PYRIMIDINE COMPOUNDS THAT INHIBIT ANAPLASTIC LYMPHOMA KINASE

FIELD OF THE INVENTION

The present invention relates to compounds capable of inhibiting the kinase activity of anaplastic lymphoma kinase (ALK), and compositions that include compounds that inhibit ALK. The compounds and compositions may be used to treat diseases or conditions modulated by ALK such as cancer and may be used to treat neurological disorders such as depression and are especially useful in treating patients with cancers expressing modified ALK or cancers related to ALK expression. For example, the compounds and compositions are especially useful in treating cancers that are positive for ALK fusion proteins EML4-ALK and/or NPM-ALK or have kinase activating point mutations in the ALK protein as well as amplifications of the ALK locus on chromosome 2p23.

BACKGROUND OF THE INVENTION

ALK is a receptor tyrosine kinase conserved across species and plays a key role in the growth and differentiation of neural tissues in the developing embryo. The receptor belongs in the insulin receptor superfamily and was initially identified as a member of a novel intracellular fusion protein with constitutive kinase activity in anaplastic large-cell lymphoma (ALCL). Bischof, D. et al., “Role of the Nucleophosmin (NPM) Portion of the Non-Hodgkin's Lymphoma-Associated NPM-Anaplastic Lymphoma Kinase Fusion Protein in Oncogenesis,” Molecular and Cellular Biology. 17, 2312-2325 (1997); Pulford, K. et al., “The Emerging Normal and Disease-Related Roles of Anaplastic Lymphoma Kinase,” Cell Mol Life Sci. 61, 2939-2953 (2004). Subsequent studies have identified ALK fusion proteins in diffuse large B-cell lymphomas, systemic histiocytosis, inflammatory myofibroblastic tumors, breast cancers, colorectal carcinomas, and non-small cell lung cancers. Morris, S. W. et al., “Fusion of a Kinase Gene, ALK, to a Nucleolar Protein Gene, NPM, in Non-Hodgkin's Lymphoma”, Science (New York, N.Y. 263, 1281-1284 (1994)); Lawrence, B. et al., “TPM3-ALK and TPM4-ALK Oncogenes in Inflammatory Myofibroblastic Tumors,” The American Journal of Pathology. 157, 377-384 (2000); Touriol, C. et al., “Further Demonstration of the Diversity of Chromosomal Changes Involving 2p23 in ALK-Positive Lymphoma: 2 Cases Expressing ALK Kinase Fused to CLTCL (Clathrin Chain Polypeptide-Like),” Blood. 95, 3204-3207 (2000); Soda, M. et al., “Identification of the Transforming EML4-ALK Fusion Gene in Non-Small-Cell Lung Cancer,” Nature. 448, 561-566 (2007); Lin, E. et al., “Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non-Small Cell Lung Cancers,” Mol Cancer Res. 7, 1466-1476 (2009). In addition, activating point mutations, as well as genomic DNA amplification and overexpression of ALK have recently been described in neuroblastomas. Mosse, Y. P. et al., “Identification of ALK as a Major Familial Neuroblastoma Predisposition Gene,” Nature. 455, 930-935 (2008).

Using immunostaining and other methods, 60-80% of ALCLs have been found to be ALK fusion-positive. Morris, S. W. et al., “Fusion of a Kinase Gene, ALK, to a Nucleolar Protein Gene, NPM, in Non-Hodgkin's Lymphoma”, Science (New York, N.Y. 263, 1281-1284 (1994)); Ladanyi, M. et al., “Reverse Transcriptase Polymerase Chain Reaction for the Ki-1 Anaplastic Large Cell Lymphoma-Associated t(2;5) Translocation in Hodgkin's Disease,” The American Journal of Pathology. 145, 1296-1300 (1994). ALK-positive ALCL cells express the cell surface protein CD30 and exhibit a cytotoxic T-cell or null phenotype. This lymphoma entity is now officially classified as ‘ALK-positive ALCL’ in the WHO classification of NHL.

More recently, ALK has been identified in a subset of non small cell lung carcinoma patients (NSCLC). In 2006, genetic analysis of a patient with NSCLC led to the discovery of a novel fusion gene between the echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) genes. Oncogenic activity of EML4-ALK requires the N-terminal coiled-coil domain within EML4 that leads to the constitutive dimerization and, thereby, activation of the fusion protein. Soda, M. et al., “Identification of the Transforming EML4-ALK Fusion Gene in Non-Small-Cell Lung Cancer,” Nature. 448, 561-566 (2007). Since both of the EML4 and ALK genes are closely mapped in an opposite direction to the same short arm of human chromosome 2, a small chromosome inversion involving the two genes is likely to be the underlining mechanism for the generation of the gene fusion, which was indeed evidenced by both Fluorescence In Situ Hybridization (FISH) and genomic PCR analyses.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of Formula I:

