X


X
X


X



X



5-519


X


X
X


X




X


5-520


X


X
X


X







5-521


X


X
X



X
X





5-522


X


X
X



X

X




5-523


X


X
X



X


X



5-524


X


X
X



X



X


5-525


X


X
X



X






5-526


X


X

X
X


X





5-527


X


X

X
X



X




5-528


X


X

X
X




X



5-529


X


X

X
X





X


5-530


X


X

X
X








5-531


X


X

X

X

X





5-532


X


X

X

X


X




5-533


X


X

X

X



X



5-534


X


X

X

X




X


5-535


X


X

X

X







5-536


X


X

X


X
X





5-537


X


X

X


X

X




5-538


X


X

X


X


X



5-539


X


X

X


X



X


5-540


X


X

X


X





X represents a halo group (Cl, Br, I or F).






Additional non-limiting examples of compounds of the invention are described in Table 6 along with several biological properties.







TABLE 6







Biological properties of exemplary compounds of the invention. 















PI3K
PI3K
PI3K
PI3K
B cell




δ
γ
α
β
proliferation


No.
Compound
IC50
IC50
IC50
IC50
EC50
















1




+++
+++
+
+
++


 


2




+++
+++
+
++
+++


 


3




+++
++
+
+
++


 


4




+++
+++
+
+
+++


 


5




+++
++
+
+
++


 


6




+++
+
+
+
++


 


7




+++
+++
+
+
++


 


8




+++
+++
+
+
+++


 


9




+++

+
+
+++


 


10




+++

+
+
++


 


11




+++



+++


 


12




+++



+++


 


13




+++



+++


 


14




++






 


15




+++



+++


 


16




+++



++


 


17




+++
+++
++
++
+++


 


18




+






 


19




+++



+++


 


20




+++



+++


 


21




+






 


22




+






 


23




+++



+++


 


24




+++
+++
++
+
+++


 


25




++
+


+


 


26




+++
+


+++


 


27




+






 


28




+






 


29




++
+
+
+



 


30




+++
+++


+++


 


31




+++
+


++


 


32




+++
++


+++


 


33




++






 


34




+++
++


+++


 


35




+
+





 


36




+
+





 


37




+
+





 


38




+++
+
+
+++
+++


 


39




+++
+
+
+
+++


 


40




+++
++
+
+
+++


 


41




+++



++


 


42




+++



+++


 


43




+++
+
+
++
++


 


44




++
+





 


45




+++
++


+++


 


46




+++
++


++


 


47




+++
+++


+++


 


48




++
+


++


 


49




++
+


++


 


50




+++
+
+
+++
+++


 


51




+






 


52




+++
++
++
++
+++


 


53




++
+





 


54




+++
++
+
+
+++


 


55




+++
++
+
+
+++


 


56




+++
+++
+
+
+++


 


57




+++
+++
++
++
+++


 


58




++
++





 


59




+++
++
+
+
+++


 


60




+
+


+


 


61




+++
+++


+++


 


62




++
++





 


63




+++
++
+
+
+++


 


64




+++
++
+
+
+++


 


65




+++
+++
++
++



 


66




+++
+++
+
++



 


67




+
+
+
+



 


68




+++
++
+
++
+++


 


69




+++
+
+
+
+++


 


70




+++
++
++
+++
+++


 


71




+++
+
+
+
++


 


72




+++
+
+
++
+++


 


73




+++
+
+
+++
+++


 


74




+++
+
+
++
+++


 


75




+++
+
+
+
+++


 


76




+
+
+
+



 


77




+++
+
+
+
+++


 


78




+++
+
+
+
++


 


79




+++
+++
+++
+
+++


 


80




+++
+++
+++
+++
+++


 


81




+++
+
+
+
++


 


82




+++
+
+
+
+++


 


83




+++
+++
+
+
+++


 


84




+++
+++
+
+
+++


 


85




+++
+++
++
+
+++


 


86




+++
+++
+
+
++


 


87




+
+
+
+



 


88




++
+
+
+



 


89




++
+
+
+



 


90




++
+
+
+



 


91




++
++
+
+



 


92




+++
+++
+
+
+++


 


93




+++
++
+
+



 


94




+++
+++
+
+
++


 


95




+++
+
+
+



 


96




+++
++
+
+



 


97




+++
++
+
++



 


98




+++
+++
+
+



 


99




+++
+++
++
++



 


100




+






 


101




++
+
+
+
++


 


102




+






 


103




+
+





 


104




+++
++
+
+
+++


 


105




+++
++
+
+
++


 


106




++
+





 


107




+++
+
+
+
+++


 


108




++
+
+
+



 


109




++
+
+
+



 


110




++
+
+
+



 


111




++
+
+
+



 


112




+++
++
+
+



 


113




+++
+
+
+



 


114




+++
+
+
+



 


115




++
+
+
+



 


116




++
+
+
+



 


117




+++
+
+
+



 


118




+++
++
+
+



 


119




+++
+++
++
+



 


120




+






 


121




+






 


122




+






 


123




+






 


124




+






 


125




+






 


126




+






 


127




+++
+


++


 


128




+++
+++
+++

+++


 


129




+++
+++
+++
++
+++


 


130




+++
+++
+++
+++
+++


 


131




+++
+++
++
+
++


 


132




+++
+++
+++
++
+++


 


133




+++
+++
+
+
++


 


134




+++
+++
+
+
++


 


135




+++
+++
++
+
+++


 


136




+++
+++
+
+
++


 


137




+++
+++
+
+
++


 


138




+++
+++
+
+
++


 


139




+++
+++
+++
+++
+++


 


140




+++
+++
+++
++
+++


 


141




+++
+++
++
+
+++


 


142




+++
+++
++
+
+++


 


143




+++
+++
++
+
+++


 


144




+++
+++
++
+
+++


 


145




+++
+++
+
+
+++


 


146




+++
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+
+
++


 


147




+++
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++

++


 


148




+++
+++

+
+++


 


149




+++
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+
+++


 


150




+++
+++

+
+++


 


151




+++
+++

++
+++


 


152




+++
+++
++
+
++


 


153




+++
+++
+++
++
++


 


154




+++
++
+++

+++


 


155




+++
+
+

++


 


156




+++
++
+
+
++


 


157




++
+
+
+
+


 


158




+
+
+
+
+


 


159




+++
+++
++
+
+


 


160




++

+
+



 


161






+
+



 


162






+
+



 


163






++
+++



 


164






+++
+++



 


165




+++
+
+
++
+++


 


166




+++
++
++
+
+++


 


167




+++
+++
+++
++
+++


 


168




+++
+
+
++
+++


 


169




+++
++
++
++
+++


 


170




+++
++
+
+



 


171




+++
+++
++
+
+++


 


172




+

+
+



 


173




+

+
+



 


174




+++

+
+++
+++


 


175




+++

++
+
+++


 


176




+++

++
+
+++


 


177




+

+
+



 


178




+

+
+



 


179




++
+
+
+
++


 


180




+++
++
+
+
++


 


181




+++
+++
+
+
++


 


182




+++
+++
+

++


 


183




++
++
+




 


184




+++
+++
+
+
++


 


185




+++
+
+
++
+++


 


186




+++

++
+
+++


 


187




+++

+++
++
+++


 


188




+

+
+



 


189




+

+
+



 


190




+
+
+
+



 


191




++
+
+
+



 


192




+++
+++
+
+
++


 


193




+
+
+
+



 


194




++
+
+
+



 


195




+++
+++
+++
+
+++


 


196




+++
+++
++
+
++


 


197




+++
+
+
++
+++


 


198




+++
++
++
+++
+++


 


199




+++
+++
++
+++
+++


 


200




+++
+
+

++





The measured activity of the compounds of the invention (EC50 or IC50) is denoted as “+++” if less or equal to 100 nM, “++” if greater than 100 nM but less than or equal to 1 μM, and “+” if greater than 1 μM.






Additional compounds of the invention are described below:










Preparation of the Compounds of the Invention
Compounds of the invention may be synthesized by the general synthetic Schemes 1 and 2 illustrated below. In general synthetic scheme 1, an aromatic group comprising two reactive groups X and Y is first coupled to the R9 group via the reactive group X. The introduction of the linker L and the heteroaromatic moiety Z is performed in a subsequent step. In general scheme 2, the linker L and heteroaromatic moiety Z are first coupled to the aromatic group comprising two reactive groups X and Y. The coupling step to introduce the R9 moiety is performed subsequently.
Various reagents may be used to perform the coupling reactions necessary to introduce the R9, L and Z moieties. X and Y are reactive groups which can react with precursors of R9 and L or Z moieties. Alternatively, X and Y are latent or protected reaction groups which are converted to reactive groups during or prior to the coupling reactions. Various coupling reactions may be suitable for this purpose. Some known types of coupling reactions which can involve aromatic ring compounds include the Heck reactions and Suzuki reactions. Such reactions are described, for example, in N. Miyaura and A. Suzuki, Chem. Rev. 1995, 95, 2457-2483.
For example, X may be a halogen atom. If R9 comprises a primary or secondary amino group, it may be attached to the aryl group via an amination reaction. Such a reaction may be performed in the presence of a base and/or a catalyst such as a palladium catalyst. In other embodiments, X is a halogen atom and R9 is an aryl group. A coupling may be effected between X and a precursor compound of R9, such as a boronic acid (Suzuki coupling) or stannane precursor (Stille coupling).








The synthesis of several compounds of the invention is illustrated in Synthetic Schemes 3-15. The general synthetic strategy employed in these schemes is believed to be widely applicable to synthesize the compounds of the invention, and the specific compounds and reagents describe serve merely to exemplify the general synthetic approaches disclosed herein. Scheme 3 shows the preparation of a compound of the invention by reduction of a starting aldehyde 3a to an alcohol in step 1. Such a reaction may be performed, for example, by sodium borohydride reduction in methanol. In step 2, compound 3b is coupled to pyrrolidine in the presence of a solvent such as 1,4-dioxane. The alcohol 3c is converted to a reactive halide in step 3 by reaction with a reagent such as CBr4/PPh3 in a solvent such as dichloromethane. A heterocyclic moiety such as a pyrazolopyrimide (e.g. 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) may be coupled to the halide 3d (e.g. in a base such as potassium carbonate and a solvent such as dimethylformamide) to form the compound 3e in step 4. In step 5, the pyrazolopyrimidine subunit is further derivatized via a reaction such as a Suzuki coupling (e.g. using Pd(PPh3)4 as a catalyst) to yield compound 3f.







Scheme 4 shows an alternative synthesis of the compound 3f. In Step 1, a starting aldehyde 3a is reduced to an alcohol. Such a reaction may be performed, for example, by sodium borohydride reduction in methanol. In Step 2, compound 3b is converted to a reactive halide 4a by reaction with a reagent such as CBr4/PPh3 in a solvent such as dichloromethane. Coupling to a heterocyclic moiety such as a pyrazolopyrimide (e.g. 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) is performed in step 3, for example in a base such as potassium carbonate and a solvent such as dimethylformamide) to yield compound 4b. Compound 4b is then coupled to pyrrolidine in Step 4 in the presence of a solvent such as 1,4-dioxane to produce compound 3e. In step 5, compound 3e is further derivatized via a reaction such as a Suzuki coupling (e.g. using Pd(PPh3)4 as a catalyst) to yield compound 3f.




