WO2007100759A2 - Method for treating common variable immunodeficiency - Google Patents

Method for treating common variable immunodeficiency Download PDF

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Publication number
WO2007100759A2
WO2007100759A2 PCT/US2007/004913 US2007004913W WO2007100759A2 WO 2007100759 A2 WO2007100759 A2 WO 2007100759A2 US 2007004913 W US2007004913 W US 2007004913W WO 2007100759 A2 WO2007100759 A2 WO 2007100759A2
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optionally substituted
heteroaryl
heterocycloalkyl
aryl
independently
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PCT/US2007/004913
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French (fr)
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WO2007100759A3 (en
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Eric Jacobson
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Synta Pharmaceuticals Corp.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • CVID Common variable immunodeficiency
  • B cell differentiation due to a primary failure of B cell differentiation and impaired secretion of immunoglobulins. This is frequently accompanied by T cell abnormalities consisting of blunted proliferative responses to mitogenic and antigenic stimuli, a relative lack of mature (CD45RO) T cells, and reduced production of IL-2 and other cytokines.
  • CD45RO mature proliferative response to mitogenic and antigenic stimuli
  • CD45RO a relative lack of mature T cells
  • IL-2 and other cytokines well-defined genetic defects are just beginning to be identified, but most CVDD is encountered as sporadic and not as inherited disease (Grimbacher et al., 2003; Salzer et al., 2005).
  • autoimmune diseases i.e., autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and pernicious anemia
  • an increased risk for lymphoproliferation and neoplasia i.e., autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and pernicious anemia
  • therapy is aimed primarily at restoring immunoglobulin levels with the administration of intravenous pooled immunoglobulin (IVIG); while this therapy clearly decreases the frequency and severity of infections it has no effect on associated autoimmune disease or neoplasia risk.
  • IVIG intravenous pooled immunoglobulin
  • the GI tract is affected in CVID not only by infectious agents that respond to IVIG but also by idiopathic inflammation and lymphoproliferative lesions, which are unresponsive to IVIG therapy.
  • CVID patients with near normal numbers of mature class-switched B cells seem to be the ones who can produce IgM and IgG in vitro (those with low numbers of mature class-switched B cells can be further defined by whether there is a concomitant excess of immature B cells (CD21-) (Warnatz et al., 2002).
  • any such classification of B cell dysfunction does not seem to clearly predict the natural history or development of complications in CVID.
  • T cells in CVID patients have been variously reported to display reduced proliferation and activation by antigens and/or mitogens (Cunningham-Rundles and Bodian, 1999; Fischer et al., 1993; Fischer et al., 1994; North et al., 1991), have impaired IL-2 production, show lower expression of cell surface CD40L (Brugnoni et al., 1996; Farringtori et al., 1994), fail to develop antigen-specific responses (Kondratenko et al., 1997; Stagg et al., 1994), and show excessive activity of CD8+ cells (Jaffe et al., 1993; North et al., 1998; Serrano et al., 2000; Wright et al., 1990; Waldmann et al., 1974).
  • CVID patients demonstrates features of persistent immune activation characterized by a ThI -skewed cytokine profile. These patients may have an abnormally low CD4/CD8 ratio ( ⁇ 0.9), and an increased incidence of splenomegaly (71%) and anergy (42%) compared to CVID patients with normal CD4/CD8 ratios (29% and 7%, respectively) (Wright et al., 1990).
  • the low CD4/CD8 ratio in this CVID group is due to an increase in CD8+ cells, which have impaired proliferation but secrete increased levels of INF- ⁇ and IL-5 (but normal amounts of IL-4) when stimulated in vitro (Jaffe et al., 1993; Wright et al., 1990). In these studies the CD4+ cells behaved normally, and in only the occasional patient could CD8+ effects potentially explain the hypogammaglobulinemia. In another study of 24 CVED patients, low CD4+ cell counts and a low CD4/CD8 ratio ⁇ 0.9 was observed that could not be attributed to an expanded CD8+ population (Aukrust et al., 1996).
  • this study group had significantly elevated serum TNF ⁇ levels which was particularly evident in the subset (11/24 patients) defined by splenomegaly, a CD4+ count ⁇ 400 x 10 6 /L, and significantly elevated serum neopterin levels.
  • Another report showed that significantly more peripheral blood monocytes (CD 14+, but not CD 14- cells in a dendritic cell pool) from CVID patients expressed high IL- 12 following LPS stimulation than normal controls or patients with X-linked agammaglobulinemia (Cambronero et al., 2000); this was associated with significantly increased expression of IFN ⁇ in CD4+ (and CD8+) T cells.
  • Cytokine production by lamina limbal mononuclear cells recently has been characterized as a polarized ThI inflammation.
  • CVID patients with gastrointestinal symptoms of diarrhea and weight loss as well as the gut inflammatory changes had this excess cytokine production; those CVED patients with similar histologic findings but no symptoms had no increased cytokine production.
  • Gastrointestinal (GI) manifestations of CVED unrelated to infections occur in upwards of 20% of patients (Cunningham-Rundles and Bodian, 1999; Sneller et al., 1993). This is most likely an underestimate since patients without overt gastrointestinal symptoms are not routinely examined for gut abnormalities. Symptoms generally include chronic diarrhea, malabsorption marked by increased excretion of fat, abnormal D-xylose uptake by the small bowel, and protein- losing enteropathy due to loss of albumin and other proteins into the fecal stream. This can lead to severe weight loss requiring the need for hyperalimentation, nutrient deficiency contributing to hypocalcemia (vitamin D malabsorption) and anemia (folate malabsorption), and hypoalbuminemia predisposing to edema.
  • histologic abnormalities are seen: in the stomach, morphologic changes consistent with acute graft-versus-host disease (apoptotic glandular epithelial cells, dense mononuclear inflammatory cell infiltrate with occasional crypt obliteration), increased intraepithelial lymphocytes, and varying degrees of gastritis (leading in some cases to atrophy and achlorhydria in the absence of Helicobacter pylori infection and anti-parietal cell and anti-intrinsic factor antibodies (Moriuchi et al., 1990; Twomy et al., 1970; Wright and Sears, 1987; Zullo et aL, 1999)); in the small intestine histologic changes include mild to marked villous atrophy (differing from celiac sprue by the absence of lamina limba plasma cells, lack of significant basal crypt hyperplasia, and relatively normal enterocyte maturation with preserved brush border and Goblet cells), increased intraepithelial lymphocyte
  • NLH intestinal nodular lymphoid hyperplasia
  • the gut inflammation and histologic changes accompanying CVID are not related to the presence of intestinal infections, although bacterial overgrowth and infection with pathogenic bacteria and parasites should be evaluated and treated as a cause of gastrointestinal symptoms.
  • the enteropathy does not respond to antibiotic or IVIG therapy. Instead it has been suggested that the gut lesions could reflect an autoimmune enteritis (Teahon et al., 1994; Washington et al., 1996).
  • autoimmune enteritis occurs in young children and generally not adults, only one case report documents the characteristic anti-enterocyte antibodies (Catassi et al., 1988) in a boy with CVID, and another report notes that 58-67% of patients with CVID and gastrointestinal symptoms also have other possible autoimmune diseases (autoimmune hemolytic anemia, thrombocytopenia with antiplatelet antibodies, neutropenia, arthritis, thyroid dysfunction, pernicious anemia, vitiligo, episcleritis, and insulin-dependent diabetes mellitus) (Washington et al., 1996).
  • a plausible immunologic mechanism for the enteropathy is the presence of a T cell dysfunction leading to autoimmune attack within the intestinal wall.
  • Such a role for T cell dysfunction in CVID is consistent with the observation that the enteropathy does not occur in X-linked agammaglobulinemia, an immunodeficiency state with impaired B cell function equal or greater than CVID but with no accompanying T cell abnormality (Lederman and Winkelstein, 1985). Furthermore, CVID patients with related enteropathy are more likely to have T cell dysfunction than those without (Cunningham-Rundles and Bodian, 1999). Even the morphologic changes suggest a primary role for T cells in the enteropathy, with T cells predominating in the lamina limba infiltrate and the epithelial apoptosis so reminiscent of graft-versus-host disease that is mainly T cell-mediated.
  • CVID cardiovascular disease
  • Current therapy for CVID is chronic replacement of immunoglobulins, and this has been a successful strategy for controlling the recurrent sino-pulmonary infections.
  • this treatment does not generally affect other conditions that can complicate CVID including autoimmune diseases (cytopenias, hypothyroidism) (Cunningham-Rundles and Bodian, 1999), nodular lymphoid hyperplasia of the intestinal mucosa, lymphoma, and an enteropathy presenting as chronic diarrhea and malabsorption.
  • the present invention addresses this need for treatment of CVID.
  • the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I):
  • R 1 is optionally substituted aryl, optionally substituted heteroaryl, or a group represented by the following formula:
  • R. 2 and R 4 are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -OR k , -SR k , -NR 11 R 1 , hydroxylalkyl, -C(O)R C , -OC(O)R C , -SC(O)R 0 , -NR k C(O)R°, -C(S)R C , -OC(S)R C , -SC(S)R C , -NR k C(S)R c , -C(NR)R C , -OC(NR)R 0 , -SC(NR)R 0 , -NR k C(NR)R c , -SO 2 R C , -S(O)R 0 , -NR k SO 2 R c , -OS(O) 2 R 0 , -OP(O)R 0 R
  • R 3 is R g ;
  • Rs and Re are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R 5 and R 6 taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
  • X is O, S, S(O), S(O) 2 , or NR k ;
  • Y is (CH(R ⁇ )) m , C(O), C(NR), O, S, S(O), S(O) 2 , N(R k ), or absent;
  • R for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R 0 , -OR k , -SR k , -NR h R j , hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O) 2 R 0 ; each of R a and R b , independently, is H, optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R° for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR k , -SR k , -NR h R j , hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;
  • R s for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR k , -SR k , -NR h R j 5 hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R 0 , -OC(O)R 0 , -SC(O)R 0 , -NR k C
  • R h and R J are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R h and R j taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl; R 5 for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl,
  • the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (II):
  • R 7 is an optionally substituted aryl or an optionally substituted heteroaryl
  • A is O, S, S(O), S(O) 2 , C(CR 8 ) 2 , or NR k ;
  • R s and R k are defined as for formula (T).
  • the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (III):
  • U and V are each, independently, N or CR g ;
  • Ring D is a 5 to 9-membered aryl, 3 to 9-membered cycloalkyl, 3 to 9- membered cyclyl, 5 to 9-membered heteroaryl, 3 to 9-membered heterocycloalkyl, or a 3 to 9-membered heterocyclyl, each of which may be further substituted with one or more substituents; one of Ai and A 2 is - X4-R'-L'-R" and the other is a group represented by the following formula:
  • Z is N or CH
  • W is O, S, S(O) 5 S(O) 2 , NR m , or NC(O)R" 1 , wherein R m , for each occurrence, is independently — H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylcarbonyl; u is 0, 1, 2, 3, or 4;
  • R' is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or absent;
  • R" is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(R k )(CH 2 ) q R g , -OR k , -SR k , -NR h R j , hydroxylalkyl, -C(O)R C , -C(S)R C , -C(NR)R C , halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, -S(O)R C , -S(O) 2 R 0 , -P(O)R 0 R 0 , -P(S)R 0
  • R, R c , R s , R h , R j , and R k are defined as for formula (I).
  • the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (X):
  • L', U 5 V, W 5 X4 5 Z, R', R", u, and Ring D are defined as for formula (III); and w is 0 or 1.
  • the invention provides a method of treating CVBD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (XIV):
  • ring A is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl, wherein the cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclycl are optionally fused to an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; and
  • Ri 6 for each occurrence, is independently, H or a lower alkyl.
  • the invention in another aspect, relates to a method of treating common variable immunodeficiency (CVID) in a subject, comprising administering to the subject an effective amount of N-(3-methyl-benzylidene)-N'-[6-morpholin-4-yl-2-(2- pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazine, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt is a mesylate salt.