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or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of the stereoisomer, or a mixture thereof,

wherein:

X is selected from —CH₂—, —N(H)—, —O—, or —S—;

V is absent or is selected from —CH₂—, —O—, —S—, or —NH—; wherein if V is —O—, —S—, or —NH—, then r is 1 and q is 1;

the subscript p is selected from 0, 1, 2, or 3, wherein X is CH₂if p is 0;

the subscript q is selected from 0 or 1;

the subscript r is selected from 0 or 1:

the custom-character symbol indicates that the bond can be a single or double bond;

Z is a C₆-C₁₀aryl or a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, or N, wherein the C₆-C₁₀aryl or the 5-10 membered heteroaryl are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —Z′, —O—Z′, —S—Z′, —NH—Z′, —CH₂Z′, —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —C(═O)NH—Z′, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —SO₂NH—Z′, —NHSO₂—(C₁-C₄)alkyl, —NHSO₂—Z′, —NHC(═O)—(C₁-C₄)alkyl, —NHC(═O)—Z′, —SO₂—(C₁-C₄)alkyl, —SO₂—Z′, —SO—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl, —CO₂H, —C(═O)—Z′, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH₄C₁-C₄)alkylene-NH((C₁-C₄)alkyl), —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄alkyl)₂, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; and two adjacent substituents on the C₆-C₁₀aryl or the 5-10 membered heteroaryl may join to form a 5 or 6 membered ring comprising 0, 1, or 2 heteroatoms selected from O, N, or S; and further wherein the C₆-C₁₀aryl and the 5-10 membered heteroaryl may be monocyclic or bicyclic and further wherein both rings of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may be aromatic or one of the rings may be partially saturated and the other ring may be aromatic and either the partially saturated ring or the aromatic ring may be bonded to V, if present, or to the C atom bearing R^band R^b′ if V is not present, or to the C atom bearing R^aand R^a′ if V is not present and q is 0, or to the N atom bonded to the C(═O) if V is not present, q is 0, and r is 0; and further wherein, the partially saturated ring of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may include a —C(═O)— ring member;

Z′ is a C₆-C₁₀aryl, a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, or N, or a 5-7 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the C₆-C₁₀aryl, the 5-10 membered heteroaryl, or the 5-7 membered heterocyclyl are unsubstituted or are optionally substituted with 1 or 2 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₄)alkyl, —SO—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl, —CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl), —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂;

R^aand R^a′ are absent if r is 0 or are independently selected from —H, —(C₁-C₆)alkyl, —C≡N, —OH, or —CF₃; or R^aand R^a′ may together represent a ═O; or R^aand R^a′ may join together with the carbon atom to which they are attached to form a cycloalkyl ring having from 3 to 6 members;

R^band R^b′ are absent if q is 0 or are independently selected from —H, —(C₁-C₆)alkyl, —C≡N, —OH, or —CF₃; or R^band R^b′ may together represent a ═O; or R^band R^b′ may join together with the carbon atom to which they are attached to form a cycloalkyl ring having from 3 to 6 members;

R^cis selected from —H, —(C₁-C₆)alkyl, —CF₃, —F, —Cl, —Br, or —I;

R^dis selected from —H, —(C₁-C₆)alkyl, —CF₃, —F, —Cl, —Br, or —I;

R^eand R^e′ are independently selected from —H or —(C₁-C₆)alkyl;

W is a C₆-C₁₀aryl, a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S, or N, or a 5-7 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the C₆-C₁₀aryl, the 5-10 membered heteroaryl, or the 5-7 membered heterocyclyl are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —W′, —O—W′, —S—W′, —N(H)—W′, —O—CH2-W′, —C(═O)—W′, —C(═O)NH—W′, —SO₂NH—W′, —NHSO₂—W′, —NHC(═O)—W′, —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl) —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₄)alkyl, —SO—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl, —CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl), —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; and two adjacent substituents on the C₆-C₁₀aryl or the 5-10 membered heteroaryl may join to form a 5 or 6 membered ring comprising 0, 1, or 2 heteroatoms selected from O, N, or S; and further wherein the C₆-C₁₀aryl and the 5-10 membered heteroaryl may be monocyclic or bicyclic and further wherein both rings of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may be aromatic or one of the rings may be partially saturated and the other ring may be aromatic and either the partially saturated ring or the aromatic ring may be bonded to the N atom to which W is attached; and further wherein, the partially saturated ring of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may include a —C(═O)— ring member and the 5-7 membered heterocyclyl group may include a —C(═O)— ring member; and

W′ is a C₆-C₁₀aryl, a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, or N, or a 5-7 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the C₆-C₁₀aryl, the 5-10 membered heteroaryl, or the 5-7 membered heterocyclyl are unsubstituted or are optionally substituted with 1 or 2 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₄)alkyl, —SO—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl, —CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl), —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂.