Scheme 5 shows an additional alternative synthesis of the compound 3f. In step 1, a starting aldehyde 3a is reduced to an alcohol. Such a reaction may be performed, for example, by sodium borohydride reduction in methanol. In step 2, compound 3b is converted to a reactive halide 4b by reaction with a reagent such as CBr4/PPh3 in a solvent such as dichloromethane. Coupling to a heterocyclic moiety such as a derivatized pyrazolopyrimide (e.g. 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) is performed in step 3, for example in a base such as potassium t-butoxide and a solvent such as dimethylformamide) to yield compound 5a. If necessary, the resulting compound 5a is deprotected, for example by removal of a methoxy group by a reagent such as BBr3 in dichloromethane. The resulting compound 5b is then coupled to pyrrolidine in the presence of a solvent such as 1,4-dioxane to yield compound 3f.







Scheme 6 shows the preparation of a compound of the invention by reduction of a starting aldehyde 6a to an alcohol in step 1. Such a reaction may be performed, for example, by sodium borohydride reduction in methanol. In step 2, compound 6b is coupled to an aryl group via, for example, a Suzuki coupling. In the example shown, o-tolylboronic acid is reacted with 6b in the presence of Pd(PPh3)4, a base such as Na2CO3 and a solvent such as DMF. The resulting alcohol 6c is converted to a reactive halide in step 3 by reaction with a reagent such as CBr4/PPh3 in a solvent such as dichloromethane. A heterocyclic moiety such as a pyrazolopyrimide (e.g. 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) may be coupled to the halide 6d (e.g. in a base such as potassium carbonate and a solvent such as dimethylformamide) to form the compound 6e in step 4. In step 5, the pyrazolopyrimidine subunit is further derivatized via a reaction such as a Suzuki coupling (e.g. using Pd(PPh3)4 as a catalyst) to yield compound 6f.




Scheme 7 shows an alternative synthesis of the compound 6f. In step 1, a starting aldehyde 6a is reduced to an alcohol. Such a reaction may be performed, for example, by sodium borohydride reduction in methanol. In step 2, compound 6b is converted to a reactive halide 7a by reaction with a reagent such as CBr4/PPh3 in a solvent such as dichloromethane. Coupling to a heterocyclic moiety such as a derivatized pyrazolopyrimide (e.g. 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine) is performed in step 3, for example in a base such as potassium t-butoxide and a solvent such as dimethylformamide). The resulting compound 7b is then coupled to an aryl group via, for example, a Suzuki coupling. In the example shown, o-tolylboronic acid is reacted with 7b in the presence of Pd(PPh3)4, a base such as Na2CO3 and a solvent such as DMF. If necessary, the resulting compound 7c is deprotected, for example by removal of a methoxy group by a reagent such as BBr3 in dichloromethane to yield compound 6f.







Scheme 8 shows the preparation of a compound of the invention by reduction of a starting acid 8a to an alcohol in step 1. Such a reaction may be performed, for example, by LiAlH4 reduction in methanol. In step 2, compound 8b is coupled to an aryl group via, for example, a Suzuki coupling. In the example shown, 2-fluorophenylboronic acid is reacted with 8b in the presence of Pd(PPh3)4, a base such as Na2CO3 and a solvent such as DME-water. The resulting alcohol 8c is converted to a reactive halide in step 3 by reaction with a reagent such as CBr4/PPh3 in a solvent such as dichloromethane. A heterocyclic moiety such as a pyrazolopyrimide (e.g. 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) may be coupled to the halide 8d (e.g. in a base such as potassium carbonate and a solvent such as dimethylformamide) to form the compound 8e in step 4. In step 5, the pyrazolopyrimidine subunit is further derivatized via a reaction such as a Suzuki coupling (e.g. using Pd(PPh3)4 as a catalyst) to yield compound 8f.







Scheme 9 shows the preparation of a compound of the invention by reduction of a starting aldehyde 9a to an alcohol in step 1. Such a reaction may be performed, for example, by sodium borohydride reduction in methanol. In step 2, compound 9b is coupled to pyrrolidine in the presence of a solvent such as 1,4-dioxane. The resulting alcohol 9c is converted to a reactive halide in step 3 by reaction with a reagent such as CBr4/PPh3 in a solvent such as acetonitrile. A heterocyclic moiety such as a pyrazolopyrimide (e.g. 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) may be coupled to the halide 9d (e.g. in a base such as potassium carbonate and a solvent such as dimethylformamide) to form the compound 9e in step 4. In step 5, the pyrazolopyrimidine subunit is further derivatized via a reaction such as a Suzuki coupling (e.g. using Pd(PPh3)4 as a catalyst) with 3-fluoro-5-hydroxyphenylboronic acid to yield compound 9f.




Scheme 10 illustrates a synthesis of the compound 10f. In step 1, a starting aldehyde 10a is converted to an alcohol, for example, by Grignard addition of an alkylmagnesium halide reagent. In step 2, compound 10b is converted to a reactive halide by reaction with a reagent such as CBr4/PPh3 in a solvent such as acetonitrile. Coupling to a heterocyclic moiety such as a pyrazolopyrimide (e.g. 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) is performed in step 3, for example in a base such as potassium t-butoxide and a solvent such as dimethylformamide). The resulting compound 10d is then coupled to pyrrolidine in the presence of a solvent such as 1,4-dioxane. In step 5, the pyrazolopyrimidine subunit is further derivatized via a reaction such as a Suzuki coupling (e.g. using Pd(PPh3)4 as a catalyst) to yield compound 10f.




Scheme 11 exemplifies a synthesis of the compound 11f. In step 1, a starting aldehyde 11a is converted to an alcohol, for example, by Grignard addition of an alkylmagnesium halide reagent. In step 2, compound 11b is coupled to an aryl group via, for example, a Suzuki coupling using phenylboronic acid in the presence of Pd(OAc)2, a base such as Na2CO3 and a solvent such as ethanol/DMF/water. The resulting compounds 11c is converted to a reactive halide by reaction with a reagent such as CBr4/PPh3 in a solvent such as acetonitrile. Coupling to a heterocyclic moiety such as a pyrazolopyrimide (e.g. 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine) is performed in step 3, for example in a base such as potassium t-butoxide and a solvent such as dimethylformamide. In step 5, the resulting compound 11d is further derivatized via a reaction such as a Suzuki coupling (e.g. using Pd(PPh3)4 as a catalyst) to yield compound 11f.




Scheme 12 shows a synthesis of the compound 12e. In step 1, a starting aldehyde 12a is converted to an alcohol, for example, by Grignard addition of an alkylmagnesium halide reagent. In step 2, compound 12b is converted to a reactive halide by reaction with a reagent such as CBr4/PPh3 in a solvent such as acetonitrile. Subsequent reaction with a heterocyclic compound such as 9H-purin-6-amine leads to formation of the intermediate 12d. This intermediate is then coupled to an aryl group via, for example, a Suzuki coupling using phenylboronic acid in the presence of Pd(OAc)2, a base such as Na2CO3 and a solvent such as ethanol/DMF/water. Alternatively, compound 12d is reacted with pyrrolidine in the presence of a solvent such as 1,4-dioxane, leading to formation of product 12f.




Scheme 13 describes the synthesis of additional compounds comprising heteroaromatic residues. The starting material is the intermediate 12c prepared as described above. Coupling with a derivatized bicyclic heteroaromatic residue (in the example shown, 9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine) results in compound 13b, which is further reacted with a group such as pyrrolidine (shown) to yield compounds 13c. Deprotection of the purine moiety in HCl/ethanol results in compound 13d.




A synthetic route to quinoxaline compounds of the invention is illustrated in Scheme 14. Quinoxaline 14b is prepared by cyclization of compound 14a with a reagent such as ethyl 3-bromo-2-oxopropanoate. Conversion to the halide 14c is performed using a reagent such as phosphorus oxychloride or similar reagents. Steps 3, 4 and 5 follow the corresponding steps in Scheme 10, yielding compound 14f.




Scheme 15 describes the synthesis of compounds such as 15g. Intermediate 15d is prepared as described for compound 4b. Treatment with NaOH in a solvent such as 1,4-dioxane at 80 C yields 15e, which is further alkylated using a reagent such as methyl iodide in potassium t-butoxide/DMF to yield 15f. Compound 15g is obtained following Suzuki coupling as described above.







A synthetic route to additional quinoxaline compounds of the invention is illustrated in Scheme 16. Quinoxaline 16b is prepared by cyclization of compound 16a with a reagent such as ethyl 3-bromo-2-oxopropanoate in ethanol. Reaction with Boc anhydride in DMAP/CH2Cl2 leads to the protected intermediate 16c. Coupling to a heterocyclic moiety such as a pyrazolopyrimide is performed in step 3. Deprotection and alkylation, e.g. using methyl iodide, results in compound 16g.