  • the subject is human.
  • this invention features a pharmaceutical composition that includes a pharmaceutically acceptable carrier and at least one compound that is suitable for treatment of CVID (e.g., an inhibitor of IL-12), optionally including a second active agent .
  • CVID e.g., an inhibitor of IL-12
  • the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I):
  • Ri is optionally substituted aryl, optionally substituted heteroaryl, or a group represented by the following formula:
  • R 2 and R 4 are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -OR k , -SR k , -NR h R j , hydroxylalkyl, -C(O)R C , -OC(O)R 0 , -SC(O)R C , -NR k C(O)R°, -C(S)R C , -OC(S)R C , -SC(S)R 0 , -NR k C(S)R°, -C(NR)R 0 , -OC(NR)R 0 , -SC(NR)R 0 , -NR k C(NR)R°, -SO 2 R 0 , -S(O)R 0 , -NR k SO 2 R°, -OS(O) 2 R 0 , -OP(O)R 0 R 0 R 0
  • R 3 is R 8 ;
  • R5 and Re are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R 5 and R 6 taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
  • X is O, S, S(O), S(O) 2 , or NR k ;
  • R for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R C , -OR k , -SR k , -NR h R j , hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O) 2 R 0 ; each of R a and R b , independently, is H, optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R c for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR k , -SR k , -NR h R j , hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;
  • R 8 for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -OR k , -SR k , -NR h R J , hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R C , -OC(O)R C , -SC(O)R C , -NR k C(O)R
  • R h and R J are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R h and R J taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
  • R k for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; n is 0, 1, 2, 3, 4, 5, 6 or 7; and m is 0, 1, 2, 3, or 4.
  • the compound is Compound 50 ((N- [3-methylbenzylidene]-N'-[6-morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4- yl]-hydrazine) as described herein.
  • each OfR 2 and R 4 is H;
  • R 3 is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; G is absent;
  • R v is H or alkyl; n is O, 1, 2, 3, 4, 5, or 6;
  • X is NR C> ;
  • Z is N or CH
  • W is O, S, S(O) 5 S(O 2 ), NR 0' , or NC(O)R C' ; in which each of R a and R b , independently, is H, alkyl, aryl, heteroaryl; and R c is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; or a pharmaceutically acceptable salt thereof.
  • the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount , of a compound of formula (II):
  • R 7 is an optionally substituted aryl or an optionally substituted heteroaryl
  • A is O, S, S(O), S(O) 2 , C(CR 8 ) 2 , orNR k ;
  • R ⁇ and R k are defined as for formula (T).
  • the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (TH):
  • U and V are each, independently, N or CR g ;
  • Ring D is a 5 to 9-membered aryl, 3 to 9-membered cycloalkyl, 3 to 9- membered cyclyl, 5 to 9-membered heteroaryl, 3 to 9-membered heterocycloalkyl, or a 3 to 9-membered heterocyclyl, each of which may be further substituted with one or more substituents; one of Ai and A 2 is -X ⁇ -R'-L'-R" and the other is a group represented by the following formula:
  • Z is N or CH;
  • W is O, S, S(O), S(O) 2 , NR m , or NC(O)R m , wherein R m , for each occurrence, is independently — H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylcarbonyl; u is O, 1, 2, 3, or 4;
  • R' is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or absent;
  • R" is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(R k )(CH 2 ) q R g , -OR k , -SR k , -NR h R j , hydroxylalkyl, -C(O)R C , -C(S)R C , -C(NR)R 0 , halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, -S(O)R 0 , -S(O) 2 R 0 , -P(O)R 0 R 0 , -P(S)R
  • the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (X):
  • G, Y, R 2 , R 3 , R 4 , and n are defined as for formula (I);
  • V, U, V, W, X4, Z 5 R', R", u, and Ring D are defined as for formula (III); and w is 0 or 1.
  • the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (XTV):
  • ring A is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl, wherein the cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclycl are optionally fused to an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; and
  • Rt6 for each occurrence, is independently, H or a lower alkyl.
  • Q 3 U, and V are N.
  • one of Q, U, or V is CR ⁇ , and the other two are N.
  • V is CR g , Q and U are N.
  • Q is CR g , V and U are N.
  • U is CR g
  • V and Q are N.
  • one ofQ, U, or V is N, and the other two are CR S .
  • V is N, and Q and U are CR S .
  • Q is N, and V and U are CR g .
  • U is N and Q, and V are CR S .
  • -NRsRe is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1-oxo-thiomorpholino, an optionally substituted 1,1-dioxo-thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.
  • X is -NR k -.
  • R k of group X is — H or a lower alkyl.
  • R 1 in the compounds represented by formula (I) or R 7 in the compounds represented by formula (II), is an optionally substituted aryl or an optionally substituted heteroaryl.
  • R 1 in the compounds represented by formula (I) or R 7 in the compounds represented by formula (II), is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally
  • R 1 in the compounds represented by formula (I) or R 7 in the compounds represented by formula (II), is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro-carbazolyl.
  • R 1 in the compounds represented by formula (I) or R 7 in the compounds represented by formula (H) is a group represented by the following formula:
  • the dashed line indicates a double or a single bond
  • X 2 is -O-, -S(O)p-, -N(R k )-, or -C(R g )(R g )-;
  • R 8 and R 9 are each, independently, R g , -C(O)R C , -C(S)R C , -C(NR)R 0 , -NR k C(O)R°, -OC(O)R C , -SC(O)R C , -NR k C(S)R c , -OC(S)R C , -SC(S)R C , -NR k C(NR)R c , -OC(NR)R 0 , or -SC(NR)R 0 ; or R 8 and R 9 , taken together with the carbons to which they are attached, form a 5- to 7-membered optionally substituted cycloalkyl, a 5- to 7-membered optionally substituted cyclyl, a 5- to 7-membered optionally substituted aryl, a 5- to 7-membered optionally substituted heterocycloalkyl, a 5- to 7-membered
  • R 10 for each occurrence, is, independently, R s , -C(O)R 0 , -C(S)R 0 , -C(NR)R 0 , -NR k C(O)R°, -OC(O)R C , -SC(O)R 0 , -NR k C(S)R c , -OC(S)R 0 , -SC(S)R 0 , -NR k C(NR)R°, -OC(NR)R 0 , or -SC(NR)R 0 ; p is 0, 1, or 2; and t is O, 1, 2, or, 3.
  • Ri in the compounds represented by formula (T) or R 7 in the compounds represented by formula (II) is (2,3-dimethyl-lH-indol-5-yl), (IH- indol-5-yl), or (6,7,8,9-tetrahydro-5H-carbazol-3-yl).
  • R 7 is a group represented by the following formula:
  • Rn and R 12 are, independently, R ⁇ , -C(O)R 0 , -C(S)R 0 , -C(NR)R C , -NR k C(O)R c , -OC(O)R C , -SC(O)R 0 , -NR k C(S)R c , -OC(S)R C , -SC(S)R 0 , -NR 15 C(NR)R 0 , -OC(NR)R 0 , or -SC(NR)R 0 ; and s is 0, 1, 2, 3, or 4.
  • Ri is a group represented by the following formula:
  • R 1 of formula (T) is group (XVIII)
  • one of R a or R b is — ⁇ or a lower alkyl, and the other is an optionally substituted aryl or an optionally substituted heteroaryl.
  • R 1 of formula (T) is group (XVIII)
  • one of R a or R b is — ⁇ or a lower alkyl, and the other is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted flu ⁇ renyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an
  • one of R a or R b is — H or a lower alkyl, and the other is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro-carbazolyl.
  • Y is O.
  • Y is a covalent bond.
  • R 3 is H.
  • R 3 is an optionally substituted aryl or an optionally substituted heteroaryl.
  • R 3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo- ⁇ yridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted tbiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted
  • R3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2- oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an
  • R 3 is a hydroxy, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
  • R. 3 is a hydroxy, an optionally substituted pyridinyl, an optionally substituted morpholino, or an optionally substituted oxazolidin-2-one.
  • R 3 is -OR k or-NR h R j , and R f , R h and R j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or-C(O)R c .
  • R 3 is -C(O)OR k , -OC(O)R k , -C(O)NR h R j , -NR k C(O)R k , -C(S)OR k , -OC(S)R k , -NR k C(0)NR h R j , -NR k C(S)NR h R j , -C(O)NRhRj, -S(O) 2 R k , -S(O) 2 NR h R j , -OC(O)NR h R j , or-NR k C(O)OR k .
  • each of R 2 and R 4 is, independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl.
  • n is 1, 2, or 3
  • R2 and R 4 for each occurrence are, independently, H or a lower alkyl.
  • G is absent.
  • G is an optionally substituted heteroaryl or an optionally substituted heterocyclyl.
  • G is -0-C(O)-NH-, -NH-C(NH)-NH-, -NR k -C(NH)-NH-, -NR k -C(NR k )- NH-, -NH-C(N(CN))-NH-, -NH-C(NS O 2 R C )-NH-, -NR k -C(NSO 2 R c )-NH-, -NH- C(NNOz)-NH-, NH-C(NC(O)R C )-NH-, -NH-C(O)-NH-, Or -NH-C(S)-NH-.
  • G is -NH-S(O) 2 -NH-, -NR k -S (O) 2 -O-, -P(O)(R C )-, -P(O)(R C )-O-, or - P(O)(R c )-NR k -.
  • G is an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.
  • G is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted cycloheptyl, an optionally substituted aziridinyl, an optionally substituted oxiranyl, an optionally substituted azetidi ⁇ yl, an optionally substituted oxetanyl, an optionally substituted morpholinyl, an optionally substituted piperazinyl or an optionally substituted piperidinyl.
  • G is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, -C(N-CN)-NH-, -Si(OH) 2 -, -C(NH)-NR k -, or - NR k -CH 2 -C(O)-.
  • G is an optionally substituted imidazolyl, an optionally substituted imidazolidinone, an optionally substituted imidazolidineamine, an optionally substituted pyrrolidinyl, an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted thienyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazolyl, an optionally substituted tetrazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted indolyl, or an optionally substituted benzothi
  • Y is O or CH 2 ; G is absent; and n is 0, 1, 2, 3 or 4.
  • Y is absent, O, S, NR k , or CH 2 ; and n is 0, 1, 2, 3, or 4.
  • the compound is represented by formula (V):
  • G, Y, R 2 , R.3, R 4 , and n are defined as for formula I; and Ring D, Ai, A 2 , U, and V are defined as for formula (111).
  • the compound in the compounds represented by formula (HT) or (V), the compound is represented by one of the following structural formulas:
  • G, Y, R 2 , R. 3 , R4, R g , and n are defined as for formula I;
  • X 5 , X ⁇ and X 7 are each, independently, N or CR ⁇ ;
  • X 8 is CR s R e , O, S(O)p, or NR k , wherein R k is defined as for formula (I).
  • U and V are N; and X 5 , X 6 and X 7 are CR g .
  • R' and V are absent.
  • R" is an optionally substituted cycloalkyi, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
  • R" is an optionally substituted aryl or an optionally substituted heteroaryl.
  • R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH 2 , a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O) P R°, and- C(O)R C .
  • Z is N and W is O.
  • Y is a covalent bond, O, S, N(R k ), or CH 2 , and n is 0, 1, 2, 3, or 4.
  • G is absent.
  • R3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyi, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, OR k , SR k , or NR h R J .
  • R 3 is optionally substituted aryl or optionally substituted heteroaryl.
  • R 3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azule ⁇ yl, an optionally substituted pyridyl.
  • an optionally substituted 1-oxo-pyridyl an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted
  • R3 is an optionally substituted heterocycloalkyl.
  • R 3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl s
  • R 3 is -OR k or -NR 11 R 1' , and R f , R h and R j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R 0 .