In some embodiments of the compound of Formula I or the pharmaceutically acceptable salt thereof, stereoisomer thereof, pharmaceutically acceptable salt of the stereoisomer, or the mixture thereof,

X is selected from —CH₂—, —N(H)—, —O—, or —S—;

V is absent or is selected from —CH₂—, —O— or —S—; wherein if V is —O—, —S—, then r is 1 and q is 1

the subscript p is selected from 0, 1, 2, or 3, wherein X is CH₂if p is 0;

the subscript q is selected from 0 or 1;

the subscript r is selected from 0 or 1:

the custom-character symbol indicates that the bond can be a single or double bond;

Z is a C₆-C₁₀aryl or a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S, or N, wherein the C₆-C₁₀aryl or the 5-10 membered heteroaryl are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —Z′, —OZ′, —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₄)alkyl, —SO—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl, —CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl), —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; and two adjacent substituents on the C₆-C₁₀aryl or the 5-10 membered heteroaryl may join to form a 5 or 6 membered ring comprising 0, 1, or 2 heteroatoms selected from O, N, or S; and further wherein the C₆-C₁₀aryl and the 5-10 membered hetero aryl may be monocyclic or bicyclic and further wherein both rings of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may be aromatic or one of the rings may be partially saturated and the other ring may be aromatic and either the partially saturated ring or the aromatic ring may be bonded to V, if present, or to the C atom bearing R^band R^b′ if V is not present, or to the C atom bearing R^aand R^a′ if V is not present and q is 0, or to the N atom bonded to the C(═O) if V is not present, q is 0, and r is 0; and further wherein, the partially saturated ring of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may include a —C(═O)— ring member;

R^aand R^a′ are absent if r is 0 or are independently selected from —H, —(C₁-C₆)alkyl, —C≡N, —OH, or —CF₃; or R^aand R^a′ may together represent a ═O;

R^band R^b′ are absent if q is 0 or are independently selected from —H, —(C₁-C₆)alkyl, —C≡N, —OH, or —CF₃; or R^band R^b′ may together represent a ═O;

R^cis selected from —H, —(C₁-C₆)alkyl, —CF₃, —F, —Cl, —Br, or —I;

R^dis selected from —H, —(C₁-C₆)alkyl, —CF₃, —F, —Cl, —Br, or —I;

R^eand R^e′ are independently selected from —H or —(C₁-C₆)alkyl;

W is a C₆-C₁₀aryl, a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S, or N, or a 5-7 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the C₆-C₁₀aryl, the 5-10 membered heteroaryl, or the 5-7 membered heterocyclyl are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —W′, —O—W′, —CH₂—W′, N(H)—W′, —O—CH2-W′, —C(═O)—W′, —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₄)alkyl, —SO—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl, —CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl), —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; and two adjacent substituents on the C₆-C₁₀aryl or the 5-10 membered heteroaryl may join to form a 5 or 6 membered ring comprising 0, 1, or 2 heteroatoms selected from O, N, or S; and further wherein the C₆-C₁₀aryl and the 5-10 membered hetero aryl may be monocyclic or bicyclic and further wherein both rings of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may be aromatic or one of the rings may be partially saturated and the other ring may be aromatic and either the partially saturated ring or the aromatic ring may be bonded to the N atom to which W is attached; and further wherein, the partially saturated ring of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may include a —C(═O)— ring member and the 5-7 membered heterocyclyl group may include a —C(═O)— ring member; and

In some embodiments, p is 2. In other embodiments, p is 1. In still further embodiments, p is 3.

In some embodiments, r is 1. In some such embodiments, r is 1 and q is 1. In other such embodiments, r is 1 and q is 0. In other embodiments, r is 0.

In some embodiments, V is absent. In other embodiments, V is —CH₂—. In still other embodiments, V is —O—.

In some embodiments, X is —CH₂—. In still other embodiments, X is —O—. In still other embodiments, X is —S—. In still further embodiments, X is —N(H)—.

In some embodiments, q is 0. In still other embodiments, q is 1. In some embodiments where q is 1, R^band R^b′ are independently selected from —H, —CH₃, or

R^band R^b′, when taken together, represent a ═O. In some such embodiments, R^band R^b′ are both —H. In other embodiments where q is 1, R^band R^b′ join together with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. In some such embodiments, R^band R^b′ join together with the carbon atom to which they are attached to form a cyclopropyl ring.

In some embodiments, the compound of Formula I is a compound of Formula IA:

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or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of the stereoisomer, or a mixture thereof, wherein the symbol custom-character indicates that the chiral carbon atom to which the is attached may have the R stereochemistry, the S stereochemistry, or may be a mixture of compounds with the R and S stereochemistry wherein the mixture may be racemic, or the mixture may include a greater amount of compounds with the R stereochemistry compared to the amount of compounds with the S stereochemistry, or the mixture may include a greater amount of compounds with the S stereochemistry compared to the amount of compounds with the R stereochemistry. In such embodiments, the variables have the same meaning as in any of the embodiments of the compounds of formula I.