In some embodiments, one or more subject compounds bind specifically to a PI3 kinase or a protein kinase selected from the group consisting of mTor, DNA-dependent protein kinase DNA-dependent protein kinase (Pubmed protein accession number (PPAN) AAA79184), Abl tyrosine kinase (CAA52387), Bcr-Abl, hemopoietic cell kinase (PPAN CAI19695), Src (PPAN CAA24495), vascular endothelial growth factor receptor 2 (PPAN ABB82619), vascular endothelial growth factor receptor-2 (PPAN ABB82619), epidermal growth factor receptor (PPAN AG43241), EPH receptor B4 (PPAN EAL23820), stem cell factor receptor (PPAN AAF22141), Tyrosine-protein kinase receptor TIE-2 (PPAN Q02858), fins-related tyrosine kinase 3 (PPAN NP_004110), platelet-derived growth factor receptor alpha (PPAN NP_990080), RET (PPAN CAA73131), and any other protein kinases listed in the appended tables and figures, as well as any functional mutants thereof. In some embodiments, the IC50 of a subject compound for p110α, p110β, p110γ, or p110δ is less than about 1 uM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than 1 nM or even less than about 0.5 nM. In some embodiments, the IC50 of a subject compound for mTor is less than about 1 uM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than 1 nM or even less than about 0.5 nM. In some other embodiments, one or more subject compounds exhibit dual binding specificity and are capable of inhibiting a PI3 kinase (e.g., a class I PI3 kinase) as well as a protein kinase (e.g., mTor) with an IC50 value less than about 1 uM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than 1 nM or even less than about 0.5 nM. One or more subject compounds are capable of inhibiting tyrosine kinases including, for example, DNA-dependent protein kinase DNA-dependent protein kinase (Pubmed protein accession number (PPAN) AAA79184), Abl tyrosine kinase (CAA52387), Bcr-Abl, hemopoietic cell kinase (PPAN CAI19695), Src (PPAN CAA24495), vascular endothelial growth factor receptor 2 (PPAN ABB82619), vascular endothelial growth factor receptor-2 (PPAN ABB82619), epidermal growth factor receptor (PPAN AG43241), EPH receptor B4 (PPAN EAL23820), stem cell factor receptor (PPAN AAF22141), Tyrosine-protein kinase receptor TIE-2 (PPAN Q02858), fins-related tyrosine kinase 3 (PPAN NP_004110), platelet-derived growth factor receptor alpha (PPAN NP_990080), RET (PPAN CAA73131), and functional mutants thereof. In some embodiments, the tyrosine kinase is Abl, Bcr-Abl, EGFR, or Flt-3, and any other kinases listed in the Tables herein.
In some embodiments, the compounds of the present invention exhibits one or more functional characteristics disclosed herein. For example, one or more subject compounds bind specifically to a PI3 kinase. In some embodiments, the IC50 of a subject compound for p110α, p110β, p110γ, or p110δ is less than about 1 uM, less than about 100 nM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5 nM, less than about 100 pM, or less than about 50 pM.
In some embodiments, one or more of the subject compounds may selectively inhibit one or more members of type I or class I phosphatidylinositol 3-kinases (PI3-kinase) with an IC50 value of about 100 nM, 50 nM, 10 nM, 5 nM, 100 pM, 10 pM or 1 pM, or less as measured in an in vitro kinase assay.
In some embodiments, one or more of the subject compound may selectively inhibit one or two members of type I or class I phosphatidylinositol 3-kinases (PI3-kinase) consisting of PI3-kinase α, PI3-kinase β, PI3-kinase γ, and PI3-kinase δ. In some aspects, some of the subject compounds selectively inhibit PI3-kinase δ as compared to all other type I PI3-kinases. In other aspects, some of the subject compounds selectively inhibit PI3-kinase δ and PI3-kinase γ as compared to the rest of the type I PI3-kinases. In yet other aspects, some of the subject compounds selectively inhibit PI3-kinase α and PI3-kinase β as compared to the rest of the type I PI3-kinases. In still yet some other aspects, some of the subject compounds selectively inhibit PI3-kinase δ and PI3-kinase α as compared to the rest of the type I PI3-kinases. In still yet some other aspects, some of the subject compounds selectively inhibit PI3-kinase δ and PI3-kinase β as compared to the rest of the type I PI3-kinases, or selectively inhibit PI3-kinase δ and PI3-kinase α as compared to the rest of the type I PI3-kinases, or selectively inhibit PI3-kinase α and PI3-kinase γ as compared to the rest of the type I PI3-kinases, or selectively inhibit PI3-kinase γ and PI3-kinase β as compared to the rest of the type I PI3-kinases.
In yet another aspect, an inhibitor that selectively inhibits one or more members of type I PI3-kinases, or an inhibitor that selectively inhibits one or more type I PI3-kinase mediated signaling pathways, alternatively can be understood to refer to a compound that exhibits a 50% inhibitory concentration (IC50) with respect to a given type I PI3-kinase, that is at least at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold, at least 10,100-fold, or lower, than the inhibitor's IC50 with respect to the rest of the other type I PI3-kinases.
The invention provides pharmaceutical compositions comprising one or more compounds of the present invention. In some embodiments, the invention provides pharmaceutical compositions for treating diseases or conditions related to an undesirable, over-active, harmful or deleterious immune response in a mammal. Such undesirable immune response can be associated with or result in, e.g., asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxsis, auto-immune diseases, rhuematoid arthritis, graft versus host disease, and lupus erythematosus. The pharmaceutical compositions of the present invention can be used to treat other respiratory diseases including but not limited to diseases affecting the lobes of lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or the nerves and muscle for breathing.
In some embodiments, the invention provides pharmaceutical compositions for the treatment of disorders such as hyperproliferative disorder including but not limited to cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS related AIDS-Related (e.g. Lymphoma and Kaposi's Sarcoma) or Viral-Induced cancer. In some embodiments, said pharmaceutical composition is for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
The invention also provides compositions for the treatment of liver diseases (including diabetes), pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-induced renal disease) or pain in a mammal.
The invention further provides a composition for the prevention of blastocyte implantation in a mammal.
The invention also relates to a composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which can manifest as tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present invention as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where desired, the pharmaceutical compositions contain pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the subject compounds and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.
In some embodiments, the concentration of one or more of the compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.
In some embodiments, the concentration of one or more of the compounds of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.
In some embodiments, the concentration of one or more of the compounds of the present invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.
In some embodiments, the concentration of one or more of the compounds of the present invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
In some embodiments, the amount of one or more of the compounds of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.
In some embodiments, the amount of one or more of the compounds of the present invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5 g, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.
In some embodiments, the amount of one or more of the compounds of the present invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
Described below are non-limiting exemplary pharmaceutical compositions and methods for preparing the same.
Pharmaceutical Compositions for Oral Administration
In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the present invention, and a pharmaceutical excipient suitable for oral administration.
In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the present invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.
In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.
Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.
Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, .epsilon.-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.
Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.
Pharmaceutical Compositions for Injection.
In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein. The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery.
In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.
Compositions of the present invention can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent.
The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Pharmaceutical Compositions for Inhalation.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
Other Pharmaceutical Compositions.
Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.
Administration of the compounds or pharmaceutical composition of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also abe administered intraadiposally or intrathecally.
The amount of the compound administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.
In some embodiments, a compound of the invention is administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition.
In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
Administration of the agents of the invention may continue as long as necessary. In some embodiments, an agent of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, an agent of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for eample, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.
A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No. 5,451,233; U.S. Pat. No. 5,040,548; U.S. Pat. No. 5,061,273; U.S. Pat. No. 5,496,346; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 3,657,744; U.S. Pat. No. 4,739,762; U.S. Pat. No. 5,195,984; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No. 6,344,053.
The compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.
When a compound of the invention, is administered in a composition that comprises one or more agents, and the agent has a shorter half-life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly.
The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
The activity of the compounds of the present invention may be determined by the following procedure, as well as the procedure described in the examples below. The activity of the kinase is assessed by measuring the incorporation of γ-33P-phosphate from γ-33P-ATP onto N-terminal His tagged substrate, which is expressed in E. coli and is purified by conventional methods, in the presence of the kinase. The assay is carried out in 96-well polypropylene plate. The incubation mixture (100 μL) comprises of 25 mM Hepes, pH 7.4, 10 mM MgCl2, 5 mM β-glycerolphosphate, 100 μM Na-orthovanadate, 5 mM DTT, 5 nM kinase, and 1 μM substrate. Inhibitors are suspended in DMSO, and all reactions, including controls are performed at a final concentration of 1% DMSO. Reactions are initiated by the addition of 10 μM ATP (with 0.5 μCi γ-33P-ATP/well) and incubated at ambient temperature for 45 minutes. Equal volume of 25% TCA is added to stop the reaction and precipitate the proteins. Precipitated proteins are trapped onto glass fiber B filterplates, and excess labeled ATP washed off using a Tomtec MACH III harvestor. Plates are allowed to air-dry prior to adding 30 μL/well of Packard Microscint 20, and plates are counted using a Packard TopCount.
The invention also provides kits. The kits include a compound or compounds of the present invention as described herein, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another agent. In some embodiments, the compound of the present invention and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound of the present invention and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.
The invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to diseases associated with malfunctioning of one or more types of PI3 kinase. A detailed description of conditions and disorders mediated by p110δ kinase activity is set forth in Sadu et al., WO 01/81346, which is incorporated herein by reference in its entirety for all purposes.
The treatment methods provided herein comprise administering to the subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides a method of treating an inflammation disorder, including autoimmune diseases in a mammal. The method comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Examples of autoimmune diseases includes but is not limited to acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease, Diabetes mellitus (type 1), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis (also known as “giant cell arteritis”), warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Chagas' disease, chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, and vulvodynia. Other disorders include bone-resorption disorders and thromobsis.
In some embodiments, the method of treating inflammatory or autoimmune diseases comprises administering to a subject (e.g. a mammal) a therapeutically effective amount of one or more compounds of the present invention that selectively inhibit PI3K-δ and/or PI3K-γ as compared to all other type I PI3 kinases. Such selective inhibition of PI3K-δ and/or PI3K-γ may be advantageous for treating any of the diseases or conditions described herein. For example, selective inhibition of PI3K-δ may inhibit inflammatory responses associated with inflammatory diseases, autoimmune disease, or diseases related to an undesirable immune response including but not limited to asthma, emphysema, allergy, dermatitis, rhuematoid arthritis, psoriasis, lupus erythematosus, or graft versus host disease. Selective inhibition of PI3K-δ may further provide for a reduction in the inflammatory or undesirable immune response without a concomittant reduction in the ability to reduce a bacterial, viral, and/or fungal infection. Selective inhibition of both PI3K-δ and PI3K-γ may be advantageous for inhibiting the inflammatory response in the subject to a greater degree than that would be provided for by inhibitors that selectively inhibit PI3K-δ or PI3K-γ alone. In one aspect, one or more of the subject methods are effective in reducing antigen specific antibody production in vivo by about 2-fold, 3-fold, 4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold, 750-fold, or about 1000-fold or more. In another aspect, one or more of the subject methods are effective in reducing antigen specific IgG3 and/or IgGM production in vivo by about 2-fold, 3-fold, 4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold, 750-fold, or about 1000-fold or more.
In one aspect, one of more of the subject methods are effective in ameliorating symptoms associated with rheumatoid arthritis including but not limited to a reduction in the swelling of joints, a reduction in serum anti-collagen levels, and/or a reduction in joint pathology such as bone resorption, cartilage damage, pannus, and/or inflammation. In another aspect, the subject methods are effective in reducing ankle inflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90%. In another aspect, the subject methods are effective in reducing knee inflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, or about 75% to 90% or more. In still another aspect, the subject methods are effective in reducing serum anti-type II collagen levels by at least about 10%, 12%, 15%, 20%, 24%, 25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87%, or about 90% or more. In another aspect, the subject methods are effective in reducing ankle histopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more. In still another aspect, the subject methods are effective in reducing knee histopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 80%, 90% or more.