  • R 3 is -C(O)OR k , -OC(O)R k , -C(O)NR h R j , -NR k C(O)R k , - C(S)OR k , -OC(S)R k , -NR k C(O)NR h R j , -NR k C(S)NR h R J , -C(O)NRhRj, -S(O) 2 R k , -S(O) 2 NR h R j , -OC(O)NR h R j , or -NR k C(O)OR k .
  • the compound in the compounds represented by formula (IH), is represented by one of the following structural formulas:
  • X 9 is CR S R S , O, S(O) P , or NR k ; one of Ri3, Ru and R15 is a group represented by the following structural formula: and the remainder of Rn, R14 and R15 are independently selected from H, R ⁇ , or isothionitro; and
  • R 2 , R 3 , R 4 , G 1 Y, R g , R k and n are defined as for formula (I).
  • R' and V are absent.
  • R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
  • R" is an optionally substituted aryl or an optionally substituted heteroaryl.
  • R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH 2 , a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O) P R C , and— C(O)R C .
  • Y is a covalent bond, O, S, N(R k ), or CH 2 , and n is O, 1, 2, 3, or 4.
  • G is absent.
  • R 3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, OR k , SR k , orNR h R j .
  • R 3 is optionally substituted aryl or optionally substituted heteroaryl.
  • R 3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl.
  • R 3 is an optionally substituted heterocycloalkyl.
  • R 3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4- ⁇ iperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide,
  • R 3 is -OR k or -NR h R j , and R f , R h and R j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R C .
  • R 3 is -C(O)OR k , -OC(O)R k , -C(O)NR h R j , -NR k C(O)R k , -C(S)OR k , -OC(S)R k , -NR k C(O)NR h R j , -NR k C(S)NR h R j , -C(O)NRhRj, -S(O) 2 R", -S(O) 2 NR h R j , -OC(O)NR h R j , or -NR k C(O)OR k .
  • the compound in the compounds represented by formula (X), is represented by one of the following structural formulas:
  • pan or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:
  • G, Y, R 2 , R-3, R 4 , R s and n are defined as for formula (I);
  • R', R", L', X 4 , U, V, W, Z, and u are defined as for formula (III); w is defined as for formula (X);
  • X 5 , Xe and X 7 are each, independently, N or CR 8 ;
  • X 8 , X10, and X n are each, independently, CR g R g , O, S(O)p, or NR k , wherein R k is defined as for formula (I).
  • V are N; and X 5 and X 6 are CR g .
  • V are N; X 5 and X 6 are CR g ; and X 7 is N.
  • V are N; X 5 and X 6 are CR 8 ; and X 7 is CR ⁇ .
  • w is 0, and R' and L' are absent.
  • R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
  • R" is an optionally substituted aryl or an optionally substituted heteroaryl.
  • R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH 2 , a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O) p R c , and — C(O)R C .
  • Z is N and W is O.
  • Y is a covalent bond, O, S, N(R k ), or CH 2 , and n is 0, 1, 2, 3, or 4.
  • R 3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, OR k , SR k , orNR h R j .
  • R 3 is optionally substituted aryl or optionally substituted heteroaryl.
  • R 3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1 -oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted inden
  • R 3 is an optionally substituted heterocycloalkyl.
  • R 3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2- oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidi ⁇ yl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an
  • R 3 is -OR k or -NR h R j , and R f , R h and R j are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R 0 .
  • R 3 is -C(O)OR k , -OC(0)R k , -C(O)NR h R j , -NR k C(0)R k , -C(S)OR 1 ", -OC(S)R k , -NR k C(O)NR h R j , -NR k C(S)NR h R j , -C(O)NRhRj, -S(O) 2 R k , -S(O) 2 NR h R j , -OC(O)NR h R j , or-NR k C(O)OR k .
  • w is 1; X 4 is O, S, or NRj 4 ; and R' and L' are absent.
  • R.!6 is defined as for formula (XIV); ring E is optionally substituted with one to four substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl;
  • X 12 is O 3 S, S(O), S(O) 2 , or CR 8 R 8 ;
  • X 13 is O 5 S, S(O), S(O) 2 , or CH 2 ;
  • Y 1 is O, S, NR k , or CH 2 ;
  • Ri 7 and Rig are independently, H or a lower alkyl; or R 17 and R 1 8 taken together with the carbon to which they are attached form a cycloalkyl; and fis O, 1, 2, or 3.
  • Ri 6 is defined as for formula (XIV);
  • Rn 5 RiS 5 X B , and f are defined as for formula (XV); ring F is optionally substituted with one or two substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl; and
  • X 14 is O, NR k , or CR g R g .
  • Ri 6 is defined as for formula (XIV);
  • X 15 is -OH, -NH 2 or -SH.
  • one of Q, U, or V is CR ⁇ , and the other two are N.
  • V is CR S , Q and U are N.
  • Q is CR g , V and U are N.
  • U is CR ⁇
  • V and Q are N.
  • one of Q, U, or V is N, and the other two are CR g .
  • V is N, and Q and U are CR g .
  • Q is N, and V and U are CR 8 .
  • U is N and Q, and V are CR g .
  • — NR 5 R 6 is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1 -oxo-thiomorpholino, an optionally substituted 1,1-dioxo-thiomorpholmo, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.
  • ring A is a ring system selected from the group consisting of:
  • rings G, H, I, and J are each, independently, an aryl or a heteroaryl; and each ring system is optionally substituted with one or more substituents.
  • ring A is a ring system selected from the group consisting of:
  • each ring system is optionally substituted with one or more substituents
  • R 49 is H, an alkyl, an aralkyl, or an alkylcarbonyl.
  • ring A is a ring system selected from the group consisting of:
  • each ring system is optionally substituted with one or more substituents.
  • Y 1 is a covalent bond.
  • Y is O or CH 2 ,- G is absent; and n is 0, 1, 2, 3 or 4.
  • Y is absent, O, S, NR k , or CH 2 ; and n is 0, 1, 2, 3, or 4.
  • Xi 2 , Xi 3 , Yi is O; and Rj 7 and R ⁇ are each, independently, H or a lower alkyl.
  • Xn, Xi 4 , and Yi are O; and Rj 7 and Ri 8 are each, independently, H or a lower alkyl.
  • Xn and Yi are O; Xi 5 is -OH; and Rn and Ri 8 are each, independently, H or a lower alkyl.
  • the compound is not a compound disclosed in U.S. Application No. 11/271,704 or U.S. Application No. 11/272,509.
  • Preferred compounds for use in the method of the invention include the following compounds:
  • the compound is a disalt of the form [Compound] 2H + ⁇ M " , in which [Compound] represents a compound of any of the formulae I — XVII disclosed herein, and each M " is a conjugate base of a Bronsted acid.
  • the term “disalt” refers to an ionic substances of formula A having a cationic, diprotonated IL- 12 production inhibitor compound, ( ⁇ )(2H 4 ), combined with anionic, charge balancing moieties, «( ⁇ ).
  • disalts can be formed by
  • IL- 12 production inhibitor compounds of any of Formulae I — XVII (( ⁇ ) in formula A) with Bronsted acids.
  • the term "Bronsted acid” includes any chemical species that can be proton (H + ) donors. While not wishing to be bound by theory, it is believed that disalt formation occurs when two or more (IT ⁇ -acceptor atoms, e.g., nitrogen atoms, of the IL- 12 production inhibitor compounds are protonated by the Bronsted acid.
  • the charge balancing moieties ( «( ⁇ ) in formula A) correspond to the conjugate base of the Bronsted acid used to protonate the IL- 12 production inhibitor compounds.
  • disalt protons ((2H + ) in formula A) and charge balancing moieties can be replaced in subsequent exchange reactions.
  • the disalt protons can be exchanged, e.g., for the corresponding isotopic deuterons (2D + ) or tritons (2T + ), and/or the disalt charge balancing moieties can be exchanged for other negatively charged counterions, e.g., via ion exchange chromatography methods.
  • Disalts prepared via anion and/or cation exchange reactions of disalt starting materials are also within the scope of the present invention.
  • the disalt is a disalt of Compound 50 (N-[3- methylbenzylidene]-N'-[6-mo ⁇ holin-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]- hydrazine), such as the bis-mesylate salt ((N-[3-methylbenzylidene]-N'-[6-morpholin- 4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazine bis-mesylate)).
  • Specific examples of compounds of the invention are set forth below in Table
  • the term "contacting" includes incubating the compound and the cell together in vitro (e.g., adding the compound to cells in culture) as well as administering the compound to a subject such that the compound and cells of the subject are contacted in vivo.
  • the term "contacting” does not include exposure of cells to a compound of the invention (e.g., an IL-12 production inhibitor) that may occur naturally in a subject (i.e., exposure that may occur as a result of a natural physiological process).
  • this invention features a pharmaceutical composition that includes a pharmaceutically acceptable carrier and at least one compound that is suitable (e.g., safe and effective) for treatment of CVID (e.g., an inhibitor of IL-12 production, a compound of an formula disclosed herein), optionally including a second active compound that is suitable (e.g., safe and effective) for treatment of CVID (e.g., immunoglobulin replacement) or a symptom thereof (e.g., an antibiotic).
  • CVID e.g., an inhibitor of IL-12 production, a compound of an formula disclosed herein
  • a second active compound that is suitable for treatment of CVID (e.g., immunoglobulin replacement) or a symptom thereof (e.g., an antibiotic).
  • the compounds of the invention can be prepared according to a variety of methods, some of which are known in the art, e.g., as disclosed in the patents and patent applications in Table 2, the entire teachings of which are incorporated herein by reference.
  • alkyl refers to a straight-chained or branched hydrocarbon group containing 1 to 12 carbon atoms.
  • an alkyl can be a lower alkyl; the term “lower alkyl” refers to a C 1 -C O alkyl chain.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n- pentyl.
  • Alkyl groups may be optionally substituted with one or more substitue ⁇ ts.
  • alkenyl refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Alkenyl groups may be optionally substituted with one or more substituents.
  • alkynyl refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing the 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.
  • the sp 2 or sp carbons of an alkenyl group and an alkynyl group, respectively, may optionally be the point of attachment of the alkenyl or alkynyl groups.
  • alkoxy refers to an alkyl or a cycloalkyl group which is linked to another moiety though an oxygen atom. Alkoxy groups can be optionally substituted with one or more substituents.
  • mercapto refers to a -SH group.
  • alkyl sulfanyl refers to an alkyl or a cycloalkyl group which is linked to another moiety though a divalent sulfer atom. Alkyl sulfanyl groups can be optionally substituted with one or more substituents.
  • halogen or halo means -F, -Cl, -Br or -I.
  • haloalkyl means and alkyl group in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from -F, -Cl, -Br, and -L
  • halomethyl means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group.
  • Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichIoroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.
  • cycloalkyl refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system which is completely saturated ring. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent.
  • Representative examples of cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and bicyclo[2.1.1]hexyl.
  • cyclyl refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one non-aromatic ring, wherein the non-aromatic ring has some degree of tmsaturation.
  • Cyclyl groups may be optionally substituted with one or more substituents. Ih one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cyclyl group may be substituted by a substituent.
  • cyclyl groups include cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, dihydronaphthalenyl, benzocyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl.cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl and the like.
  • aryl refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system.
  • Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.
  • aralkyl means an aryl group that is attached to another group by a (Ci-C ⁇ )alkylene group.
  • Aralkyl groups may be optionally substituted, either on the aryl portion of the aralkyl group or on the alkylene portion of the aralkyl group, with one or more substituent.
  • Representative aralkyl groups include benzyl, 2-phenyl-eth.yl, naphth-3-yl-methyl and the like.
  • alkylene refers to an alkyl group that has two points of attachment.
  • (Ci-C ⁇ )alkylene refers to an alkylene group that has from one to six carbon atoms.
  • alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n-propylene (-CH 2 CH 2 CH 2 -), isopropylene (-CH 2 CH(CH 3 )-), and the like.
  • Alkylene groups may be optionally substituted.
  • cycloalkylene refers to a cycloalkyl group that has two points of attachment. Cycloalkylene groups may be optionally substituted.