In some embodiments, the compound of Formula I is a compound of Formula II:

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In some embodiments, the compound of Formula II is a compound of Formula IIA:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula II is a compound of Formula IIB:

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or a pharmaceutically acceptable salt thereof.

In some embodiments, R^eand R^e′ are independently selected from —H or —CH₃. In some such embodiments, R^eand R^e′ are both —H.

In some embodiments, R^aand R^a′ are independently selected from —H or —CH₃. In some such embodiments, R^aand R^a′ are both —H.

In some embodiments, R^aand R^a′ join together with the carbon atom to which they are attached to form a cyclopropyl, butyl, cyclopentyl, or cyclohexyl ring. In some such embodiments, R^aand R^a′ join together with the carbon atom to which they are attached to a cyclopropyl ring.

In some embodiments, R^cis selected from —H or —CH₃. In some such embodiments, R^cis —H.

In some embodiments, R^dis selected from —H or —CH₃. In some such embodiments, R^dis —H.

In some embodiments, Z is an unsubstituted or substituted phenyl, pyridyl, pyrimidinyl, naphthyl, indanyl, 2,3-dihydrobenzofuranyl, benzofuranyl, benzothiophenyl, indolyl, thiazolyl, imidazolyl, imidazo[1,2-a]pyridyl, quinolinyl, isoquinolinyl, 1,2,3,4,4a,8a-hexahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridazinyl, pyrazinyl, indazolyl, isothiazolyl, or oxazolyl.

In some embodiments, Z is an unsubstituted or substituted phenyl, pyridyl, pyrimidinyl, naphthyl, indanyl, 2,3-dihydrobenzofuranyl, benzofuranyl, benzothiophenyl, indolyl, thiazolyl, imidazolyl, imidazo[1,2-a]pyridyl, quinolinyl, isoquinolinyl, 1,2,3,4,4a,8a-hexahydroquinolinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl. In some such embodiments, Z is an unsubstituted or substituted phenyl. In still other such embodiments, Z is selected from

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wherein the symbol custom-character when drawn through a bond indicates the point of attachment to the rest of the molecule.

In some embodiments, Z is selected from

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wherein the symbol custom-character when drawn through a bond indicates the point of attachment to the rest of the molecule.

In some embodiments, Z is substituted with at least one substituent selected from —Z′ or —OZ′. In some such embodiments, Z is phenyl and Z′ is an optionally substituted phenyl.

In some embodiments, W is an unsubstituted or substituted phenyl, pyridyl, pyrimidinyl, naphthyl, indanyl, 2,3-dihydrobenzofuranyl, benzofuranyl, benzothiophenyl, indolyl, thiazolyl, imidazolyl, imidazo[1,2-a]pyridyl, isoindolin-1-onyl, indolinyl, pyrazolyl, pyridinonyl, quinolinyl, isoquinolinyl, 1,2,3,4,4a,8a-hexahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, pyridazinyl, pyrazinyl, indazolyl, isothiazolyl, or oxazolyl

In some embodiments, W is an unsubstituted or substituted phenyl, pyridyl, indolyl, isoindolin-1-onyl, indolinyl, pyrazolyl, pyridinonyl, quinolinyl, isoquinolinyl, or 2,3-dihydrobenzo[b][1,4]dioxinyl. In some such embodiments, W is an unsubstituted or substituted phenyl.

In some embodiments, W is selected from

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wherein the symbol custom-character when drawn through a bond indicates the point of attachment to the rest of the molecule.

In some embodiments, W is substituted with at least one substituent selected from —W′, —O—W′, N(H)—W′, —O—CH2-W′, or —C(═O)—W′.

In some embodiments, W is a phenyl substituted with at least one —O—(C₁-C₆)alkyl group such as a —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —OCH(CH₃)₂, or —OC(CH₃)₃group. In some such embodiments, W is a phenyl substituted with at least two —O—(C₁-C₆)alkyl group which may be the same or different. In still further embodiments, W is a phenyl substituted with at least three —O—(C₁-C₆)alkyl groups which may be the same or different.

In some embodiments, the compound is selected from

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or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a salt. Such salts may be anhydrous or associated with water as a hydrate.

In some embodiments, the compound is a prodrug.

Also provided are pharmaceutical formulations that include at least one pharmaceutically acceptable carrier, excipient or diluent and a therapeutically effective amount of the compound of any of the embodiments described herein. In some such embodiments, the compound is present in an amount effective for the treatment of cancer.

Further provided are pharmaceutical formulations that include at least one pharmaceutically acceptable carrier, and a therapeutically effective amount of the composition of matter of any of the embodiments described herein in combination with at least one additional compound such as a cytotoxic agent or a compound that inhibits another kinase.