In other embodiments, the present invention provides methods of using the compounds or pharmaceutical compositions to treat respiratory diseases including but not limited to diseases affecting the lobes of lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or the nerves and muscle for breathing. For example, methods are provided to treat obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD) is an umbrella term for a group of respiratory tract diseases that are characterized by airflow obstruction or limitation. Conditions included in this umbrella term are: chronic bronchitis, emphysema, and bronchiectasis.
In another embodiment, the compounds described herein are used for the treatment of asthma. Also, the compounds or pharmaceutical compositions described herein may be used for the treatment of endotoxemia and sepsis. In one embodiment, the compounds or pharmaceutical compositions described herein are used to for the treatment of rheumatoid arthritis (RA). In yet another embodiment, the compounds or pharmaceutical compositions described herein is used for the treatment of contact or atopic dermatitis. Contact dermatitis includes irritant dermatitis, phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis, contact urticaria, systemic contact-type dermatitis and the like. Irritant dermatitis can occur when too much of a substance is used on the skin of when the skin is sensitive to certain substance. Atopic dermatitis, sometimes called eczema, is a kind of dermatitis, an atopic skin disease.
The invention also relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, said method relates to the treatment of cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-related (e.g. Lymphoma and Kaposi's Sarcoma) or viral-induced cancer. In some embodiments, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).
The invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
Patients that can be treated with compounds of the present invention, or pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative of said compounds, according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis; restenosis; atherosclerosis; BPH; breast cancer such as a ductal carcinoma in duct tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervix epithelial including squamous cell carcinoma and adenocarcinomas; prostate cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarinoma that has migrated to the bone; pancreatic cancer such as epitheliod carcinoma in the pancreatic duct tissue and an adenocarcinoma in a pancreatic duct; bladder cancer such as a transitional cell carcinoma in urinary bladder, urothelial carcinomas (transitional cell carcinomas), tumors in the urothelial cells that line the bladder, squamous cell carcinomas, adenocarcinomas, and small cell cancers; leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bone cancer; lung cancer such as non-small cell lung cancer (NSCLC), which is divided into squamous cell carcinomas, adenocarcinomas, and large cell undifferentiated carcinomas, and small cell lung cancer; skin cancer such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis, which is a skin condition that sometimes develops into squamous cell carcinoma; eye retinoblastoma; cutaneous or intraocular (eye) melanoma; primary liver cancer (cancer that begins in the liver); kidney cancer; thyroid cancer such as papillary, follicular, medullary and anaplastic; AIDS-related lymphoma such as diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma and small non-cleaved cell lymphoma; Kaposi's Sarcoma; viral-induced cancers including hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1) and adult T-cell leukemia/lymphoma; and human papilloma virus (HPV) and cervical cancer; central nervous system cancers (CNS) such as primary brain tumor, which includes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma, Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancers such as acoustic neuromas and malignant peripheral nerve sheath tumor (MPNST) including neurofibromas and schwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mixed Müllerian tumor; oral cavity and oropharyngeal cancer such as, hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer such as lymphomas, gastric stromal tumors, and carcinoid tumors; testicular cancer such as germ cell tumors (GCTs), which include seminomas and nonseminomas, and gonadal stromal tumors, which include Leydig cell tumors and Sertoli cell tumors; thymus cancer such as to thymomas, thymic carcinomas, Hodgkin disease, non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; and colon cancer.
The invention also relates to a method of treating diabetes in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
In addition, the compounds described herein may be used to treat acne.
In addition, the compounds described herein may be used for the treatment of arteriosclerosis, including atherosclerosis. Arteriosclerosis is a general term describing any hardening of medium or large arteries. Atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque.
Further the compounds described herein may be used for the treatment of glomerulonephritis. Glomerulonephritis is a primary or secondary autoimmune renal disease characterized by inflammation of the glomeruli. It may be asymptomatic, or present with hematuria and/or proteinuria. There are many recognized types, divided in acute, subacute or chronic glomerulonephritis. Causes are infectious (bacterial, viral or parasitic pathogens), autoimmune or paraneoplastic.
Additionally, the compounds described herein may be used for the treatment of bursitis, lupus, acute disseminated encephalomyelitis (ADEM), addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac disease, crohn's disease, diabetes mellitus (type 1), goodpasture's syndrome, graves' disease, guillain-barré syndrome (GBS), hashimoto's disease, inflammatory bowel disease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, ord's thyroiditis, ostheoarthritis, uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis, reiter's syndrome, takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, wegener's granulomatosis, alopecia universalis, chagas' disease, chronic fatigue syndrome, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, vulvodynia, appendicitis, arteritis, arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.
The invention also relates to a method of treating a cardiovascular disease in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Examples of cardiovascular conditions include, but are not limited to, atherosclerosis, restenosis, vascular occlusion and carotid obstructive disease.
In another aspect, the present invention provides methods of disrupting the function of a leukocyte or disrupting a function of an osteoclast. The method includes contacting the leukocyte or the osteoclast with a function disrupting amount of a compound of the invention.
In another aspect of the present invention, methods are provided for treating ophthalmic disease by administering one or more of the subject compounds or pharmaceutical compositions to the eye of a subject.
Methods are further provided for administering the compounds of the present invention via eye drop, intraocular injection, intravitreal injection, topically, or through the use of a drug eluting device, microcapsule, implant, or microfluidic device. In some cases, the compounds of the present invention are administered with a carrier or excipient that increases the intraocular penetrance of the compound such as an oil and water emulsion with colloid particles having an oily core surrounded by an interfacial film.
In some cases, the colloid particles include at least one cationic agent and at least one non-ionic surfactant such as a poloxamer, tyloxapol, a polysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester, or a polyoxyl stearate. In some cases, the cationic agent is an alkylamine, a tertiary alkyl amine, a quarternary ammonium compound, a cationic lipid, an amino alcohol, a biguanidine salt, a cationic compound or a mixture thereof. In some cases the cationic agent is a biguanidine salt such as chlorhexidine, polyaminopropyl biguanidine, phenformin, alkylbiguanidine, or a mixture thereof. In some cases, the quaternary ammonium compound is a benzalkonium halide, lauralkonium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallyl methenamine halide, myristylalkonium halide, stearalkonium halide or a mixture of two or more thereof. In some cases, cationic agent is a benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide or a mixture of two or more thereof. In some cases, the oil phase is mineral oil and light mineral oil, medium chain triglycerides (MCT), coconut oil; hydrogenated oils comprising hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castor oil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oil derivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.
The invention further provides methods of modulating kinase activity by contacting a kinase with an amount of a compound of the invention sufficient to modulate the activity of the kinase. Modulate can be inhibiting or activating kinase activity. In some embodiments, the invention provides methods of inhibiting kinase activity by contacting a kinase with an amount of a compound of the invention sufficient to inhibit the activity of the kinase. In some embodiments, the invention provides methods of inhibiting kinase activity in a solution by contacting said solution with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said solution. In some embodiments, the invention provides methods of inhibiting kinase activity in a cell by contacting said cell with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said cell. In some embodiments, the invention provides methods of inhibiting kinase activity in a tissue by contacting said tissue with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said tissue. In some embodiments, the invention provides methods of inhibiting kinase activity in an organism by contacting said organism with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said organism. In some embodiments, the invention provides methods of inhibiting kinase activity in an animal by contacting said animal with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said animal. In some embodiments, the invention provides methods of inhibiting kinase activity in a mammal by contacting said mammal with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said mammal. In some embodiments, the invention provides methods of inhibiting kinase activity in a human by contacting said human with an amount of a compound of the invention sufficient to inhibit the activity of the kinase in said human. In some embodiments, the % of kinase activity after contacting a kinase with a compound of the invention is less than 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% of the kinase activity in the absence of said contacting step.
In some embodiments, the kinase is a lipid kinase or a protein kinase. In some embodiments, the kinase is selected from the group consisting of PI3 kinase including different isoforms such as PI3 kinase α, PI3 kinase β, PI3 kinase γ, PI3 kinase δ; DNA-PK; mTor; Abl, VEGFR, Ephrin receptor B4 (EphB4); TEK receptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3); Platelet derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1; Hck; Src; Epidermal growth factor receptor (EGFR); KIT; Inulsin Receptor (IR) and IGFR.
The invention further provides methods of modulating PI3 kinase activity by contacting a PI3 kinase with an amount of a compound of the invention sufficient to modulate the activity of the PI3 kinase. Modulate can be inhibiting or activating PI3 kinase activity. In some embodiments, the invention provides methods of inhibiting PI3 kinase activity by contacting a PI3 kinase with an amount of a compound of the invention sufficient to inhibit the activity of the PI3 kinase. In some embodiments, the invention provides methods of inhibiting PI3 kinase activity. Such inhibition can take place in solution, in a cell expressing one or more PI3 kinases, in a tissue comprising a cell expressing one or more PI3 kinases, or in an organism expressing one or more PI3 kinases. In some embodiments, the invention provides methods of inhibiting PI3 kinase activity in an animal (including mammal such as humans) by contacting said animal with an amount of a compound of the invention sufficient to inhibit the activity of the PI3 kinase in said animal.
The present invention also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In one aspect, such therapy includes but is not limited to the combination of the subject compound with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.
In one aspect, the compounds or pharmaceutical compositions of the present invention may present synergistic or additive efficacy when administered in combination with agents that inhibit IgE production or activity. Such combination can reduce the undesired effect of high level of IgE associated with the use of one or more PI3Kδ inhibitors, if such effect occurs. This may be particularly useful in treatment of autoimmune and inflammatory disorders (AIID) such as rheumatoid arthritis. Additionally, the administration of PI3Kδ or PI3δ/γ inhibitors of the present invention in combination with inhibitors of mTOR may also exhibit synergy through enhanced inhibition of the PI3K pathway.
In a separate but related aspect, the present invention provides a combination treatment of a disease associated with PI3Kδ comprising administering to a PI3Kδ inhibitor and an agent that inhibits IgE production or activity. Other exemplary PI3Kδ inhibitors are applicable and they are described, e.g., U.S. Pat. No. 6,800,620. Such combination treatment is particularly useful for treating autoimmune and inflammatory diseases (AIID) including but not limited to rheumatoid arthritis.
Agents that inhibit IgE production are known in the art and they include but are not limited to one or more of TEI-9874, 2-(4-(6-cyclohexyloxy-2-naphtyloxy)phenylacetamide)benzoic acid, rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2 inhibitors, and any other compounds that inhibit mTORC1 and mTORC2. Agents that inhibit IgE activity include, for example, anti-IgE antibodies such as for example Omalizumab and TNX-901.
For treatment of autoimmune diseases, the subject compounds or pharmaceutical compositions can be used in combination with commonly prescribed drugs including but not limited to Enbrel®, Remicade®, Humira®, Avonex®, and Rebif®. For treatment of respiratory diseases, the subject compounds or pharmaceutical compositions can be administered in combination with commonly prescribed drugs including but not limited to Xolair®, Advair®, Singulair®, and Spiriva®.