  • cyclylene refers to a cyclyl group that has two points of attachment. Cyclylene groups may be optionally substituted.
  • arylene refers to an aryl group that has two points of attachment. Arylene groups may be optionally substituted.
  • aralkylene refers to an aralkyl group that has two points of attachment. Aralkylene groups may be optionally substituted.
  • arylalkoxy refers to an alkoxy substituted with an aryl.
  • heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon.
  • Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent.
  • heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[l,3]dioxolyl, benzo[l,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetra
  • heteroarylkyl or “heteroarylalkyl” means a heteroaryl group that is attached to another group by a (Ct-C ⁇ lkylene.
  • Heteroaralkyl groups may be optionally substituted, either on the heteroaryl portion of the heteroaralkyl group or on the alkylene portion of the heteroaralkyl group, with one or more substituent.
  • Representative heteroaralkyl groupss include 2-(pyridin-4-yl)- propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl and the like.
  • heteroarylene refers to a heteroaryl group that has two points of attachment. Heteroarylene groups may be optionally substituted.
  • heteroaralkylene refers to a heteroaralkyl group that has two points of attachment. Heteroaralkylene groups may be optionally substituted.
  • heterocycloalkyl refers to a nonaromatic, completely saturated 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si.
  • Heterocycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted by a substituent.
  • heterocycloalkyl groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4- piperidonyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, an thiirene.
  • heterocyclyl refers to a nonaromatic 5-8 membered monocyclic, 7- 12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si, wherein the nonaromatic ring system has some degree of unsaturation.
  • Heterocyclyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocyclyl group may be substituted by a substituent.
  • Examples of these groups include thiirenyl, thiadiazirinyl, dioxazolyl, 1,3-oxathiolyl, 1,3-dioxolyI, 1,3-dithiolyl, oxathiazinyl, dioxazinyl, dithiazinyl, oxadiazinyl, thiadiazinyl, oxazinyl, thiazinyl, l,4-oxathiin,l,4-dioxin, 1,4-dithiin, lH-pyranyl, oxathiepinyl, 5H- 1,4- dioxepinyl, 5H-l,4-dithiepinyl, 6H-isoxazolo[2,3-d]l,2,4-oxadiazolyl, 7H- oxazolo[3,2-d]l,2,4-oxadiazolyl, and the like.
  • heterocycloalkylene refers to a heterocycloalkyl group that has two points of attachment. Heterocycloalkylene groups may be optionally substituted. As used herein, the term “heterocyclylene” refers to a heterocyclyl group that has two points of attachment. Heterocyclylene groups may be optionally substituted.
  • a cycloalkyl, cyclyl, heterocycloalkyl, or heterocyclyl is fused to another ring (e.g., a cycloalkyl, cyclyl, heterocycloalkyl, heterocyclyl, aryl, heteroaryl), it shares two or more ring atoms, preferably two to four ring atoms, with the other ring.
  • amino refers to -NH 2 .
  • alkylamino refers to an amino in which one hydrogen is replaced by an alkyl group.
  • dialkylamino refers to an amino in which each of the hydrogens is replaced by an independently selected alkyl group.
  • aminoalkyl refers to an alkyl substituent which is further substituted with one or more amino groups.
  • mercaptoalkyl refers to an alkyl substituent which is further substituted with one or more mercapto groups.
  • hydroxyalkyl or "hydroxylalkyl” refers to an alkyl substituent which is further substituted with one or more hydroxy groups.
  • sulfonylalkyl refers to an alkyl substituent which is further substituted with one or more sulfonyl groups.
  • sulfonylaryl refers to an aryl substituent which is further substituted with one or more sulfonyl groups.
  • alkylcarbonyl refers to an -C(O)-alkyl.
  • mercaptoalkoxy refers to an alkoxy substituent which is further substituted with one or more mercapto groups.
  • alkylcarbonylalkyl refers to an alkyl substituent which is further substituted with -C(O)-alkyl.
  • the alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.
  • Suitable substituents for an alkyl, alkoxy, alkyl sulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cyclyl, heterocycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkylene, cyclylene, heterocyclo alkylene, heterocyclylene, arylene, aralkylene, heteroalkylene and heteroaryalkylene groups include any substituent which will form a stable compound of the invention.
  • substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cyclyl, heterocycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkylene, cyclylene, heterocycloalkylene, heterocyclylene, arylene, aralkyle ⁇ e, heteroalkylene and heteroaryalkylene include an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted hetero
  • heterocyclyl. heteroaryl, or heteroaralkyl group When a heterocyclyl. heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent the nitrogen may be a quaternary nitrogen.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). Typically, such compounds are stable at a temperature of 40 0 C or less, in the absence of excessive moisture, for at least one week. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.
  • lower refers to a group having up to six atoms.
  • a “lower alkyl” refers to an alkyl radical having from 1 to 6 carbon atoms
  • a “lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, respectively.
  • a “lower alkoxy” or “lower alkyl sulfanyl” group refers to an alkoxy or alkyl sulfanyl group that has from 1 to 6 carbon atoms.
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • the compounds of this invention include the compounds themselves, as well as their salts, solvate, clathrate, hydrate, polymorph, or prodrugs, if applicable.
  • pharmaceutically acceptable salt is a salt formed from, for example, an acid and a basic group of a compound of any one of the formulae disclosed herein.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,/>-toluenesulfonate, and pamoate ⁇ i.e., 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylarnine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of any one of the formulae disclosed herein having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • suitable acids include hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fur ⁇ aric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and/?-toluenesulfonic acid.
  • Salts of the compounds disclosed herein can be prepared by several methods, some of which are known in the art. Exemplary methods for making certain salts are disclosed in U.S. Application No. 11/105,818, filed April 13, 2005, and U.S. Provisional Application No. 60/731,038, filed October 27, 2005 and PCT Application No. PCT/US06/42211, filed October 27, 3006, the contents of which are incorporated herein by reference.
  • polymorph means solid crystalline forms of a compound of the present invention or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability).
  • Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
  • chemical reactivity e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical characteristics e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph
  • both e.g., tablets of one polymorph are more susceptible to breakdown at high humidity.
  • Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another
  • hydrate means a compound of the present invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule ⁇ e.g. , a solvent or water) trapped within.
  • prodrug means a derivative of a compound that can hydro lyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, or they may have activity in their unreacted forms.
  • prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of any one of the formulae disclosed herein that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Other examples of prodrugs include derivatives of compounds of any one of the formulae disclosed herein that comprise -NO, -NO 2 , -ONO, or -ONO2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-
  • biohydrolyzable amide means an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound.
  • biohydrolyzable amides include, but are not limited to, lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
  • biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamin ⁇ alkyl esters, and choline esters.
  • biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amxnoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
  • some of the compounds of this invention have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms. AU such isomeric forms of these compounds are expressly included in the present invention.
  • the compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
  • the aforementioned compounds also include their iV-oxides.
  • the term 'W-oxides refers to one or more nitrogen atoms, when present in a heterocyclic or heteroaryl compound, are in iV-oxide form, i.e., N ⁇ O.
  • N ⁇ O i.e., N ⁇ O
  • compounds of any one of the formula d or Table 1 when one of Q, U, or V is N also included are compounds in which Q, U, or V, respectively, is N ⁇ O.
  • solvate is a solvate formed from the association of one or more solvent molecules to one of the compounds of any of the formulae disclosed herein.
  • solvate includes hydrates (e.g., hemi-hydrate, mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • the method can also include the step of identifying that the subject is in need of treatment for CVID.
  • the identification can be in the judgment of a subject or a health professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or a diagnostic method).
  • one embodiment of the present invention is directed to treating subjects with CVID.
  • Treating a subject with a CVID includes achieving, partially or substantially, one or more of the following: ameliorating or improving a clinical symptom or indicator associated with CVID (such as hypogammaglobulinemia, bacterial infection, autoimmune diseases (i.e., autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and pernicious anemia), and increased risk for lymphoproliferation and/or neoplasia).
  • An "effective amount” is the quantity of compound in which a beneficial clinical outcome is achieved when the compound is administered to a subject with CVID.
  • a "beneficial clinical outcome” includes increase in gamma globulin level, and/or a reduction in the severity of the symptoms associated with CVID and/or an increase in the longevity of the subject compared with the absence of the treatment.
  • the precise amount of compound administered to a subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree and severity of CVDD. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compounds typically range between about 1 mg per day to 100 mgper day, or between 10 mg/day and 500 mg/day, or between 50 to 250 mg/day, or between 50 to 150 mg/day.
  • the disclosed compounds can be administered once daily or in divided doses.
  • an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for existing agents used for the thereapy of CVID and can be adjusted by the skilled artisan according to the condition of the subject, the severity of CVID and the amount of the compound of the invention being used.
  • a compound of the invention- alone, or as a component of a pharmaceutical composition can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • a sterile injectable composition for example, a sterile injectable aqueous or oleaginous suspension, can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • suitable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
  • a composition for oral administration can be any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • a nasal aerosol or inhalation composition can be prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • a compound of this invention can also be administered in the form of suppositories for rectal administration.
  • the carrier in the pharmaceutical composition must be "acceptable” in the sense of being compatible with the active ingredient of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated.
  • solubilizing agents such as cyclodextrins, which form specific, more soluble complexes with the compounds of this invention, or one or more solubilizing agents, can be utilized as pharmaceutical excipients for delivery of the compounds of the invention.
  • examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
  • the terms "animal”, “subject,” “mammal” and “patient”, include, but are not limited to, a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human (preferably, a human).
  • the methods for treating CVID in a patient in need thereof can further comprise administering, to the patient being administered a compound of this invention, an effective amount of one or more other therapeutic agents.
  • Such therapeutic agents may include other therapeutic agents such as those conventionally used to treat CVED or the symptoms thereof.
  • the compounds of the invention can be co-administered with immunoglobulin (Ig), immunosupresants such as steroids or cyclosporin A 5 anti-CD20 monclonal antibody, IL-2, antibiotics (for treatment of infection), inhaled corticosteroids and other asthma medications for treatment of lung disease, anti-neoplastic agents (for prevention and/or treatment of cancers associated with CVID), and the like.
  • immunoglobulin Ig
  • immunosupresants such as steroids or cyclosporin A 5 anti-CD20 monclonal antibody
  • IL-2 immunoglobulin-2
  • antibiotics for treatment of infection
  • inhaled corticosteroids and other asthma medications for treatment of lung disease
  • anti-neoplastic agents for prevention and/or treatment of cancers associated with CVID
  • the IL- 12 production inhibitory activity of the compounds disclosed herein can be tested according to methods known in the art, for example, by the representative method described below.
  • Staphylococcus aureus Cowan I (SAC) is obtained from Calbiochem (La Jolla, CA), and lipopolysaccharide (LPS, Serratia marscencens) is obtained from Sigma (St. Louis, MO).
  • SAC Staphylococcus aureus Cowan I
  • LPS lipopolysaccharide
  • Human and mouse recombinant IFN ⁇ are purchased from Boehringer Mannheim (Mannheim, Germany) and Pharmingen (San Diego, CA), respectively. Human In Vitro Assay.
  • Human PBMC are isolated by centrifiigation using Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden) and prepared in RPMI medium supplemented with 10% fetal calf serum (FCS), 100 U/mL penicillin, and 100 ⁇ g/mL streptomycin.
  • PBMC are plated in wells of a 96-well plate at a concentration of 5 x 10 5 cells/well, and primed by adding IFNy (30 U/mL) for 22 h and stimulated by adding LPS (1 ⁇ g/mL), or by adding IFN ⁇ (100 U/mL) and then stimulated by adding SAC (0.01%).
  • test compound is dissolved in DMSO, and added to wells of the 96- well plate. The final DMSO concentration is adjusted to 0.25% in all cultures, including the compound-free control.
  • Human THP-I cells are plated in wells, primed by adding IFN ⁇ (100 U/mL) for 22 h and stimulated by adding SAC (0.025%) in the presence of different concentrations of the test compound.