In other embodiments, the invention provides a method of treating cancer. Such methods typically include administering to a subject an effective amount of a compound of any one of the embodiments or a pharmaceutical composition that includes any of the compounds of any of the embodiments. In some such embodiments, the subject has a cancer that expresses an ALK fusion protein, point mutation, or overexpression. In other such embodiments, the ALK fusion protein is EML4-ALK fusion protein or NPM-ALK fusion protein. In some embodiments, the subject is a human cancer patient, and the cancer is selected from adenocarcinoma, lung cancer, non-small cell lung carcinoma, breast cancer, colorectal cancer, lymphoma, neuroblastoma, ovarian cancer, mesothelioma, melanoma, glioblastoma, diffuse large B-cell lymphomas, systemic histiocytosis, or inflammatory myofibroblastic tumors. In some such embodiments, the cancer is non-small cell lung carcinoma (NSCLC). In some embodiments, the cancer is an EML4-ALK positive cancer or is a NPM-ALK positive cancer.

In still other embodiments, the invention provides a method of treating a condition where it is desired to inhibit ALK activity. Such methods typically include administering to a subject an effective amount of a compound of any of the embodiments or a pharmaceutical composition that includes a compound of any of the embodiments.

In some embodiments, the compound of any of the embodiments is used in the preparation of a medicament. In some such embodiments, the medicament is for use in treating cancer. In some such embodiments, a medicament is for use in inhibiting ALK. In still other such embodiments, the medicament is for use in treating a cancer that expresses an ALK fusion protein. In some such embodiments, the ALK fusion protein is EML4-ALK fusion protein or NPM-ALK fusion protein. In some such embodiments, the ALK fusion protein is EML4-ALK fusion protein. In other such embodiments, the ALK fusion protein is NPM-ALK fusion protein.

In some such embodiments, a compound or pharmaceutical formulation of any of the embodiments is provided for use in treating cancer. In some such embodiments, the cancer expresses an ALK fusion protein. In some such embodiments, the ALK fusion protein is EML4-ALK fusion protein or NPM-ALK fusion protein. In some such embodiments, the ALK fusion protein is EML4-ALK fusion protein. In other such embodiments, the ALK fusion protein is NPM-ALK fusion protein. In some embodiments, a compound or pharmaceutical formulation of any of the embodiments is provided for use in treating cancer and the cancer is selected from adenocarcinoma, lung cancer, non-small cell lung carcinoma, breast cancer, colorectal cancer, lymphoma, neuroblastoma, ovarian cancer, mesothelioma, melanoma, glioblastoma, diffuse large B-cell lymphomas, systemic histiocytosis, or inflammatory myofibroblastic tumors. In some such embodiments, the cancer is non-small cell lung carcinoma (NSCLC). In still other embodiments, a compound or pharmaceutical formulation of any of the embodiments is provided for use in inhibiting ALK or for use in treating a disease or condition wherein inhibition of ALK is desired.

Other objects, features and advantages of the invention will become apparent to those skilled in the art from the following description and claims.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective testing measurements.

As used herein, if any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.

Certain compounds of the invention may possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. Furthermore, atropisomers and mixtures thereof such as those resulting from restricted rotation about two aromatic or hetero aromatic rings bonded to one another are intended to be encompassed within the scope of the invention.

As used herein and unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. A bond drawn with a wavy line indicates that both stereoisomers are encompassed.

Various compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, N.Y., 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

As known by those skilled in the art, certain compounds of the invention may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that convenience, referral to a compound of a given structural formula includes tautomers of the structure represented by the structural formula:

Compounds of the present disclosure include, but are not limited to, compounds of Formula I and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. As used herein, the term “compound” encompasses not only the compound itself, but also a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a prodrug thereof, and mixtures of any of the foregoing. In some embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers, and ester prodrugs such as (C₁-C₄)alkyl esters. In other embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers.

As noted above, prodrugs also fall within the scope of chemical entities, for example, ester or amide derivatives of the compounds of Formula I. The term “prodrugs” includes any compounds that become compounds of Formula I when administered to a patient, e.g., upon metabolic processing of the prodrug. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate, carbomethoxy, carboethoxy and like derivatives of functional groups (such as alcohol, carboxylic acid, ether, ester, or amine groups) in the compounds of Formula I.

The term “solvate” refers to the compound formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.

The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the 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). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., GPR40 assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. For example, if a variable is said to be H, this means that variable may also be deuterium (D) or tritium (T).

“ALK” refers to anaplastic lymphoma kinase, tyrosine kinase. ALK was originally identified as part of the chimeric nucleophosmin-ALK protein in the t(2;5) chromosomal rearrangement associated with anaplastic large cell lymphoma.

“EML4-ALK fusion protein” refers to a protein that results from a fusion of echinoderm microtubule-associated protein-like 4 (EML4) and ALK.

“NPM-ALK fusion protein” refers to a protein that results from a fusion of nucleophosmin (NPM) with ALK.