The compounds of the invention may be formulated or administered in conjunction with other agents that act to relieve the symptoms of inflammatory conditions such as encephalomyelitis, asthma, and the other diseases described herein. These agents include non-steroidal anti-inflammatory drugs (NSAIDs), e.g. acetylsalicylic acid; ibuprofen; naproxen; indomethacin; nabumetone; tolmetin; etc. Corticosteroids are used to reduce inflammation and suppress activity of the immune system. The most commonly prescribed drug of this type is Prednisone. Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be very useful in some individuals with lupus. They are most often prescribed for skin and joint symptoms of lupus. Azathioprine (Imuran) and cyclophosphamide (Cytoxan) suppress inflammation and tend to suppress the immune system. Other agents, e.g. methotrexate and cyclosporin are used to control the symptoms of lupus. Anticoagulants are employed to prevent blood from clotting rapidly. They range from aspirin at very low dose which prevents platelets from sticking, to heparin/coumadin.
In another one aspect, this invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, in combination with an amount of an anti-cancer agent (e.g. a chemotherapeutic agent). Many chemotherapeutics are presently known in the art and can be used in combination with the compounds of the invention.
In some embodiments, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec (Imatinib Mesylate), Velcade (bortezomib), Casodex (bicalutamide), Iressa (gefitinib), and Adriamycin as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, CasodexTM, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM; razoxane; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2′′-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel (TAXOLTM, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERETM, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included as suitable chemotherapeutic cell conditioners are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen (NolvadexTM), raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Where desired, the compounds or pharmaceutical composition of the present invention can be used in combination with commonly prescribed anti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, and Velcade®.
This invention further relates to a method for using the compounds or pharmaceutical composition in combination with radiation therapy in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein.
Radiation therapy can be administered through one of several methods, or a combination of methods, including without limitation external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachytherapy. The term “brachytherapy,” as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended without limitation to include exposure to radioactive isotopes (e.g. At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive micro spheres.
Without being limited by any theory, the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation. The amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
The compounds or pharmaceutical compositions of the present invention can be used in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can be used in conjunction with a compound of the present invention and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European Patent Application No. 97304971.1 (filed Jul. 8, 1997), European Patent Application No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European Patent Publication 606,046 (published Jul. 13, 1994), European Patent Publication 931, 788 (published Jul. 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21, 1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filed Jul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar. 25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent Publication 780,386 (published Jun. 25, 1997), all of which are incorporated herein in their entireties by reference. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or AMP-9 relative to the other matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, and RS 13-0830.
The invention also relates to a method of and to a pharmaceutical composition of treating a cardiovascular disease in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, or an isotopically-labeled derivative thereof, and an amount of one or more therapeutic agents use for the treatment of cardiovascular diseases.
Examples for use in cardiovascular disease applications are anti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolytic agents, e.g., streptokinase, urokinase, tissue plasminogen activator (TPA) and anisoylated plasminogen-streptokinase activator complex (APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) and clopidrogel, vasodilating agents, e.g., nitrates, calcium channel blocking drugs, anti-proliferative agents, e.g., colchicine and alkylating agents, intercalating agents, growth modulating factors such as interleukins, transformation growth factor-beta and congeners of platelet derived growth factor, monoclonal antibodies directed against growth factors, anti-inflammatory agents, both steroidal and non-steroidal, and other agents that can modulate vessel tone, function, arteriosclerosis, and the healing response to vessel or organ injury post intervention. Antibiotics can also be included in combinations or coatings comprised by the invention. Moreover, a coating can be used to effect therapeutic delivery focally within the vessel wall. By incorporation of the active agent in a swellable polymer, the active agent will be released upon swelling of the polymer.
The compounds describe herein may be formulated or administered in conjunction with liquid or solid tissue barriers also known as lubricants. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed and hyaluronic acid.
Medicaments which may be administered in conjunction with the compounds described herein include any suitable drugs usefully delivered by inhalation for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti-infectives, e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol, orciprenaline or (−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, e.g. insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimize the activity and/or stability of the medicament.
Other exemplary therapeutic agents useful for a combination therapy include but are not limited to agents as described above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones, insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas, agents affecting calcification and bone turnover: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such as water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents acting at the neuromuscular junction and/or autonomic ganglia; catecholamines, sympathomimetic drugs, and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.
Therapeutic agents can also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances that are generated by biotransformation of the products of the selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesic-antipyretic agents, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of the inducible cyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers and leukotriene inhibitors.
Additional therapeutic agents contemplated herein include diuretics, vasopressin, agents affecting the renal conservation of water, rennin, angiotensin, agents useful in the treatment of myocardial ischemia, anti-hypertensive agents, angiotensin converting enzyme inhibitors, β-adrenergic receptor antagonists, agents for the treatment of hypercholesterolemia, and agents for the treatment of dyslipidemia.
Other therapeutic agents contemplated include drugs used for control of gastric acidity, agents for the treatment of peptic ulcers, agents for the treatment of gastroesophageal reflux disease, prokinetic agents, antiemetics, agents used in irritable bowel syndrome, agents used for diarrhea, agents used for constipation, agents used for inflammatory bowel disease, agents used for biliary disease, agents used for pancreatic disease. Therapeutic agents used to treat protozoan infections, drugs used to treat Malaria, Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs used in the chemotherapy of helminthiasis. Other therapeutic agents include antimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, penicillins, cephalosporins, and other, β-Lactam antibiotics, an agent comprising an aminoglycoside, protein synthesis inhibitors, drugs used in the chemotherapy of tuberculosis, mycobacterium avium complex disease, and leprosy, antifungal agents, antiviral agents including nonretroviral agents and antiretroviral agents.
Examples of therapeutic antibodies that can be combined with a subject compound include but are not limited to anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies (rituximab, tositumomab), and other antibodies such as alemtuzumab, bevacizumab, and gemtuzumab.
Moreover, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogens, and immunostimulants are contemplated by the methods herein. In addition, therapeutic agents acting on the blood and the blood-forming organs, hematopoietic agents, growth factors, minerals, and vitamins, anticoagulant, thrombolytic, and antiplatelet drugs.
Further therapeutic agents that can be combined with a subject compound may be found in Goodman and Gilman's “The Pharmacological Basis of Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.
The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the compounds of the invention will be co-administer with other agents as described above. When used in combination therapy, the compounds described herein may be administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the present invention and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present invention can be administered just followed by and any of the agents described above, or vice versa. In the separate administration protocol, a compound of the present invention and any of the agents described above may be administered a few minutes apart, or a few hours apart, or a few days apart.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
Administration of the compounds of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent. Compounds can also abe administered intraadiposally or intrathecally.
The amount of the compound administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. bydividing such larger doses into several small doses for administration throughout the day.
The compound may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; anti-metabolites, for example 5-fluorouracil, cytosine arabinside and hydroxyurea, or, for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid; growth factor inhibitors; cell cycle inhibitors; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example, interferon; and anti-hormones, for example anti-estrogens such as NolvadexTM (tamoxifen) or, for example anti-androgens such as CasodexTM (4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl) propionanilide). Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of treatment.
In some embodiments, a compound of the invention is administered in a single dose. Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition.
In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
Administration of the agents of the invention may continue as long as necessary. In some embodiments, an agent of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, an agent of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for eample, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the invention may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.
A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No. 5,451,233; U.S. Pat. No. 5,040,548; U.S. Pat. No. 5,061,273; U.S. Pat. No. 5,496,346; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 3,657,744; U.S. Pat. No. 4,739,762; U.S. Pat. No. 5,195,984; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No. 6,344,053; U.S. Pat. No. 4,762,129; U.S. Pat. No. 6,152,946; U.S. Pat. No. 6,663,652; U.S. Pat. No. 6,027,520; U.S. Pat. No. 6,676,682; U.S. Pat. No. 6,663,652; U.S. Pat. No. 6,872,216; U.S. Pat. No. 6,027,520; U.S. Pat. No. 6,114,653; U.S. Pat. No. 5,852,277; U.S. Pat. No. 5,843,120; U.S. Pat. No. 5,643,312; U.S. Pat. No. 5,733,303; U.S. Pat. No. 5,597,378; U.S. Pat. No. 5,653,727; U.S. Pat. No. 4,762,129; U.S. Pat. No. 5,922,021; U.S. Pat. No. 3,657,744; U.S. Pat. No. 4,739,762; U.S. Pat. No. 5,195,984; U.S. Pat. No. 5,451,233; U.S. Pat. No. 3,657,744; U.S. Pat. No. 4,739,762; U.S. Pat. No. 5,195,984; U.S. Pat. No. 4,739,762; U.S. Pat. No. 3,657,744; U.S. Pat. No. 4,739,762; U.S. Pat. No. 5,195,984; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,643,312; U.S. Pat. No. 5,879,370; U.S. Pat. No. 5,421,955; U.S. Pat. No. 5,514,154; U.S. Pat. No. 5,603,721; U.S. Pat. No. 5,421,955; U.S. Pat. No. 5,514,154; U.S. Pat. No. 5,603,721; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No. 6,344,053; U.S. Pat. No. 5,728,067; U.S. Pat. No. 5,980,486; U.S. Pat. No. 6,129,708; U.S. Pat. No. 5,733,303; U.S. Pat. No. 5,843,120; U.S. Pat. No. 5,972,018; U.S. Pat. No. 5,972,018; U.S. Pat. No. 5,733,303; U.S. Pat. No. 5,843,120; U.S. Pat. No. 4,739,762; U.S. Pat. No. 5,195,984; U.S. Pat. No. 5,902,332; U.S. Pat. No. 5,156,594; U.S. Pat. No. 5,395,334; U.S. Pat. No. 6,090,083; U.S. Pat. No. 5,639,278; U.S. Pat. No. 6,051,020; U.S. Pat. No. 6,117,167; U.S. Pat. No. 5,632,772; U.S. Pat. No. 6,165,213; U.S. Pat. No. 4,762,129; U.S. Pat. No. 5,156,594; U.S. Pat. No. 5,217,482; U.S. Pat. No. 5,395,334; U.S. Pat. No. 4,641,653; U.S. Pat. No. 4,739,762; U.S. Pat. No. 5,922,021; U.S. Pat. No. 5,895,406; U.S. Pat. No. 6,251,920; U.S. Pat. No. 6,120,536; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No. 6,344,053; U.S. Pat. No. 5,609,627; U.S. Pat. No. 6,251,920; U.S. Pat. No. 5,733,303; U.S. Pat. No. 5,843,120; U.S. Pat. No. 5,972,018; U.S. Pat. No. 6,344,053; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No. 5,653,760; U.S. Pat. No. 6,190,358; U.S. Pat. No. 6,210,364; U.S. Pat. No. 6,283,939; U.S. Pat. No. 6,605,057; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No. 6,344,053; U.S. Pat. No. 5,423,851; U.S. Pat. No. 6,007,575; U.S. Pat. No. 5,501,759; U.S. Pat. No. 5,674,208; U.S. Pat. No. 5,843,032; U.S. Pat. No. 5,961,765; U.S. Pat. No. 6,027,477; U.S. Pat. No. 6,319,228; U.S. Pat. No. 6,471,673; U.S. Pat. No. 6,190,358; U.S. Pat. No. 6,605,057; U.S. Pat. No. 6,858,037; U.S. Pat. No. 7,001,358; U.S. Pat. No. 5,156,594; U.S. Pat. No. 5,217,482; U.S. Pat. No. 5,395,334; U.S. Pat. No. 5,702,439; U.S. Pat. No. 5,501,759; U.S. Pat. No. 5,674,208; U.S. Pat. No. 5,843,032; U.S. Pat. No. 5,961,765; U.S. Pat. No. 6,027,477; U.S. Pat. No. 6,319,228; U.S. Pat. No. 6,471,673; U.S. Pat. No. 5,759,192; U.S. Pat. No. 6,527,789; U.S. Pat. No. 5,147,302; U.S. Pat. No. 5,342,307; U.S. Pat. No. 6,290,485; U.S. Pat. No. 6,352,551; U.S. Pat. No. 6,402,778; U.S. Pat. No. 6,488,694; U.S. Pat. No. 6,511,505; U.S. Pat. No. 6,613,073; U.S. Pat. No. 6,582,458; U.S. Pat. No. 5,820,594; U.S. Pat. No. 5,824,173; U.S. Pat. No. 5,538,510; U.S. Pat. No. 4,323,071; U.S. Pat. No. 4,762,129; U.S. Pat. No. 4,846,186; U.S. Pat. No. 5,156,594; U.S. Pat. No. 5,217,482; U.S. Pat. No. 5,395,334; U.S. Pat. No. 5,156,594; U.S. Pat. No. 4,323,071; U.S. Pat. No. 5,040,548; U.S. Pat. No. 5,061,273; U.S. Pat. No. 5,451,233; U.S. Pat. No. 5,496,346; U.S. Pat. No. 5,496,275; U.S. Pat. No. 5,496,346; U.S. Pat. No. 5,040,548; U.S. Pat. No. 5,061,273; U.S. Pat. No. 5,451,233; U.S. Pat. No. 5,496,346; U.S. Pat. No. 4,596,563; U.S. Pat. No. 5,040,548; U.S. Pat. No. 5,061,273; U.S. Pat. No. 5,350,395; U.S. Pat. No. 5,451,233; U.S. Pat. No. 5,445,625; U.S. Pat. No. 6,083,213; U.S. Pat. No. 6,475,195; U.S. Pat. No. 5,421,955; U.S. Pat. No. 5,514,154; U.S. Pat. No. 5,603,721; U.S. Pat. No. 5,292,331; U.S. Pat. No. 5,674,278; U.S. Pat. No. 5,879,382; U.S. Pat. No. 6,344,053; U.S. Pat. No. 6,238,415; U.S. Pat. No. 5,421,955; U.S. Pat. No. 5,514,154; and U.S. Pat. No. 5,603,721.
The compounds of the invention may be administered in dosages as described herein (see, e.g., Compositions). It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation.