  • Cell-free supernatants are taken 18 h later for measurement of cytokines.
  • Cell viability is assessed using the bioreduction of MTS.
  • Cell survival is estimated by determining the ratio of the absorbance in compound-treated groups versus compound-free control.
  • the supernatant is assayed for the amount of EL-12p40, IL-12p70, or IL-10 by using a sandwich ELISA with anti-human antibodies, i.e., a Human IL-12 p40 ELISA kit from R&D Systems (Berkeley, CA), and a Human IL-12 p70 or IL-10 ELISA kit from Endogen (Cambridge, MA). Assays are based on the manufacturer's instructions.
  • IL-12 production inhibitory activity of certain other compounds useful in the present invention is described, e.g., in certain of the patents and patent applications of Table 2, supra.
  • VAN DEN BRANDE P. et al. Intestinal Nodular Lymphoid Hyperplasia in Patients With Common Variable Immunodeficiency: Local Accumulation of B and Cd8(+) Lymphocytes. Journal of Clinical Immunology, v. 8, n. p. 296-306, 1988.
  • AUKRUST P. et al. Persistent Activation of the Tumor Necrosis Factor System in a Subgroup of Patients With Common Variable
  • ECKARDT V. F.
  • GAEDERTZ C
  • EIDNER C. Colonic Perforation With Endoscopic Biopsy.. Gastrointest. Endosc, v. 46, n. p. 560-562, 1997.
  • FARRINGTON M. et al. Cd40 Ligand Expression is Defective in a Subset of Patients With Common Variable Immunodeficiency.. Proceedings of the National Academy of Sciences of the United States of America, v. 91, n. p. 1099-1103, 1994.
  • FISCHER M. B. et al. Activation of Cvid Patients' T Cells With Conventional Antigens and Superantigens. Immunodeficiency, v. 4, n. p. 15-16, 1993.
  • FISCHER M. B. et al. A Defect in the Early Phase of T-CeIl Receptor-Mediated T- CeIl Activation in Patients With Common Variable Immunodeficiency. Blood, v. 84, n. p. 4234-4241, 1994.
  • GRIMBACHER B. et al. Homozygous Loss of Icos is Associated With Adult- Onset Common Variable Immunodeficiency. Nature Immunol, v. 4, n. p. 261-268, 2003.
  • IRVINE E. J.; HUNT, R. H. Endoscopy-Lower Intestinal Tract.
  • SHIFFMAN M. L.; FARREL, M. T.; YEE, Y. S. Risk of Bleeding After Endoscopic Biopsy Or Polypectomy in Patients Taking Aspirin Or Other Nsaids. Gastrointest. Endosc, v. 40, n. p. 458-462, 1994.
  • Trinchieri G Proinflammatory and immunoregulatory functions of interleukin-12. Int Rev Immunol 1998;16(3-4):365-96.
  • WAGNER D. et al. Dysgonic Fermenteor 3- Associated Gastrointestinal Disease in a Patient With Common Variable Hypogammaglobulinemia.. American Journal of Medicine, v. 84, n. p. 315-318, 1988.

Abstract

The invention relates to a method for treating common variable immunodeficiency.

Description

METHOD FOR TREATING COMMON VARIABLE IMMUNODEFICIENCY
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application Nos. 60/775,737, filed on February 22, 2006, and 60/872,629, filed November 30, 2006, the entire teachings of which are incorporated herein by reference.
BACKGROUND
Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia due to a primary failure of B cell differentiation and impaired secretion of immunoglobulins. This is frequently accompanied by T cell abnormalities consisting of blunted proliferative responses to mitogenic and antigenic stimuli, a relative lack of mature (CD45RO) T cells, and reduced production of IL-2 and other cytokines. Well-defined genetic defects are just beginning to be identified, but most CVDD is encountered as sporadic and not as inherited disease (Grimbacher et al., 2003; Salzer et al., 2005). The major manifestations of this disease include bacterial infections, autoimmune diseases (i.e., autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and pernicious anemia), and an increased risk for lymphoproliferation and neoplasia. Generally, therapy is aimed primarily at restoring immunoglobulin levels with the administration of intravenous pooled immunoglobulin (IVIG); while this therapy clearly decreases the frequency and severity of infections it has no effect on associated autoimmune disease or neoplasia risk. Furthermore, it is recognized that the GI tract is affected in CVID not only by infectious agents that respond to IVIG but also by idiopathic inflammation and lymphoproliferative lesions, which are unresponsive to IVIG therapy.
While the hallmark of CVID is the inability to make antibodies to specific antigens, this has been attributed to abnormalities in both B and T cell status and function. Low B cell (CD 19+) numbers (in 5-10% of CVID patients) are associated with failure to produce antibodies in vitro (Farrant et al., 1994), and the majority of CVED patients with normal B cell numbers are lacking in mature class-switched B cells (i.e., CD27+IgM-IgD- memory B cells) (Warnatz et al., 2002; Jacquot et al., 2001). This latter observation is consistent with the lack of plasma cells (particularly those producing class-switched antibodies, as CD27 is known to promote interaction with T cells for differentiation into plasma cells) in the lamina propria (Herbst et al., 1994; Washington et al., 1996). Additionally, among those with normal B cell numbers, B cells may be induced in vitro to produce IgM alone, IgM and IgG, or remain unresponsive (Bryant et al., 1990) suggesting the mechanism for producing antibodies is not due to primary B cell defects in some patients. CVID patients with near normal numbers of mature class-switched B cells (CD27+IgM-IgD-) seem to be the ones who can produce IgM and IgG in vitro (those with low numbers of mature class-switched B cells can be further defined by whether there is a concomitant excess of immature B cells (CD21-) (Warnatz et al., 2002). However, any such classification of B cell dysfunction does not seem to clearly predict the natural history or development of complications in CVID.
T cells in CVID patients have been variously reported to display reduced proliferation and activation by antigens and/or mitogens (Cunningham-Rundles and Bodian, 1999; Fischer et al., 1993; Fischer et al., 1994; North et al., 1991), have impaired IL-2 production, show lower expression of cell surface CD40L (Brugnoni et al., 1996; Farringtori et al., 1994), fail to develop antigen-specific responses (Kondratenko et al., 1997; Stagg et al., 1994), and show excessive activity of CD8+ cells (Jaffe et al., 1993; North et al., 1998; Serrano et al., 2000; Wright et al., 1990; Waldmann et al., 1974). Although antigen-presentation appears to be intact for CVID monocytes and macrophages (Gupta and Damle, 1983; Thon et al., 1997), dendritic cells and monocytes may have altered cytokine production that could affect the function and differentiation of B cells (Cambronero et al., 2000; Cunningham- Rundles and Radigan, 2005). In sum, the variety of the altered cellular immune response observed in CVID lymphocytes supports the notion that failure to produce antibodies may be a primary B cell defect but more likely is contributed to by defective T cell signals and interactions.
Patients with CVID are more susceptible to protozoan and bacterial gastrointestinal pathogens. Infection with Giardia lamblia is frequently encountered and is characterized by clinical disease after lower levels of parasite exposure as well as increased resistance to eradication with conventional therapy. In addition, there is an increased incidence of infections with common gastrointestinal pathogens (e.g., Salmonella, Shigella, and Campylobacter species). Severe diarrhea has been associated with the fastidious gram-negative rod known as dysgonic fermenter-3 (DF- 3) (Wagner et al., 1988). While the incidence of Giardia infection has decreased significantly in patients on chronic IVIG therapy (Teahon et al., 1994), the rate is still higher than seen in normal individuals. This supports the idea that a T cell defect is contributing to a persistent mucosal immune abnormality.
In recent years it has been shown that a significant subset of CVID patients demonstrates features of persistent immune activation characterized by a ThI -skewed cytokine profile. These patients may have an abnormally low CD4/CD8 ratio (< 0.9), and an increased incidence of splenomegaly (71%) and anergy (42%) compared to CVID patients with normal CD4/CD8 ratios (29% and 7%, respectively) (Wright et al., 1990). The low CD4/CD8 ratio in this CVID group is due to an increase in CD8+ cells, which have impaired proliferation but secrete increased levels of INF-γ and IL-5 (but normal amounts of IL-4) when stimulated in vitro (Jaffe et al., 1993; Wright et al., 1990). In these studies the CD4+ cells behaved normally, and in only the occasional patient could CD8+ effects potentially explain the hypogammaglobulinemia. In another study of 24 CVED patients, low CD4+ cell counts and a low CD4/CD8 ratio < 0.9 was observed that could not be attributed to an expanded CD8+ population (Aukrust et al., 1996). In addition, this study group had significantly elevated serum TNFα levels which was particularly evident in the subset (11/24 patients) defined by splenomegaly, a CD4+ count < 400 x 106/L, and significantly elevated serum neopterin levels. Furthermore, another report showed that significantly more peripheral blood monocytes (CD 14+, but not CD 14- cells in a dendritic cell pool) from CVID patients expressed high IL- 12 following LPS stimulation than normal controls or patients with X-linked agammaglobulinemia (Cambronero et al., 2000); this was associated with significantly increased expression of IFNγ in CD4+ (and CD8+) T cells. A more recent study confirmed the lack of IL- 12 production in CVED dendritic cells (CD 14-) compared to its induced production in normals, but other monocytes were not studied(Cunningham-Rundles and Radigan, 2005). Lastly, in CVID patients with granulomatous disease or reduced numbers of class-switched memory B cells, plasmacytoid dendritic cells (promoting Th2 responses) were disproportionately decreased compared to myeloid dendritic cells (promoting ThI responses), suggesting a possible bias toward ThI inflammatory responses (Viallard et aL, 2005). While it is not known whether gastrointestinal disease is experienced at a higher rate in high-TNF or any of these other CVED subsets, given the role of TNF in gut granulomatous inflammation and its role in Crohn's disease, these data support the idea that immune activation, with a ThI skewness, may be associated with gastrointestinal disease in CVID. It is believed that excess TNFα can contribute to gastrointestinal inflammatory states as seen in transgenic animal models (Kontoyiannis et al., 1999) and in the beneficial response of human Crohn's disease to TNFα immunoneutralization.
Cytokine production by lamina propria mononuclear cells recently has been characterized as a polarized ThI inflammation. Interestingly, only CVID patients with gastrointestinal symptoms of diarrhea and weight loss as well as the gut inflammatory changes had this excess cytokine production; those CVED patients with similar histologic findings but no symptoms had no increased cytokine production.
Gastrointestinal (GI) manifestations of CVED unrelated to infections occur in upwards of 20% of patients (Cunningham-Rundles and Bodian, 1999; Sneller et al., 1993). This is most likely an underestimate since patients without overt gastrointestinal symptoms are not routinely examined for gut abnormalities. Symptoms generally include chronic diarrhea, malabsorption marked by increased excretion of fat, abnormal D-xylose uptake by the small bowel, and protein- losing enteropathy due to loss of albumin and other proteins into the fecal stream. This can lead to severe weight loss requiring the need for hyperalimentation, nutrient deficiency contributing to hypocalcemia (vitamin D malabsorption) and anemia (folate malabsorption), and hypoalbuminemia predisposing to edema.