“Alkyl” refers to a saturated, branched, straight-chain, or cyclic monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-1-yl, propan-2-yl, and cyclopropan-1-yl, butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, tert-butyl, and the like. In certain embodiments, an alkyl group comprises 1 to 20 carbon atoms. In some embodiments, alkyl groups include 1 to 6 carbon atoms whereas in other embodiments, alkyl groups include 1 to 4 carbon atoms. In still other embodiments, an alkyl group includes 1 or 2 carbon atoms. Cyclic and branched chain alkyl groups include at least 3 carbon atoms and typically include 3 to 7, or in some embodiments, 3 to 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms may be referred to as a —(C₁-C₆)alkyl group and an alkyl group having 1 to 4 carbon atoms may be referred to as a —(C₁-C₄)alkyl.

“Alkenyl” refers to an unsaturated branched, straight-chain, or cyclic hydrocarbon group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the Z- or E-form (cis or trans) about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl; and the like. In certain embodiments, an alkenyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkenyl group having 2 to 6 carbon atoms may be referred to as a —(C₂-C₆)alkenyl group

“Alkynyl” refers to an unsaturated branched or straight-chain hydrocarbon having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. In certain embodiments, an alkynyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkynyl group having 2 to 6 carbon atoms may be referred to as a —(C₂-C₆)alkynyl group

“Alkoxy” refers to a radical —OR where R represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like. Typical alkoxy groups include 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms in the R group. Alkoxy groups that include 1 to 6 carbon atoms may be designated as —O(C_1-6) alkyl or as —O—(C_1-6) alkyl groups. In some embodiments, an alkoxy group may include 1 to 4 carbon atoms and may be designated as an —O(C_1-4) alkyl or as an —O—(C_1-4) alkyl group.

“Alkylene” refers to a divalent saturated hydrocarbon group derived from a parent alkane by removal of two hydrogen atoms. Examples of alkylene group include, but are not limited to, —CH₂—, —CH₂CH₂—, —CH(CH₃)—, —CH₂CH₂CH₂—, —CH₂C(CH₃)(H)—, and the like. In some embodiments an alkylene may include 1 to 6 carbon atoms and in other embodiments may include 1 to 4 carbon atoms. Such groups may be designated as —(C₁-C₆)alkylene- and —(C₁-C₄)alkylene- groups.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl encompasses monocyclic carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene. Aryl groups may include fused ring systems where one ring is a carbocyclic aromatic ring and the other ring(s) are not aromatic and may be heterocyclic or carcocyclic. For example, aryl groups include systems where a carbocyclic aromatic ring is fused to a 5- to 7-membered heterocyclic ring containing 1 or more hetero atoms chosen from N, O, and S. In certain embodiments, an aryl group includes 6 to 10 carbon atoms. Such groups may be referred to as C₆-C₁₀aryl groups. Aryl, however, does not encompass or overlap in any way with heteroaryl as separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein. Bicyclic and tricyclic aryl groups include at least one ring that is aromatic. The other rings in such systems may be partially unsaturated. For example, tetralin (1,2,3,4-tetrahydronaphthalene) includes a benzene ring fused to a ring that includes saturation and is therefore, partially saturated. Examples of other aryl groups with a partially saturated ring include, but are not limited to, indane, 1,4-dihydronaphthalene, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, 1,2,3,4-tetrahydroquinoline, and indoline. The nonaromatic rings of such systems may also include a carbon that is double-bonded to an O. Examples of such aryl groups include, but are not limited to, 2-indanone, 1-indanone, 3,4-dihydronaphthalen-2(1H)-one, chroman-3-one, indolin-2-one, and 1,2-dihydroquinolin-3(4H)-one.

“Carbonyl” refers to the radical —C(O) or —C(═O) group.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Cycloalkyl” refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl group. Where a specific level of saturation is intended, the nomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In certain embodiments, the cycloalkyl group can be C_3-10cycloalkyl, such as, for example, C_3-6cycloalkyl.

“Heterocyclic”, “heterocyclo” or “heterocyclyl” refer to a saturated or unsaturated, but non-aromatic, cyclic hydrocarbon group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or a different heteroatom and its associated hydrogen atoms, where appropriate. Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, O, and S. In some embodiments, a heterocyclyl group includes 3 to 10 ring members of which 1, 2, or 3 ring members are independently selected from N, O, or S. In other embodiments, a heterocyclyl group includes 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S. Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran and the like. Substituted heterocyclyl also includes ring systems substituted with one or more oxo (═O) or oxide (—O⁻) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

“Disease” refers to any disease, disorder, condition, symptom, or indication.

“Halo” or “halogen” refers to a fluoro, chloro, bromo, or iodo group.