When a compound of the invention, is administered in a composition that comprises one or more agents, and the agent has a shorter half-life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly. See e.g., Compositions.
The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
The activity of the compounds of the present invention may be determined by the following procedure, as well as the procedure described in the examples below. N-terminal 6 His-tagged, constitutively active kinase is expressed in E. coli and protein is purified by conventional methods (Ahn et al. Science 1994, 265, 966-970). The activity of the kinase is assessed by measuring the incorporation of γ-33P-phosphate from γ-33P-ATP onto N-terminal His tagged substrate, which is expressed in E. coli and is purified by conventional methods, in the presence of the kinase. The assay is carried out in 96-well polypropylene plate. The incubation mixture (100 μL) comprises of 25 mM Hepes, pH 7.4, 10 mM MgCl2, 5 mM β-glycerolphosphate, 100 μM Na-orthovanadate, 5 mM DTT, 5 nM kinase, and 1 μM substrate. Inhibitors are suspended in DMSO, and all reactions, including controls are performed at a final concentration of 1% DMSO. Reactions are initiated by the addition of 10 μM ATP (with 0.5 μCi γ-33P-ATP/well) and incubated at ambient temperature for 45 minutes. Equal volume of 25% TCA is added to stop the reaction and precipitate the proteins. Precipitated proteins are trapped onto glass fiber B filterplates, and excess labeled ATP washed off using a Tomtec MACH III harvestor. Plates are allowed to air-dry prior to adding 30 μL/well of Packard Microscint 20, and plates are counted using a Packard TopCount.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
EXAMPLES
Example 1
Expression and Inhibition Assays of p110α/p85α, p110β/p85α, p110δ/p85α, and p110γ
Class I PI3-Ks can be either purchased (p110α/p85α, p110β/p85α, p110δ/p85α from Upstate, and p110γ from Sigma) or expressed as previously described (Knight et al., 2004). IC50 values are measured using either a standard TLC assay for lipid kinase activity (described below) or a high-throughput membrane capture assay. Kinase reactions are performed by preparing a reaction mixture containing kinase, inhibitor (2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mM MgCl2), and freshly sonicated phosphatidylinositol (100 μg/ml). Reactions are initiated by the addition of ATP containing 10 μCi of γ-32P-ATP to a final concentration 10 or 100 μM and allowed to proceed for 5 minutes at room temperature. For TLC analysis, reactions are then terminated by the addition of 105 μl 1N HCl followed by 160 μl CHCl3:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged, and the organic phase is transferred to a new tube using a gel loading pipette tip precoated with CHCl3. This extract is spotted on TLC plates and developed for 3-4 hours in a 65:35 solution of n-propanol:1M acetic acid. The TLC plates are then dried, exposed to a phosphorimager screen (Storm, Amersham), and quantitated. For each compound, kinase activity is measured at 10-12 inhibitor concentrations representing two-fold dilutions from the highest concentration tested (typically, 200 μM). For compounds showing significant activity, IC50 determinations are repeated two to four times, and the reported value is the average of these independent measurements.
Other commercial kits or systems for assaying PI3-K activities are available. The commercially available kits or systems can be used to screen for inhibitors and/or agonists of PI3-Ks including but not limited to PI 3-Kinase α, β, δ, and γ. An exemplary system is PI 3-Kinase (human) HTRFTM Assay from Upstate. The assay can be carried out according to the procedures suggested by the manufacturer. Briefly, the assay is a time resolved FRET assay that indirectly measures PIP3 product formed by the activity of a PI3-K. The kinase reaction is performed in a microtitre plate (e.g., a 384 well microtitre plate). The total reaction volume is approximately 20 ul per well. In the first step, each well receives 2 ul of test compound in 20% dimethylsulphoxide resulting in a 2% DMSO final concentration. Next, approximately 14.5 ul of a kinase/PIP2 mixture (diluted in 1× reaction buffer) is added per well for a final concentration of 0.25-0.3 ug/ml kinase and 10 uM PIP2. The plate is sealed and incubated for 15 minutes at room temperature. To start the reaction, 3.5 ul of ATP (diluted in 1× reaction buffer) is added per well for a final concentration of 10 uM ATP. The plate is sealed and incubated for 1 hour at room temperature. The reaction is stopped by adding 5 ul of Stop Solution per well and then 5 ul of Detection Mix is added per well. The plate is sealed, incubated for 1 hour at room temperature, and then read on an appropriate plate reader. Data is analyzed and IC50s are generated using GraphPad Prism 5.
Example 2
Expression and Inhibition Assays of Abl
The compounds described herein can be assayed in triplicate against recombinant full-length Abl or Abl (T315I) (Upstate) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5 mg/mL BSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used as phosphoacceptor (200 μM). Reactions are terminated by spotting onto phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 3
Expression and Inhibition Assays of Hck
The compounds described herein can be assayed in triplicate against recombinant full-length Hck in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5 mg/mL BSA. The optimized Src family kinase peptide substrate EIYGEFKKK is used as phosphoacceptor (200 μM). Reactions are terminated by spotting onto phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 4
Expression and Inhibition Assays of Inulsin Receptor (IR)
The compounds described herein can be assayed in triplicate against recombinant insulin receptor kinase domain (Upstate) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 10 mM MnCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5 mg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate. Reactions are terminated by spotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 5
Expression and Inhibition Assays of Src
The compounds described herein can be assayed in triplicate against recombinant full-length Src or Src (T338I) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi of γ-32P-ATP), and 0.5 mg/mL BSA. The optimized Src family kinase peptide substrate EIYGEFKKK is used as phosphoacceptor (200 μM). Reactions are terminated by spotting onto phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets were dried and the transferred radioactivity quantitated by phosphorimaging.
Example 6
Expression and Inhibition Assays of DNA-PK (DNAK)
DNA-PK can be purchased from Promega and assayed using the DNA-PK Assay System (Promega) according to the manufacturer's instructions.
Example 7
Expression and Inhibition Assays mTOR
The compounds described herein can be tested against recombinant mTOR (Invitrogen) in an assay containing 50 mM HEPES, pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2.5 mM, 0.01% Tween, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. Rat recombinant PHAS-1/4EBP1 (Calbiochem; 2 mg/mL) is used as a substrate. Reactions are terminated by spotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Other kits or systems for assaying mTOR activity are commercially available. For instance, one can use Invitrogen's LanthaScreenTM Kinase assay to test the inhibitors of mTOR disclosed herein. This assay is a time resolved FRET platform that measures the phosphorylation of GFP labeled 4EBP1 by mTOR kinase. The kinase reaction is performed in a white 384 well microtitre plate. The total reaction volume is 20 ul per well and the reaction buffer composition is 50 mM HEPES pH7.5, 0.01% Polysorbate 20, 1 mM EGTA, 10 mM MnCl2, and 2 mM DTT. In the first step, each well receives 2 ul of test compound in 20% dimethylsulphoxide resulting in a 2% DMSO final concentration. Next, 8 ul of mTOR diluted in reaction buffer is added per well for a 60 ng/ml final concentration. To start the reaction, 10 ul of an ATP/GFP-4EBP1 mixture (diluted in reaction buffer) is added per well for a final concentration of 10 uM ATP and 0.5 uM GFP-4EBP1. The plate is sealed and incubated for 1 hour at room temperature. The reaction is stopped by adding 10 ul per well of a Tb-anti-pT46 4EBP1 antibody/EDTA mixture (diluted in TR-FRET buffer) for a final concentration of 1.3 nM antibody and 6.7 mM EDTA. The plate is sealed, incubated for 1 hour at room temperature, and then read on a plate reader set up for LanthaScreenTM TR-FRET. Data is analyzed and IC50s are generated using GraphPad Prism 5.
Example 8
Expression and Inhibition Assays of Vascular Endothelial Growth Receptor
The compounds described herein can be tested against recombinant KDR receptor kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 0.1% BME, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate. Reactions are terminated by spotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 9
Expression and Inhibition Assays of Ephrin Receptor B4 (EphB4)
The compounds described herein can be tested against recombinant Ephrin receptor B4 kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 0.1% BME, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate. Reactions are terminated by spotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 10
Expression and Inhibition Assays of Epidermal Growth Factor Receptor (EGFR)
The compounds described herein can be tested against recombinant EGF receptor kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 0.1% BME, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate. Reactions are terminated by spotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 11
Expression and Inhibition Assays of KIT Assay
The compounds described herein can be tested against recombinant KIT kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM DTT, 10 mM MnCl2, 10 μM ATP (2.5 of μ-32P-ATP), and 3 μg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate. Reactions are terminated by spotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 12
Expression and Inhibition Assays of RET
The compounds described herein can be tested against recombinant RET kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 2.5 mM DTT, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used as phosphoacceptor (200 μM). Reactions are terminated by spotting onto phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 13
Expression and Inhibition Assays of Platelet Derived Growth Factor Receptor (PDGFR)
The compounds described herein can be tested against recombinant PDG receptor kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 2.5 mM DTT, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used as phosphoacceptor (200 μM). Reactions are terminated by spotting onto phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 14
Expression and Inhibition Assays of FMS-Related Tyrosine Kinase 3 (FLT-3)
The compounds described herein can be tested against recombinant FLT-3 kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 2.5 mM DTT, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used as phosphoacceptor (200 μM). Reactions are terminated by spotting onto phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 15
Expression and Inhibition Assays of TEK Receptor Tyrosine Kinase (TIE2)
The compounds described herein can be tested against recombinant TIE2 kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 2 mM DTT, 10 mM MnCl2, 10 μM ATP (2.5 μCi of μ-32P-ATP), and 3 μg/mL BSA. Poly E-Y (Sigma; 2 mg/mL) is used as a substrate. Reactions are terminated by spotting onto nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Sheets are dried and the transferred radioactivity quantitated by phosphorimaging.
Example 16
B Cell Activation and Proliferation Assay
The ability of one or more subject compounds to inhibit B cell activation and proliferation is determined according to standard procedures known in the art. For example, an in vitro cellular proliferation assay is established that measures the metabolic activity of live cells. The assay is performed in a 96 well microtiter plate using Alamar Blue reduction. Balb/c splenic B cells are purified over a Ficoll-PaqueTM PLUS gradient followed by magnetic cell separation using a MACS B cell Isolation Kit (Miletenyi). Cells are plated in 90 ul at 50,000 cells/well in B Cell Media (RPMI+10% FBS+Penn/Strep+50 uM bME+5 mM HEPES). A compound disclosed herein is diluted in B Cell Media and added in a 10 ul volume. Plates are incubated for 30 min at 37 C and 5% CO2 (0.2% DMSO final concentration). A 50 ul B cell stimulation cocktail is then added containing either 10 ug/ml LPS or 5 ug/ml F(ab′)2 Donkey anti-mouse IgM plus 2 ng/ml recombinant mouse IL4 in B Cell Media. Plates are incubated for 72 hours at 37° C. and 5% CO2. A volume of 15 uL of Alamar Blue reagent is added to each well and plates are incubated for 5 hours at 37 C and 5% CO2. Alamar Blue fluoresce is read at 560Ex/590Em, and IC50 or EC50 values are calculated using GraphPad Prism 5.
Example 17
Tumor Cell Line Proliferation Assay
The ability of one or more subject compounds to inhibit tumor cell line proliferation is determined according to standard procedures known in the art. For instance, an in vitro cellular proliferation assay can be performed to measure the metabolic activity of live cells. The assay is performed in a 96 well microtiter plate using Alamar Blue reduction. Human tumor cell lines are obtained from ATCC (e.g., MCF7, U-87 MG, MDA-MB-468, PC-3), grown to confluency in T75 flasks, trypsinized with 0.25% trypsin, washed one time with Tumor Cell Media (DMEM+10% FBS), and plated in 90 ul at 5,000 cells/well in Tumor Cell Media. A compound disclosed herein is diluted in Tumor Cell Media and added in a 10 ul volume. Plates are incubated for 72 hours at 37 C and 5% CO2. A volume of 10 uL of Alamar Blue reagent is added to each well and plates are incubated for 3 hours at 37 C and 5% CO2. Alamar Blue fluoresce is read at 560Ex/590Em, and IC50 values are calculated using GraphPad Prism 5.
Example 18
Antitumor Activity In Vivo
The compounds described herein can be evaluated in a panel of human and murine tumor models.
Paclitaxel-Refractory Tumor Models
1. Clinically-Derived Ovarian Carcinoma Model.
This tumor model is established from a tumor biopsy of an ovarian cancer patient. Tumor biopsy is taken from the patient.
The compounds described herein are administered to nude mice bearing staged tumors using an every 2 days×5 schedule.
2. A2780Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin).
A2780Tax is a paclitaxel-resistant human ovarian carcinoma model. It is derived from the sensitive parent A2780 line by co-incubation of cells with paclitaxel and verapamil, an MDR-reversal agent. Its resistance mechanism has been shown to be non-MDR related and is attributed to a mutation in the gene encoding the beta-tubulin protein.
The compounds described herein can be administered to mice bearing staged tumors on an every 2 days×5 schedule.
3. HCT116/VM46 Human Colon Carcinoma Xenograft (Multi-Drug Resistant).
HCT116/VM46 is an MDR-resistant colon carcinoma developed from the sensitive HCT116 parent line. In vivo, grown in nude mice, HCT116/VM46 has consistently demonstrated high resistance to paclitaxel.
The compounds described herein can be administered to mice bearing staged tumors on an every 2 days×5 schedule.
5. M5076 Murine Sarcoma Model
M5076 is a mouse fibrosarcoma that is inherently refractory to paclitaxel in vivo.
The compounds described herein can be administered to mice bearing staged tumors on an every 2 days×5 schedule.