In one study, 51% (22/43) of patients with CVTD had accompanying GI symptoms (i.e., chronic or bloody diarrhea, documented Giardia or other parasitic infection, pernicious anemia, pneumatosis coli, malabsorption, and perirectal abscess) and of those with gut tissue examined histologically (10/22), 100% had striking abnormalities (Washington et al., 1996). A wide range of histologic abnormalities are seen: in the stomach, morphologic changes consistent with acute graft-versus-host disease (apoptotic glandular epithelial cells, dense mononuclear inflammatory cell infiltrate with occasional crypt obliteration), increased intraepithelial lymphocytes, and varying degrees of gastritis (leading in some cases to atrophy and achlorhydria in the absence of Helicobacter pylori infection and anti-parietal cell and anti-intrinsic factor antibodies (Moriuchi et al., 1990; Twomy et al., 1970; Wright and Sears, 1987; Zullo et aL, 1999)); in the small intestine histologic changes include mild to marked villous atrophy (differing from celiac sprue by the absence of lamina propria plasma cells, lack of significant basal crypt hyperplasia, and relatively normal enterocyte maturation with preserved brush border and Goblet cells), increased intraepithelial lymphocytes, nodular lymphoid hyperplasia (NLH), frank lymphomatous changes as well as the occurrence of non-granulomatous transmural inflammation with evidence of fibrosis and strictures (Teahon et al., 1994; Washington et al., 1996); finally in the colon there can be inflammation that resembles lymphocytic colitis (with increased lymphocytes in the surface epithelium), ulcerative colitis (with acute inflammatory cells in the crypt epithelium and lamina propria, and loss of crypts in severe disease, but lacking the plasma cell infiltrate seen in classical ulcerative colitis), or graft- versus-host disease. One study notes Crohn's disease, and ulcerative colitis/proctitis associated with CVID (Cunningham-Rundles and Bodian, 1999), but other more detailed studies of the accompanying enteropathy do not support its meeting the full histologic criteria for these diseases (Teahon et al., 1994; Washington et al., 1996).
The lesions of intestinal nodular lymphoid hyperplasia (NLH) are said to be virtually pathognomonic for CVID, but NLH does occur rarely in otherwise normal individuals. These macroscopic collections of lymphocytes are found primarily in the small bowel and sometimes in the colon, appearing as submucosal nodules to the endoscopist. Histologic examination shows that the nodules consist of B cells bearing surface IgM surrounded by T cells, most of which are CD8+ (van den Brande et al., 1988) suggesting they are attempts to form productive B cell follicles that are not properly down-regulated by T cells. ' While not the source of symptoms themselves, they may be associated with an increased risk of intestinal lymphoma (Castellano et al., 1992; Ryan, 1996).
The gut inflammation and histologic changes accompanying CVID are not related to the presence of intestinal infections, although bacterial overgrowth and infection with pathogenic bacteria and parasites should be evaluated and treated as a cause of gastrointestinal symptoms. The enteropathy does not respond to antibiotic or IVIG therapy. Instead it has been suggested that the gut lesions could reflect an autoimmune enteritis (Teahon et al., 1994; Washington et al., 1996). Although autoimmune enteritis occurs in young children and generally not adults, only one case report documents the characteristic anti-enterocyte antibodies (Catassi et al., 1988) in a boy with CVID, and another report notes that 58-67% of patients with CVID and gastrointestinal symptoms also have other possible autoimmune diseases (autoimmune hemolytic anemia, thrombocytopenia with antiplatelet antibodies, neutropenia, arthritis, thyroid dysfunction, pernicious anemia, vitiligo, episcleritis, and insulin-dependent diabetes mellitus) (Washington et al., 1996). A plausible immunologic mechanism for the enteropathy is the presence of a T cell dysfunction leading to autoimmune attack within the intestinal wall. Such a role for T cell dysfunction in CVID is consistent with the observation that the enteropathy does not occur in X-linked agammaglobulinemia, an immunodeficiency state with impaired B cell function equal or greater than CVID but with no accompanying T cell abnormality (Lederman and Winkelstein, 1985). Furthermore, CVID patients with related enteropathy are more likely to have T cell dysfunction than those without (Cunningham-Rundles and Bodian, 1999). Even the morphologic changes suggest a primary role for T cells in the enteropathy, with T cells predominating in the lamina propria infiltrate and the epithelial apoptosis so reminiscent of graft-versus-host disease that is mainly T cell-mediated.
There is at present no standard treatment that ameliorates the gastrointestinal disease in CVID patients. Current therapy for CVID is chronic replacement of immunoglobulins, and this has been a successful strategy for controlling the recurrent sino-pulmonary infections. However, this treatment does not generally affect other conditions that can complicate CVID including autoimmune diseases (cytopenias, hypothyroidism) (Cunningham-Rundles and Bodian, 1999), nodular lymphoid hyperplasia of the intestinal mucosa, lymphoma, and an enteropathy presenting as chronic diarrhea and malabsorption.
Therapeutic interventions for weight loss are aimed at hyperalimentation, including total parenteral nutrition when indicated, and identifying any treatable causes of malabsorption such as small bowel bacterial overgrowth. The approach to chronic diarrhea is little different than in other immunodeficient patients, with an emphasis on ruling out treatable infectious etiologies. Often nonspecific antidiarrheal agents are all that can be offered. SUMMARY
The present invention addresses this need for treatment of CVID.
In one aspect, the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I):
Figure imgf000008_0001
(I) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, wherein:
R1 is optionally substituted aryl, optionally substituted heteroaryl, or a group represented by the following formula:
Figure imgf000008_0002
R.2 and R4, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -ORk, -SRk, -NR11R1, hydroxylalkyl, -C(O)RC, -OC(O)RC, -SC(O)R0, -NRkC(O)R°, -C(S)RC, -OC(S)RC, -SC(S)RC, -NRkC(S)Rc, -C(NR)RC, -OC(NR)R0, -SC(NR)R0, -NRkC(NR)Rc, -SO2RC, -S(O)R0, -NRkSO2Rc, -OS(O)2R0, -OP(O)R0R0, -P(O)R0R0, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R2 and R4 taken together are =O, =S, or =NR;
R3 is Rg; Rs and Re are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R5 and R6 taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
X is O, S, S(O), S(O)2, or NRk;
Y is (CH(Rε))m, C(O), C(NR), O, S, S(O), S(O)2, N(Rk), or absent;
G is a bond, -C(O)NRkNRk-, -NRkNRkC(O>, -NRkN=CRk-, -CRk=NNRk-, -NRkNRk-, -N(OH)-, -NRkO-, -ONRk-, -C(O)-, -C(NR)-, -NRkC(O)-, -C(O)NRk-, -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NRk-, -NRkC(S)0-, -OC(S)NRk-, -NRk-C(NR)-NRk-, -NRk-C(O)-NRk-, -NRk-C(S)-NRk-, -NRk-S(O)2-NRk-, -P(O)(R0)-, -P(O)(RC)O-, -OP(O)(R0)-, -OP(O)(RC)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NRk-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(QRk)2-, -B(ORk)-, -C(NR)-NRk-, -NRk-CRgR8-C(O)-, -C(O)-ONRk-, -C(O)-NRkO-, -C(S)-ONR1S -C(S)-NRkO-, -C(NR)-ONRk-, -C(NR)-NRkO-, -OS(O)2-NRkNRk-, -OC(O)-NRkNRk-, -OC(S)-NRkNRk-, -OC(NR)-NRkNRk-, -NRkNRkS(O)2O-, -NRkNRkC(S)O-, -NRkNRkC(NR)O-, -OP(O)(RC)O-, -NRkP(O)(Rc)O-, -OP(O)(Rc)NRk-, -NRkP(O)(Rc)NRk-, -P(O)(Rc)NRk-, -NRkP(O)(Rc)-,
-O-alkylene-heterocycloalkylene-NR1"-,. -NRk-CHR8-C(O)-NRk-CHRε-C(O)-, -NRk-CHR8-C(O)-, -NRk-C(O)-CHRg-, or -C(O)-NRk-CHRg-C(O)-; and each of Q, U, and V are independently N or CRε, wherein at least one of Q, U, or V is N; and each CR8 may be the same or different;
R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R0, -ORk, -SRk, -NRhRj, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)2R0; each of Ra and Rb, independently, is H, optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
R°, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;
Rs, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj 5 hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R0, -OC(O)R0, -SC(O)R0, -NRkC(O)R°, -C(S)R0, -OC(S)RC, -SC(S)Rc,-NRkC(S)Rc, -C(NR)R0, -OC(NR)R0, -SC(NR)R0, -NRkC(NR)R°, -SO2R0, -S(O)R0, -NRkSO2R°, -OS(O)2R0, -OP(O)R0R0, -P(O)R0R0, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;
Rh and RJ, for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or Rh and Rj taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl; R 5 for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; n is 0, 1, 2, 3, 4, 5, 6 or 7; and m is O, 1, 2, 3, or 4.
In another aspect, the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (II):
Figure imgf000011_0001
(H) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrug or polymorph thereof, wherein G, Q, U, V, Y, R2, R3, R4, R5, R<s, and n are defined as for formula (I);
R7 is an optionally substituted aryl or an optionally substituted heteroaryl;
X3 is -C(Rg)=N-A-;
A is O, S, S(O), S(O)2, C(CR8)2, or NRk;
Rs and Rk are defined as for formula (T).
In another aspect, the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (III):
Figure imgf000012_0001
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrugs thereof, wherein:
U and V are each, independently, N or CRg;
Ring D is a 5 to 9-membered aryl, 3 to 9-membered cycloalkyl, 3 to 9- membered cyclyl, 5 to 9-membered heteroaryl, 3 to 9-membered heterocycloalkyl, or a 3 to 9-membered heterocyclyl, each of which may be further substituted with one or more substituents; one of Ai and A2 is - X4-R'-L'-R" and the other is a group represented by the following formula:
Figure imgf000012_0002
Z is N or CH;
W is O, S, S(O)5 S(O)2, NRm, or NC(O)R"1, wherein Rm, for each occurrence, is independently — H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylcarbonyl; u is 0, 1, 2, 3, or 4;
X4 is O, S, S(O), S(O)2, N(Rk), C(O), C(S), C(S)NRk, C(NR), C(NR)NRk, C(O)NRk, C(O)NRkNRk, C(0)ONRk, C(O)NRkO, C(O)O5 OC(O), OC(O)O5 (C(Rg)(R8))q, (C(R8)(Rg))qNRk, (C(Rg)(R8))qO5 (C(Rg)(R8))qS(O)P5 (C(Rs)(Rs))qN=C(Rε), C(R8)=N, C(Rg)=N-O, C(Rg)=N-S(O)p, C(Rg)=N-NRk, C(Rg)=N-C(CRg)2 , (C(Rg)(R8))qC(Rg)=N, (C(R8)(R8))qN=N,
(C(Rg)(Rg))qC(Rg)=C(Rg), C(Rg)=C(Rg)5 N=C(Rg), N(Rk)N=C(R8)5 N(Rk)C(Rg)=N, N(Rk)C(Rg)=C(Rε), N=N, N(Rk)N=N, NRkC(O)NRk, NRkC(S)NRk, NRkC(O), NRkC(O)O, NRkC(NR)NRk, NRkC(S)O, NRkS(O)pNRk, OC(O)NRk, OC(S)NRk, OC(NR)NRk, OS(O)pNRk, C(NR)O, S(O)pNRk, or S(O)pNRkNRk;
R' is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or absent;
L1 is O, S, S(O), S(O)2, N(Rk), C(O), C(S)7 C(S)NRk, C(NR), C(NR)NR\ C(O)NRk, C(O)NRkNRk, C(O)ONRk, C(O)NRkO, C(O)O, OC(O), OC(O)O, (C(Rε)(Rg))q, (C(Rs)(Rg))qNRk, (C(Rg)(Rε))qO, (C(Rg)(Rg))qS(O)p, (C(Rs)(R8))qN=C(Rg), C(Rg)=N, C(Rε)=N-O, C(RS)=N-S(O)P, C(Rg)=N-NRk, C(Rε)=N-C(CRg)2, (C(Rg)(Rg))qC(Rg)=N, (C(Rg)(Rg))qN=N,
(C(Rg)(Rg))qC(Rε)=C(Rs), C(Rg)=C(Rg), N=C(Rg), N(Rk)N=C(Rg), N(Rk)C(Rg)=N, N(Rk)C(Rg)=C(Rs), N=N, N(Rk)N=N, NRkC(O)NRk, NRkC(S)NRk, NRkC(O), NRkC(O)O5 NRkC(NR)NRk, NRkC(S)O, NRkS(O)pNRk, OC(O)NRk, OC(S)NRk, 0C(NR)NRk, OS(O)pNRk, C(NR)O, S(O)pNRk, S(O)pNRkNRk or absent; and
R" is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(Rk)(CH2)qRg, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)RC, -C(S)RC, -C(NR)RC, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, -S(O)RC, -S(O)2R0, -P(O)R0R0, -P(S)R0R0, or an optionally substituted alkylcarbonylalkyl; q, for each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, or 8; p, for each occurrence, is independently O, 1, or 2; and
R, Rc, Rs, Rh, Rj, and Rk are defined as for formula (I).