“Haloalkyl” refers to an alkyl group in which at least one hydrogen is replaced with a halogen. Thus, the term “haloalkyl” includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with two or more halogen atoms). The term “perhaloalkyl” means, unless otherwise stated, an alkyl group in which each of the hydrogen atoms is replaced with a halogen atom. For example, the term “perhaloalkyl”, includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl groups typically include 5- to 10-membered aromatic, monocyclic and bicyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon. The term heteroaryl may also encompass tricyclic ring systems containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring. For example, heteroaryl includes a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-membered cycloalkyl ring or to a carbocyclic aromatic ring or to a 5-7 membered heteroaromatic ring, and heteroaryl includes a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-membered heterocyclic ring. For fused, bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at the heteroaromatic ring or the carbocyclic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Heteroaryl does not encompass or overlap with aryl as defined above. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, β-carboline, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, and the like. In certain embodiments, the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 10 membered heteroaryl. In certain embodiments, heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.

“Sulfonyl” refers to a radical —S(O)₂R where R is an alkyl, substituted alkyl, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

“Sulfanyl” refers to a radical —SR where R is an alkyl, substituted alkyl, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl group as defined herein that may be optionally substituted as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

“Pharmaceutically acceptable” refers to generally recognized for use in animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the like.

“Pharmaceutically acceptable excipient,” “pharmaceutically acceptable carrier,” or “pharmaceutically acceptable adjuvant” refer, respectively, to an excipient, carrier or adjuvant with which at least one compound of the present disclosure is administered. “Pharmaceutically acceptable vehicle” refers to any of a diluent, adjuvant, excipient or carrier with which at least one compound of the present disclosure is administered.

“Stereoisomer” refers to an isomer that differs in the arrangement of the constituent atoms in space. Stereoisomers that are mirror images of each other and optically active are termed “enantiomers,” and stereoisomers that are not mirror images of one another and are optically active are termed “diastereomers.”

“Subject” includes mammals and humans. The terms “human” and “subject” are used interchangeably herein.

“Therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The “therapeutically effective amount” can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.

“Treating” or “treatment” of any disease or disorder refers to arresting or ameliorating a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the development of a disease, disorder or at least one of the clinical symptoms of the disease or disorder, or reducing the risk of developing a disease or disorder or at least one of the clinical symptoms of a disease or disorder. “Treating” or “treatment” also refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, or inhibiting at least one physical parameter which may not be discernible to the subject. Further, “treating” or “treatment” refers to delaying the onset of the disease or disorder or at least symptoms thereof in a subject which may be exposed to or predisposed to a disease or disorder even though that subject does not yet experience or display symptoms of the disease or disorder.

Reference will now be made in detail to embodiments of the present disclosure. While certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims.

In one aspect, the invention provides a compound of Formula I:

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or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a pharmaceutically acceptable salt of the stereoisomer, or a mixture thereof,

wherein:

X is selected from —CH₂—, —N(H)—, —O—, or —S—;

V is absent or is selected from —CH₂—, —O—, —S—, or —NH—; wherein if V is —O—, —S—, or —NH—, then r is 1 and q is 1;

the subscript p is selected from 0, 1, 2, or 3, wherein X is CH₂if p is 0;

the subscript q is selected from 0 or 1;

the subscript r is selected from 0 or 1:

the custom-character symbol indicates that the bond can be a single or double bond;

Z is a C₆-C₁₀aryl or a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, or N, wherein the C₆-C₁₀aryl or the 5-10 membered heteroaryl are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —Z′, —O—Z′, —S—Z′, —NH—Z′, —CH₂Z′—F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —C(═O)NH—Z′, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —SO₂NH—Z′, —NHSO₂—(C₁-C₄)alkyl, —NHSO₂—Z′, —NHC(═O)—(C₁-C₄)alkyl, —NHC(═O)—Z′, —SO₂—(C₁-C₄)alkyl, —SO—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl, —CO₂H, —C(═O)—Z′, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl), —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; and two adjacent substituents on the C₆-C₁₀aryl or the 5-10 membered heteroaryl may join to form a 5 or 6 membered ring comprising 0, 1, or 2 heteroatoms selected from O, N, or S; and further wherein the C₆-C₁₀aryl and the 5-10 membered heteroaryl may be monocyclic or bicyclic and further wherein both rings of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may be aromatic or one of the rings may be partially saturated and the other ring may be aromatic and either the partially saturated ring or the aromatic ring may be bonded to V, if present, or to the C atom bearing R^band R^b′ if V is not present, or to the C atom bearing R^aand R^a′ if V is not present and q is 0, or to the N atom bonded to the C(═O) if V is not present, q is 0, and r is 0; and further wherein, the partially saturated ring of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may include a —C(═O)— ring member;

R^cis selected from —H, —(C₁-C₆)alkyl, —CF₃, —F, —Cl, —Br, or —I;

R^dis selected from —H, —(C₁-C₆)alkyl, —CF₃, —F, —Cl, —Br, or —I;