One or more compounds of the invention can be used in combination other therapeutic agents in vivo in the multidrug resistant human colon carcinoma xenografts HCT/VM46 or any other model known in the art including those described herein.
Example 19
Microsome Stability Assay
The stability of one or more subject compounds is determined according to standard procedures known in the art. For example, stability of one or more subject compounds is established by an in vitro assay. In particular, an in vitro microsome stability assay is established that measures stability of one or more subject compounds when reacting with mouse, rat or human microsomes from liver. The microsome reaction with compounds is performed in 1.5 mL Eppendorf tube. Each tube contains 0.1 μL of 10.0 mg/ml NADPH; 75 μL, of 20.0 mg/ml mouse, rat or human liver microsome; 0.4 μL of 0.2 M phosphate buffer, and 425 μL of ddH2O, Negative control (without NADPH) tube contains 75 μL of 20.0 mg/ml mouse, rat or human liver microsome; 0.4 μL of 0.2 M phosphate buffer, and 525 μL of ddH2O. The reaction is started by adding 1.0 μL of 10.0 mM tested compound. The reaction tubes are incubated at 37° C. 100 μL sample is collected into new Eppendorf tube containing 300 μL cold Methanol at 0, 5, 10, 15, 30 and 60 minutes of reaction. Samples are centrifuged at 15,000 rpm to remove protein. Supernatant of centrifuged sample is transferred to new tube. Concentration of stable compound after reaction with microsome in the supernatant is measured by Liquid Chromatography/Mass Spectrometry (LC-MS).
Example 20
Plasma Stability Assay
The stability of one or more subject compounds in plasma is determined according to standard procedures known in the art. See, e.g., Rapid Commun. Mass Spectrom., 10: 1019-1026. The following procedure is an HPLC-MS/MS assay using human plasma; other species including monkey, dog, rat, and mouse are also available. Frozen, heparinized human plasma is thawed in a cold water bath and spun for 10 minutes at 2000 rpm at 4° C. prior to use. A subject compound is added from a 400 μM stock solution to an aliquot of pre-warmed plasma to give a final assay volume of 400 μL (or 800 μL for half-life determination), containing 5 μM test compound and 0.5% DMSO. Reactions are incubated, with shaking, for 0 minutes and 60 minutes at 37° C., or for 0, 15, 30, 45 and 60 minutes at 37 C for half life determination. Reactions are stopped by transferring 50 μL of the incubation mixture to 200 μL of ice-cold acetonitrile and mixed by shaking for 5 minutes. The samples are centrifuged at 6000×g for 15 minutes at 4° C. and 120 μL of supernatant removed into clean tubes. The samples are then evaporated to dryness and submitted for analysis by HPLC-MS/MS.
Where desired, one or more control or reference compounds (5 μM) are tested simultaneously with the test compounds: one compound, propoxycaine, with low plasma stability and another compound, propantheline, with intermediate plasma stability.
Samples are reconstituted in acetonitrile/methanol/water (1/1/2, v/v/v) and analyzed via (RP)HPLC-MS/MS using selected reaction monitoring (SRM). The HPLC conditions consist of a binary LC pump with autosampler, a mixed-mode, C12, 2×20 mm column, and a gradient program. Peak areas corresponding to the analytes are recorded by HPLC-MS/MS. The ratio of the parent compound remaining after 60 minutes relative to the amount remaining at time zero, expressed as percent, is reported as plasma stability. In case of half-life determination, the half-life is estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming first order kinetics.
Example 21
Chemical Stability
The chemical stability of one or more subject compounds is determined according to standard procedures known in the art. The following details an exemplary procedure for ascertaining chemical stability of a subject compound. The default buffer used for the chemical stability assay is phosphate-buffered saline (PBS) at pH 7.4; other suitable buffers can be used. A subject compound is added from a 100 μM stock solution to an aliquot of PBS (in duplicate) to give a final assay volume of 400 μL, containing 5 μM test compound and 1% DMSO (for half-life determination a total sample volume of 700 μL is prepared). Reactions are incubated, with shaking, for 0 minutes and 24 hours at 37° C.; for half-life determination samples are incubated for 0, 2, 4, 6, and 24 hours. Reactions are stopped by adding immediately 100 μL of the incubation mixture to 100 μL of acetonitrile and vortexing for 5 minutes. The samples are then stored at −20° C. until analysis by HPLC-MS/MS. Where desired, a control compound or a reference compound such as chlorambucil (5 μM) is tested simultaneously with a subject compound of interest, as this compound is largely hydrolyzed over the course of 24 hours. Samples are analyzed via (RP)HPLC-MS/MS using selected reaction monitoring (SRM). The HPLC conditions consist of a binary LC pump with autosampler, a mixed-mode, C12, 2×20 mm column, and a gradient program. Peak areas corresponding to the analytes are recorded by HPLC-MS/MS. The ratio of the parent compound remaining after 24 hours relative to the amount remaining at time zero, expressed as percent, is reported as chemical stability. In case of half-life determination, the half-life is estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming first order kinetics.
Example 22
Akt Kinase Assay
Cells comprising components of the Akt/mTOR pathway, including but not limited to L6 myoblasts, B-ALL cells, B-cells, T-cells, leukemia cells, bone marrow cells, p190 transduced cells, philladelphia chromosome positive cells (Ph+), and mouse embryonic fibroblasts, are typically grown in cell growth media such as DMEM supplemented with fetal bovine serum and/or antibiotics, and grown to confluency.
In order to compare the effect of one or more compounds disclosed herein on Akt activation, said cells are serum starved overnight and incubated with one or more compounds disclosed herein or about 0.1% DMSO for approximately 1 minute to about 1 hour prior to stimulation with insulin (e.g. 100 nM) for about 1 minutes to about 1 hour. Cells are lysed by scraping into ice cold lysis buffer containing detergents such as sodium dodecyl sulfate and protease inhibitors (e.g., PMSF). After contacting cells with lysis buffer, the solution is briefly sonicated, cleared by centrifugation, resolved by SDS-PAGE, transferred to nitrocellulose or PVDF and immunoblotted using antibodies to phospho-Akt S473, phospho-Akt T308, Akt, and β-actin (Cell Signaling Technologies).
The results demonstrate that one or more compounds of the present disclosure inhibit insulin stimulated phosphorylation of Akt at S473. Alternatively, some compounds disclosed herein additionally inhibit insulin stimulated phosphorylation of Akt at T308. Such class of compounds can inhibit Akt more effectively than rapamycin and may be indicative of mTORC2 inhibitors or inhibitors of upstream kinases such as PI3K or Akt.
Example 23
Kinase Signaling in Blood
PI3K/Akt/mTor signaling is measured in blood cells using the phosflow method (Methods Enzymol. 2007; 434:131-54). The advantage of this method is that it is by nature a single cell assay so that cellular heterogeneity can be detected rather than population averages. This allows concurrent dinstinction of signaling states in different populations defined by other markers. Phosflow is also highly quantitative. To test the effects of one or more compounds disclosed herein, unfractionated splenocytes, or peripheral blood mononuclear cells are stimulated with anti-CD3 to initiate T-cell receptor signaling. The cells are then fixed and stained for surface markers and intracellular phosphoproteins. It is expected that inhibitors disclosed herein inhibit anti-CD3 mediated phosphorylation of Akt-S473 and S6, whereas rapamycin inhibits S6 phosphorylation and enhances Akt phosphorylation under the conditions tested.
Similarly, aliquots of whole blood are incubated for 15 minutes with vehicle (e.g. 0.1% DMSO) or kinase inhibitors at various concentrations, before addition of stimuli to crosslink the T cell receptor (TCR) (anti-CD3 with secondary antibody) or the B cell receptor (BCR) using anti-kappa light chain antibody (Fab′2 fragments). After approximately 5 and 15 minutes, samples are fixed (e.g. with cold 4% paraformaldehyde) and used for phosflow. Surface staining is used to distinguish T and B cells using antibodies directed to cell surface markers that are known to the art. The level of phosphorylation of kinase substrates such as Akt and S6 are then measured by incubating the fixed cells with labeled antibodies specific to the phosphorylated isoforms of these proteins. The population of cells are then analyzed by flow cytometry.
Example 24
Colony Formation Assay
Murine bone marrow cells freshly transformed with a p190 BCR-Abl retrovirus (herein referred to as p190 transduced cells) are plated in the presence of various drug combinations in M3630 methylcellulose media for about 7 days with recombinant human IL-7 in about 30% serum, and the number of colonies formed is counted by visual examination under a microscope.
Alternatively, human peripheral blood mononuclear cells are obtained from Philadelphia chromosome positive (Ph+) and negative (Ph−) patients upon initial diagnosis or relapse. Live cells are isolated and enriched for CD19+ CD34+ B cell progenitors. After overnight liquid culture, cells are plated in methocult GF+ H4435, Stem Cell Tehcnologies) suplemented with cytokines (IL-3, IL-6, IL-7, G-CSF, GM-CSF, CF, Flt3 ligand, and erythropoietin) and various concentrations of known chemotherapeutic agents in combination with either compounds of the present disclosure. Colonies are counted by microscopy 12-14 days later. This method can be used to test for evidence of additive or synergistic activity.
Example 25
In Vivo Effect of Kinase Inhibitors on Leukemic Cells
Female recipient mice are lethally irradiated from a γ source in two doses about 4 hr apart, with approximately 5Gy each. About 1 hr after the second radiation dose, mice are injected i.v. with about 1×106 leukemic cells (e.g. Ph+ human or murine cells, or p190 transduced bone marrow cells). These cells are administered together with a radioprotective dose of about 5×106 normal bone marrow cells from 3-5 week old donor mice. Recipients are given antibiotics in the water and monitored daily. Mice who become sick after about 14 days are euthanized and lymphoid organs are harvested for analysis. Kinase inhibitor treatment begins about 10 days after leukemic cell injection and continues daily until the mice become sick or a maximum of approximately 35 days post-transplant. Inhibitors are given by oral lavage.
Peripheral blood cells are collected approximately on day 10 (pre-treatment) and upon euthanization (post treatment), contacted with labeled anti-hCD4 antibodies and counted by flow cytometry. This method can be used to demonstrate that the synergistic effect of one or more compounds disclosed herein in combination with known chemotherapeutic agents significantly reduce leukemic blood cell counts as compared to treatment with known chemotherapeutic agents (e.g. Gleevac) alone under the conditions tested.
Example 26
Treatment of Lupus Disease Model Mice
Mice lacking the inhibitory receptor FcγRIIb that opposes PI3K signaling in B cells develop lupus with high penetrance. FcγRIIb knockout mice (R2KO, Jackson Labs) are considered a valid model of the human disease as some lupus patients show decreased expression or function of FcγRIIb (S. Bolland and J. V. Ravtech 2000. Immunity 12:277-285).
The R2KO mice develop lupus-like disease with anti-nuclear antibodies, glomerulonephritis and proteinurea within about 4-6 months of age. For these experiments, the rapamycin analogue RAD001 (available from LC Laboratories) is used as a benchmark compound, and administered orally. This compound has been shown to ameliorate lupus symptoms in the B6.Sle1z.Sle3z model (T. Wu et al. J. Clin Invest. 117:2186-2196).
Lupus disease model mice such as R2KO, BXSB or MLR/lpr are treated at about 2 months old, approximately for about two months. Mice are given doses of: vehicle, RAD001 at about 10 mg/kg, or compounds disclosed herein at approximately 1 mg/kg to about 500 mg/kg. Blood and urine samples are obtained at approximately throughout the testing period, and tested for antinuclear antibodies (in dilutions of serum) or protein concentration (in urine). Serum is also tested for anti-ssDNA and anti-dsDNA antibodies by ELISA. Animals are euthanized at day 60 and tissues harvested for measuring spleen weight and kidney disease. Glomerulonephritis is assessed in kidney sections stained with H&E. Other animals are studied for about two months after cessation of treatment, using the same endpoints.
This model established in the art can be employed to demonstrate that the kinase inhibitors disclosed herein can suppress or delay the onset of lupus symptoms in lupus disease model mice.
Example 27
Murine Bone Marrow Transplant Assay
Female recipient mice are lethally irradiated from a γ ray source. About 1 hr after the radiation dose, mice are injected with about 1×106 leukemic cells from early passage p190 transduced cultures (e.g. as described in Cancer Genet Cytogenet. 2005 August; 161(1):51-6). These cells are administered together with a radioprotective dose of approximately 5×106 normal bone marrow cells from 3-5 wk old donor mice. Recipients are given antibiotics in the water and monitored daily. Mice who become sick after about 14 days are euthanized and lymphoid organs harvested for flow cytometry and/or magnetic enrichment. Treatment begins on approximately day 10 and continues daily until mice become sick, or after a maximum of about 35 days post-transplant. Drugs are given by oral gavage (p.o.). In a pilot experiment a dose of chemotherapeutic that is not curative but delays leukemia onset by about one week or less is identified; controls are vehicle-treated or treated with chemotherapeutic agent, previously shown to delay but not cure leukemogenesis in this model (e.g. imatinib at about 70 mg/kg twice daily). For the first phase p190 cells that express eGFP are used, and postmortem analysis is limited to enumeration of the percentage of leukemic cells in bone marrow, spleen and lymph node (LN) by flow cytometry. In the second phase, p190 cells that express a tailless form of human CD4 are used and the postmortem analysis includes magnetic sorting of hCD4+ cells from spleen followed by immunoblot analysis of key signaling endpoints: p Akt-T308 and S473; pS6 and p4EBP-1. As controls for immunoblot detection, sorted cells are incubated in the presence or absence of kinase inhibitors of the present disclosure inhibitors before lysis. Optionally, “phosflow” is used to detect p Akt —S473 and pS6-S235/236 in hCD4-gated cells without prior sorting. These signaling studies are particularly useful if, for example, drug-treated mice have not developed clinical leukemia at the 35 day time point. Kaplan-Meier plots of survival are generated and statistical analysis done according to methods known in the art. Results from p190 cells are analyzed separated as well as cumulatively.
Samples of peripheral blood (100-200 μl) are obtained weekly from all mice, starting on day 10 immediately prior to commencing treatment. Plasma is used for measuring drug concentrations, and cells are analyzed for leukemia markers (eGFP or hCD4) and signaling biomarkers as described herein.
This general assay known in the art may be used to demonstrate that effective therapeutic doses of the compounds disclosed herein can be used for inhibiting the proliferation of leukemic cells.