In another aspect, the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (X):
Figure imgf000014_0001
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, prodrug thereof, wherein:
Q Y, R-2, R3, Ri, and n are defined as for formula (I);
L', U5 V, W5 X45 Z, R', R", u, and Ring D are defined as for formula (III); and w is 0 or 1.
In another aspect, the invention provides a method of treating CVBD in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (XIV):
Figure imgf000014_0002
(XIV) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:
Q Q, U, V, Y, R2, R35 R4, R5, Re and n are defined as for formula (I): ring A is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl, wherein the cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclycl are optionally fused to an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; and
Ri 6, for each occurrence, is independently, H or a lower alkyl.
In another aspect, the invention relates to a method of treating common variable immunodeficiency (CVID) in a subject, comprising administering to the subject an effective amount of N-(3-methyl-benzylidene)-N'-[6-morpholin-4-yl-2-(2- pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazine, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutically acceptable salt is a mesylate salt. In one embodiment, the subject is human.
In another aspect, this invention features a pharmaceutical composition that includes a pharmaceutically acceptable carrier and at least one compound that is suitable for treatment of CVID (e.g., an inhibitor of IL-12), optionally including a second active agent .
Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
DETAILED DESCRIPTION
In one aspect, the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I):
Figure imgf000015_0001
(I) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, wherein:
Ri is optionally substituted aryl, optionally substituted heteroaryl, or a group represented by the following formula:
Figure imgf000016_0001
R2 and R4, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)RC, -OC(O)R0, -SC(O)RC, -NRkC(O)R°, -C(S)RC, -OC(S)RC, -SC(S)R0, -NRkC(S)R°, -C(NR)R0, -OC(NR)R0, -SC(NR)R0, -NRkC(NR)R°, -SO2R0, -S(O)R0, -NRkSO2R°, -OS(O)2R0, -OP(O)R0R0, -P(O)R0R0, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R2 and R4 taken together are =O, =S, or =NR;
R3 is R8;
R5 and Re are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R5 and R6 taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
X is O, S, S(O), S(O)2, or NRk;
Yis (CH(Rs))m, C(O), C(NR), O, S, S(O), S(O)2, N(Rk), or absent;
G is a bond, -C(O)NRkNRk-, -NRkNRkC(O)-, -NRkN=CRk-, -CRk=NNRk-, -NRkNRk-, -N(OH)-, -NRkO-, -ONRk-, -C(O)-, -C(NR)-, -NRkC(O)-, -C(O)NRk-, -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NRk-, -NRkC(S)O-, -OC(S)NRk-, -NRk-C(NR)-NRk-, -NRk-C(O)-NRk-, -NRk-C(S)-NRk-, -NRk-S(O)2-NRk-, -P(O)(RC)-, -P(O)(R°)O-, -OP(O)(R0)-, -OP(O)(RC)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclyl ene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NRk-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(ORk)2-, -B(ORk)-, -C(NR)-NRk-, -NRk-CRgRg-C(O)-, -C(0)-0NRk-, -C(O)-NRkO-, -C(S)-ONR1S -C(S)-NRkO-, -C(NR)-ONR1S -C(NR)-NR1O-, -OS(O)2-NRkNRk-, -OC(O)-NRkNRk-, -OC(S)-NRkNRk-, -OC(NR)-NR1WS -NRkNRkS(O)2O-, -NRkNRkC(S)O-, -NRkNRkC(NR)O-, -OP(0)(RC)0-, -NRkP(O)(Rc)O-, -OP(O)(Rc)NRk-, -NRkP(O)(Rc)NRk-, -P(O)(Rc)NRk-, -NRkP(O)(R°)-,
-O-alkylene-heterocycloalkylene-NR'S -NRk-CHRg-C(O)-NRk-CHRg-C(O)-5 -NRk-CHRg-C(O)-, -NRk-C(O)-CHRg-, or -C(O)-NRk-CHRg-C(O)-; and each of Q, U, and V are independently N or CR8, wherein at least one of Q, U, or V is N; and each CRg may be the same or different;
R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)RC, -ORk, -SRk, -NRhRj, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)2R0; each of Ra and Rb, independently, is H, optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
Rc, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;
R8, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRJ, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)RC, -OC(O)RC, -SC(O)RC, -NRkC(O)R°, -C(S)RC, -OC(S)RC, -SC(S)Rc,-NRkC(S)Rc, -C(NR)RC, -OC(NR)R0, -SC(NR)R0, -NRkC(NR)Rc, -SO2RC, -S(O)R0, -NRkSO2R°, -OS(O)2R0, -OP(O)R0R0, -P(0)R°Rc, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;
Rh and RJ, for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or Rh and RJ taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
Rk, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; n is 0, 1, 2, 3, 4, 5, 6 or 7; and m is 0, 1, 2, 3, or 4. In one embodiment, the compound is Compound 50 ((N- [3-methylbenzylidene]-N'-[6-morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4- yl]-hydrazine) as described herein.
In certain embodiments: each OfR2 and R4 is H;
R3 is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; G is absent;
Rs and Re, taken together with the nitrogen atom to which they are attached, form a moiety represented by the structure: njxrux,
Figure imgf000019_0001
Rv is H or alkyl; n is O, 1, 2, 3, 4, 5, or 6;
X is NRC>;
Y is covalent bond, CH2, C(O), C=N-RC', C=N-ORC>, C=N-SRC>, O, S, S(O),
S(O2), or NRC>;
Z is N or CH;
Q is N; one of U and V is N, and the other is CRC ; and
W is O, S, S(O)5 S(O2), NR0', or NC(O)RC'; in which each of Ra and Rb, independently, is H, alkyl, aryl, heteroaryl; and Rc is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount , of a compound of formula (II):
Figure imgf000019_0002
(H) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrug or polymorph thereof, wherein G, Q, U, V, Y, R2, R3, R4, R5, R6, and n are defined as for formula (I);
R7 is an optionally substituted aryl or an optionally substituted heteroaryl;
X3 is -C(RS)=N-A-;
A is O, S, S(O), S(O)2, C(CR8)2, orNRk;
Rε and Rk are defined as for formula (T).
In another aspect, the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (TH):
Figure imgf000020_0001
(HI), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrugs thereof, wherein:
U and V are each, independently, N or CRg;
Ring D is a 5 to 9-membered aryl, 3 to 9-membered cycloalkyl, 3 to 9- membered cyclyl, 5 to 9-membered heteroaryl, 3 to 9-membered heterocycloalkyl, or a 3 to 9-membered heterocyclyl, each of which may be further substituted with one or more substituents; one of Ai and A2 is -Xφ-R'-L'-R" and the other is a group represented by the following formula:
Figure imgf000020_0002
Z is N or CH; W is O, S, S(O), S(O)2, NRm, or NC(O)Rm, wherein Rm, for each occurrence, is independently — H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylcarbonyl; u is O, 1, 2, 3, or 4;
X4 is O, S, S(O), S(O)2, N(Rk), C(O), C(S), C(S)NRk, C(NR), C(NR)NRk, C(O)NRk, C(O)NRkNRk, C(O)ONRk, C(O)NRkO, C(O)O, OC(O), OC(O)O, (C(Rg)(Rg))q, (C(Rg)(Rg))qNRk, (C(Rε)(Rg))qO, (C(Rg)(Rs))qS(O)p, (C(R8)(R8))qN=C(R8), C(R8)=N, C(R8)=N-O, C(Rg)=N-S(O)p, C(R8)=N-NRk, C(Rg)=N-C(CRε)2, (C(Rs)(Rε))qC(Rs)=N, (C(Rg)(Rg))qN=N,
(C(Rg)(Rg))qC(Rg)=C(Rg), C(Rg)=C(Rg), N=C(Rg), N(Rk)N=C(Rg), N(Rk)C(Rg)=N, N(Rk)C(R8)=C(R8), N=N, N(Rk)N=N, NRkC(O)NRk, NRkC(S)NRk, NRkC(O), NRkC(0)0, NRkC(NR)NRk, NRkC(S)O, NRkS(O)pNRk, OC(O)NRk, OC(S)NRk, OC(NR)NRk, OS(O)pNRk, C(NR)O, S(O)pNRk, or S(O)pNRkNRk;
R' is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or absent;
L' is O, S, S(O), S(O)2, N(Rk), C(O), C(S)5 C(S)NRk, C(NR), C(NR)NRk, C(O)NRk, C(O)NRkNRk, C(O)ONRk, C(O)NRkO, C(O)O, OC(O), OC(O)O, (C(Rs)(Rg))q, (C(Rg)(Rg))qNRk, (C(Rg)(Rε))qO, (C(Rg)(Rg))qS(O)p,
Figure imgf000021_0001
C(R8)=N-C(CR8)2 , (C(Rg)(Rg))qC(Rg)=N, (C(Rg)(Rg))qN=N,
(C(Rs)(Rs))qC(Rε)=C(R8), C(Rg)=C(Rε), N=C(R6), N(Rk)N=C(Rs), N(Rk)C(Rg)=N, N(Rk)C(Rg)=C(R8), N=N, N(Rk)N=N, NRkC(O)NRk, NRkC(S)NRk, NRkC(O), NRkC(O)O, NRkC(NR)NRk, NRkC(S)O, NRkS(O)pNRk, OC(O)NRk, OC(S)NRk, OC(NR)NRk, OS(O)pNRk, C(NR)O, S(O)pNRk, S(O)pNRkNRk or absent; and
R" is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(Rk)(CH2)qRg, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)RC, -C(S)RC, -C(NR)R0, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, -S(O)R0, -S(O)2R0, -P(O)R0R0, -P(S)R0R0, or an optionally substituted alkylcarbonylalkyl; q, for each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, or 8; p, for each occurrence, is independently 0, 1, or 2; and R, Rc, Rg, Rh, RJ, and Rk are defined as for formula (I).
In another aspect, the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (X):
Figure imgf000022_0001
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, prodrug thereof, wherein:
G, Y, R2, R3, R4, and n are defined as for formula (I);
V, U, V, W, X4, Z5 R', R", u, and Ring D are defined as for formula (III); and w is 0 or 1.
hi another aspect, the invention provides a method of treating CVID in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (XTV):
Figure imgf000023_0001
(XIV) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:
G, Q, U, V, Y, R-2, R3, R4, R5, R5 and n are defined as for formula (T): ring A is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl, wherein the cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclycl are optionally fused to an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; and
Rt6, for each occurrence, is independently, H or a lower alkyl.
In some embodiments, in the compounds represented by formula (T), (II), or (XIV), Q3 U, and V are N.
In some embodiments, in the compounds represented by formula (I), (II), or (XIV), one of Q, U, or V is CRε, and the other two are N.
In some embodiments, in the compounds represented by formula (I), (II), or (XIV), V is CRg, Q and U are N.
In some embodiments, in the compounds represented by formula (I), (H), or (XIV), Q is CRg, V and U are N.
In some embodiments, in the compounds represented by formula (T), (II), or (XIV), U is CRg, V and Q are N. hi some embodiments, in the compounds represented by formula (I), (II), or (XIV), one ofQ, U, or V is N, and the other two are CRS.
In some embodiments, in the compounds represented by formula (I), (II), or (XrV), V is N, and Q and U are CRS. In some embodiments, in the compounds represented by formula (T), (II), or (XIV), Q is N, and V and U are CRg.
In some embodiments, in the compounds represented by formula (I), (II), or (XW), U is N and Q, and V are CRS.