R^eand R^e′ are independently selected from —H or —(C₁-C₆)alkyl;

W is a C₆-C₁₀aryl, a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S, or N, or a 5-7 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the C₆-C₁₀aryl, the 5-10 membered heteroaryl, or the 5-7 membered heterocyclyl are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —W′, —O—W′, —S—W′, —N(H)—W′, —O—CH2-W′, —C(═O)—W′, —C(═O)NH—W′, —SO₂NH—W′, —NHSO₂—W′, —NHC(═O)—W′, —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₄)alkyl, —SO—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl, —CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl), —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; and two adjacent substituents on the C₆-C₁₀aryl or the 5-10 membered heteroaryl may join to form a 5 or 6 membered ring comprising 0, 1, or 2 heteroatoms selected from O, N, or S; and further wherein the C₆-C₁₀aryl and the 5-10 membered heteroaryl may be monocyclic or bicyclic and further wherein both rings of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may be aromatic or one of the rings may be partially saturated and the other ring may be aromatic and either the partially saturated ring or the aromatic ring may be bonded to the N atom to which W is attached; and further wherein, the partially saturated ring of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may include a —C(═O)— ring member and the 5-7 membered heterocyclyl group may include a —C(═O)— ring member; and

W′ is a C₆-C₁₀aryl, a 5-10 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, or N, or a 5-7 membered heterocyclyl comprising 1, 2, or 3 heteroatoms selected from O, S, or N, wherein the C₆-C₁₀aryl, the 5-10 membered heteroaryl, or the 5-7 membered heterocyclyl are unsubstituted or are optionally substituted with 1 or 2 substituents independently selected from —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₄)alkyl, —SO—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl, —CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl), —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄alkyl)₂, —(C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂.

In some embodiments of the compound of Formula I or the pharmaceutically acceptable salt thereof, stereoisomer thereof, pharmaceutically acceptable salt of the stereoisomer, or the mixture thereof,

X is selected from —CH₂—, —N(H)—, —O—, or —S—;

V is absent or is selected from —CH₂—, —O— or —S—; wherein if V is —O—, —S—, then r is 1 and q is 1

the subscript p is selected from 0, 1, 2, or 3, wherein X is CH₂if p is 0;

the subscript q is selected from 0 or 1;

the subscript r is selected from 0 or 1:

the custom-character symbol indicates that the bond can be a single or double bond;

Z is a C₆-C₁₀aryl or a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S, or N, wherein the C₆-C₁₀aryl or the 5-10 membered heteroaryl are unsubstituted or are optionally substituted with 1, 2, 3, or 4 substituents independently selected from —Z′, —OZ′, —CH₂Z′, —F, —Cl, —Br, —I, —C≡N, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₄)alkylene-OH, —NH₂, —NH((C₁-C₄)alkyl), —N((C₁-C₄)alkyl)₂, —C(═O)NH₂, —C(═O)NH((C₁-C₄)alkyl), —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —SO₂NH((C₁-C₄)alkyl), —SO₂N((C₁-C₄)alkyl)₂, —NHSO₂—(C₁-C₄)alkyl, —NHC(═O)—(C₁-C₄)alkyl, —SO₂—(C₁-C₄)alkyl, —SO—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-NH—C(═O)—(C₁-C₄)alkyl, —CF₃, —C(═O)—(C₁-C₄)alkyl, —CO₂H, —C(═O)—O—(C₁-C₄)alkyl, —C(═O)NH—(C₁-C₄)alkylene-NH₂, —C(═O)NH—(C₁-C₄)alkylene-NH((C₁-C₄)alkyl), —C(═O)NH—(C₁-C₄)alkylene-N((C₁-C₄)alkyl)₂, (C₁-C₄)alkylene-C(═O)—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—O—(C₁-C₄)alkyl, —(C₁-C₄)alkylene-C(═O)—OH, —OH, —O—(C₁-C₆)alkyl, —SH, —S—(C₁-C₆)alkyl, —OCF₃, or —OCHF₂; and two adjacent substituents on the C₆-C₁₀aryl or the 5-10 membered heteroaryl may join to form a 5 or 6 membered ring comprising 0, 1, or 2 heteroatoms selected from O, N, or S; and further wherein the C₆-C₁₀aryl and the 5-10 membered hetero aryl may be monocyclic or bicyclic and further wherein both rings of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may be aromatic or one of the rings may be partially saturated and the other ring may be aromatic and either the partially saturated ring or the aromatic ring may be bonded to V, if present, or to the C atom bearing R^band R^b′ if V is not present, or to the C atom bearing R^aand R^a′ if V is not present and q is 0, or to the N atom bonded to the C(═O) if V is not present, q is 0, and r is 0; and further wherein, the partially saturated ring of a bicyclic C₆-C₁₀aryl or a bicyclic 5-10 membered heteroaryl may include a —C(═O)— ring member;