## Claims

1. A compound of formula I-E:



or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
n is an integer from 0 to 2;
L1 is a bond, alkylene, heteroalkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
R2 is —NH2;
R3 is hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R4 and R5 are independently hydrogen or R6, or R4 and R5 are taken together to form a 5, 6 or 7 membered ring, wherein the 5, 6, or 7 membered ring is unsubstituted;
z is 1;
each of R6 is independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R7 and R8 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, or R7 and R8 taken together form a cycloalkyl, heterocycloalkyl or aryl ring;
R9 is halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the heterocycloalkyl or heteroaryl is attached to the rest of the molecule through a carbon atom;
each R10 is independently hydrogen, —C(O)R15, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R11 is independently —NR16R17, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R12 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R13 is independently hydrogen, —S(O)nR18, —C(O)R19, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R14 is independently —NR20R21, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R15 is independently —NR22R23, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R16 and R17 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R16 and R17 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR16R17; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R18 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R19 is independently —NR24R25, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R20 and R21 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R20 and R21 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR20R21; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R22 and R23 are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R22 and R23 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR22R23; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R24 and R25 are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R24 and R25 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR24R25; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted; and
W is CR6 or N.

2. The compound of claim 1, wherein R4 and R5 are taken together to form a 6-membered ring.

3. The compound of claim 1, wherein z is 1 and one of R7 and R8 is hydrogen and the other is alkyl.

4. The compound of claim 1, wherein W is CH.

5. The compound of claim 1, wherein R9 is heterocycloalkyl or aryl.

6. A compound of formula I-J-1:



or a pharmaceutically acceptable salt thereof, wherein:
q is an integer from 0 to 5;
each of R6 is independently hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R9 is hydrogen, halogen, —CN, —OR10, —S(O)nR11, —NR12R13, —C(O)R14, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the heterocycloalkyl or heteroaryl is attached to the rest of the molecule through a carbon atom;
n is an integer from 0 to 2;
each R10 is independently hydrogen, —C(O)R15, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R11 is independently —NR16R17, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R12 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R13 is independently hydrogen, —S(O)nR18, —C(O)R19, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R14 is independently —NR20R21, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R15 is independently —NR22R23, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R16 and R17 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R16 and R17 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR16R17; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R18 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R19 is independently —NR24R25, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each of R20 and R21 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R20 and R21 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR20R21; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted;
each R22 and R23 are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R22 and R23 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR22R23; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted; and
each R24 and R25 are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R24 and R25 are taken together to form a 5, 6, 7, or 8 membered ring, wherein the 5, 6, 7, or 8 membered ring contains 0, 1, 2 or 3 ring heteroatoms selected from N, S, or O in addition to the nitrogen atom of —NR24R25; and further wherein the 5, 6, 7, or 8 membered ring is optionally substituted.

7. The compound of claim 1, wherein R4 and R5 are taken together to form a 5-membered ring.

8. The compound of claim 1, wherein W is N.

9. The compound of claim 5, wherein R9 is aryl.

10. The compound of claim 9, wherein R9 is phenyl.

11. The compound of claim 1, wherein z is 1 and R7 and R8 are hydrogen.

12. The compound of claim 1, wherein L′ is a bond and R′ is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

13. The compound of claim 12, wherein R′ is aryl or heteroaryl.

14. The compound of claim 13, wherein R′ is phenyl.

15. The compound of claim 1, wherein R3 is hydrogen.

16. The compound of claim 1, wherein R4 and R5 are taken together to form a 6-membered ring, W is CH, R9 is phenyl, and R2 is NH2.

17. The compound of claim 1, wherein the compound is











































































or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17, wherein the compound is



or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is



or a pharmaceutically acceptable salt thereof.

20. The compound of claim 6, wherein the compound is



or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

22. A pharmaceutical composition comprising a compound of claim 6 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.