In preferred embodiments, in the compounds represented by formula (I), (II), or (XIV), -NRsRe is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1-oxo-thiomorpholino, an optionally substituted 1,1-dioxo-thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.
In some embodiments, in the compounds represented by formula (I), X is -NRk-. In a preferred embodiment, the Rk of group X is — H or a lower alkyl.
In some embodiments, R1 in the compounds represented by formula (I) or R7 in the compounds represented by formula (II), is an optionally substituted aryl or an optionally substituted heteroaryl.
In some embodiments, R1 in the compounds represented by formula (I) or R7 in the compounds represented by formula (II), is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazoiyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4-tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyriπiidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
In some embodiments, R1 in the compounds represented by formula (I) or R7 in the compounds represented by formula (II), is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro-carbazolyl.
In some embodiments, R1 in the compounds represented by formula (I) or R7 in the compounds represented by formula (H) is a group represented by the following formula:
Figure imgf000025_0001
wherein: the dashed line indicates a double or a single bond;
X2 is -O-, -S(O)p-, -N(Rk)-, or -C(Rg)(Rg)-;
R8 and R9 are each, independently, Rg, -C(O)RC, -C(S)RC, -C(NR)R0, -NRkC(O)R°, -OC(O)RC, -SC(O)RC, -NRkC(S)Rc, -OC(S)RC, -SC(S)RC, -NRkC(NR)Rc, -OC(NR)R0, or -SC(NR)R0; or R8 and R9, taken together with the carbons to which they are attached, form a 5- to 7-membered optionally substituted cycloalkyl, a 5- to 7-membered optionally substituted cyclyl, a 5- to 7-membered optionally substituted aryl, a 5- to 7-membered optionally substituted heterocycloalkyl, a 5- to 7-membered optionally substituted heterocyclyl, a 5- to 7-membered optionally substituted heteroaryl;
R10, for each occurrence, is, independently, Rs, -C(O)R0, -C(S)R0, -C(NR)R0, -NRkC(O)R°, -OC(O)RC, -SC(O)R0, -NRkC(S)Rc, -OC(S)R0, -SC(S)R0, -NRkC(NR)R°, -OC(NR)R0, or -SC(NR)R0; p is 0, 1, or 2; and t is O, 1, 2, or, 3. In some embodiments, Ri in the compounds represented by formula (T) or R7 in the compounds represented by formula (II) is (2,3-dimethyl-lH-indol-5-yl), (IH- indol-5-yl), or (6,7,8,9-tetrahydro-5H-carbazol-3-yl).
In some embodiments, in the compounds represented by formula (II), R7 is a group represented by the following formula:
Figure imgf000026_0001
wherein:
Rn and R12, for each occurrence, are, independently, Rε, -C(O)R0, -C(S)R0, -C(NR)RC, -NRkC(O)Rc, -OC(O)RC, -SC(O)R0, -NRkC(S)Rc, -OC(S)RC, -SC(S)R0, -NR15C(NR)R0, -OC(NR)R0, or -SC(NR)R0; and s is 0, 1, 2, 3, or 4.
1 In some embodiments, in the compounds represented by formula (T), Ri is a group represented by the following formula:
Figure imgf000026_0002
(XVUT)
In some embodiments, when R1 of formula (T) is group (XVIII), one of Ra or Rb is — Η or a lower alkyl, and the other is an optionally substituted aryl or an optionally substituted heteroaryl.
In some embodiments, when R1 of formula (T) is group (XVIII), one of Ra or Rb is — Η or a lower alkyl, and the other is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluσrenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyL, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4-tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyτrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
In some embodiments, when Ri of formula (I) is group (XVIII), one of Ra or Rb is — H or a lower alkyl, and the other is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro-carbazolyl.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), Y is O.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), Y is a covalent bond.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), R3 is H.
In some embodiments, in the compounds represented by formula (T), (II), (X) or (XIV), R3 is an optionally substituted aryl or an optionally substituted heteroaryl.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV)j R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-ρyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted tbiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)tbienyl.
In some embodiments, in the compounds represented by formula (I), (II), (III), (X) or (XIV), R3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2- oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl. In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), R3 is a hydroxy, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), R.3 is a hydroxy, an optionally substituted pyridinyl, an optionally substituted morpholino, or an optionally substituted oxazolidin-2-one.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), R3 is -ORk or-NRhRj, and Rf, Rh and Rj are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or-C(O)Rc.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), R3 is -C(O)ORk, -OC(O)Rk, -C(O)NRhRj, -NRkC(O)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(0)NRhRj, -NRkC(S)NRhRj, -C(O)NRhRj, -S(O)2Rk, -S(O)2NRhRj, -OC(O)NRhRj, or-NRkC(O)ORk.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), each of R2 and R4 is, independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), n is 1, 2, or 3, and R2 and R4, for each occurrence are, independently, H or a lower alkyl.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), G is absent.
In some embodiments, in the compounds represented by formula (T), (II), (X) or (XIV), G is an optionally substituted heteroaryl or an optionally substituted heterocyclyl.
In some embodiments, in the compounds represented by formula (I), (H), (X) or (XIV), G is -C(O)NHNH-, -NHNHC(O)-, -CH=N-NH-, -NH-N=CH-,-NHNH-,- NHO-, -O-NH-, -NRk-O-, -CH=N-O-, -O-N=CH-, -0-C(S)-NH-, or -NH-C(S)-O-.
In some embodiments, in the compounds represented by formula (I), (IT), (X) or (XIV), G is -0-C(O)-NH-, -NH-C(NH)-NH-, -NRk-C(NH)-NH-, -NRk-C(NRk)- NH-, -NH-C(N(CN))-NH-, -NH-C(NS O2RC)-NH-, -NRk-C(NSO2Rc)-NH-, -NH- C(NNOz)-NH-, NH-C(NC(O)RC)-NH-, -NH-C(O)-NH-, Or -NH-C(S)-NH-.
In some embodiments, in the compounds represented by formula (T), (II), (X) or (XIV), G is -NH-S(O)2-NH-, -NRk-S (O)2-O-, -P(O)(RC)-, -P(O)(RC)-O-, or - P(O)(Rc)-NRk-.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), G is an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), G is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted cycloheptyl, an optionally substituted aziridinyl, an optionally substituted oxiranyl, an optionally substituted azetidiπyl, an optionally substituted oxetanyl, an optionally substituted morpholinyl, an optionally substituted piperazinyl or an optionally substituted piperidinyl.
In some embodiments, in the compounds represented by formula (T), (II), (X) or (XrV), G is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, -C(N-CN)-NH-, -Si(OH)2-, -C(NH)-NRk-, or - NRk-CH2-C(O)-.
In some embodiments, in the compounds represented by formula (I), (II), (X) or (XIV), G is an optionally substituted imidazolyl, an optionally substituted imidazolidinone, an optionally substituted imidazolidineamine, an optionally substituted pyrrolidinyl, an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted thienyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazolyl, an optionally substituted tetrazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted indolyl, or an optionally substituted benzothiazolyl.
In some embodiments, in the compounds represented by formula (T), (II), (X) or (XIV), Y is O or CH2; G is absent; and n is 0, 1, 2, 3 or 4.
In some embodiments, in the compounds represented by formula (T), (JT), (X) or (XIV), Y is absent, O, S, NRk, or CH2; and n is 0, 1, 2, 3, or 4. In some embodiments, in the compounds represented by formula (III), the compound is represented by formula (V):
Figure imgf000031_0001
(V) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:
G, Y, R2, R.3, R4, and n are defined as for formula I; and Ring D, Ai, A2, U, and V are defined as for formula (111).
In some embodiments, in the compounds represented by formula (HT) or (V), the compound is represented by one of the following structural formulas:
Figure imgf000031_0002
(VI)
Figure imgf000031_0003
(vπ)
Figure imgf000032_0001
(VIE)
Figure imgf000032_0002
(IX) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:
G, Y, R2, R.3, R4, Rg, and n are defined as for formula I;
U, V, L, X4, W, Z, R', R", and u are defined as for formula (III);
X5, Xδ and X7 are each, independently, N or CRε;
X8 is CRsRe, O, S(O)p, or NRk, wherein Rk is defined as for formula (I).
In some embodiments, in the compounds represented by formula (VI) or formula (VII), U and V are N; and X5, X6 and X7 are CRg.
In some embodiments, in the compounds represented by formula (III), (V), (VI), (VII)3 (VIII), or (IX), R' and V are absent. In some embodiments, in the compounds represented by formula (III), (V), (VI)5 (VII), (VIII), or (IX), R" is an optionally substituted cycloalkyi, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
In some embodiments, in the compounds represented by formula (III), (V), (VI), (VII), (Viπ), or (IX), R" is an optionally substituted aryl or an optionally substituted heteroaryl.
In some embodiments, in the compounds represented by formula (III), (V), (VI), (VII), (VIII), or (IX), R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH2, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)PR°, and- C(O)RC.
In some embodiments, in the compounds represented by formula (III), (V), (VI), (VII), (Vπi), or (IX), Z is N and W is O.
In some embodiments, in the compounds represented by formula (V), (VI), (VII), (Vπi), or (IX), Y is a covalent bond, O, S, N(Rk), or CH2, and n is 0, 1, 2, 3, or 4.
In some embodiments, in the compounds represented by formula (V), (VI), (Vπ), (VIII), or (IX), G is absent.
Li some embodiments, in the compounds represented by formula (V), (VI), (VH), (Vπi), or (IX), G is >C=N-R, -NRkC(O)-, -C(O)NRk-, -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NRk-, -NRkC(S)O-, -OC(S)NRk-, -NRkC(NR)NRk-5 -NRkC(O)NRk-, -NRkC(S)NRk-, -NRkS(O)2NRk-, -C(NR)NRk-, or -NRkCRgRgC(O)-.
In some embodiments, in the compounds represented by formula (V), (VI), (VII), (Vπi), or (IX), R3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyi, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, ORk, SRk, or NRhRJ.
In some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), R3 is optionally substituted aryl or optionally substituted heteroaryl.
In some embodiments, in the compounds represented by formula (V), (VI), (VII), (VIII), or (IX), R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azuleπyl, an optionally substituted pyridyl. an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
In some embodiments, in the compounds represented by formula (V), (VI), (VII), (Vπi), or (IX)3 R3 is an optionally substituted heterocycloalkyl.
In some embodiments, in the compounds represented by formula (V), (VI), (VII), (Viπ), or (IX), R3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3- dioxolanyl, an optionally substituted [l ,4]dioxanyl, an optionally substituted 2-oxo- imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.
In some embodiments, in the compounds represented by formula (V), (VI), (Vπ), (VIII), or (EK), R3 is -ORk or -NR11R1', and Rf, Rh and Rj are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R0.
In some embodiments, in the compounds represented by formula (V), (VI), (VTI), (VTO), or (IX), R3 is -C(O)ORk, -OC(O)Rk, -C(O)NRhRj, -NRkC(O)Rk, - C(S)ORk, -OC(S)Rk, -NRkC(O)NRhRj, -NRkC(S)NRhRJ, -C(O)NRhRj, -S(O)2Rk, -S(O)2NRhRj, -OC(O)NRhRj, or -NRkC(O)ORk.
In some embodiments, in the compounds represented by formula (IH), the compound is represented by one of the following structural formulas:
Figure imgf000035_0001
(XIX) (XX) (XXI)
Figure imgf000035_0002
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein;
U, V, A1, and A2 are defined as for formula (III);
X9 is CRSRS, O, S(O)P, or NRk; one of Ri3, Ru and R15 is a group represented by the following structural formula:
Figure imgf000036_0001
and the remainder of Rn, R14 and R15 are independently selected from H, Rε, or isothionitro; and
R2, R3, R4, G1 Y, Rg, Rk and n are defined as for formula (I).
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV). U and V are N.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R' and V are absent.
Ih some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV)7 R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R" is an optionally substituted aryl or an optionally substituted heteroaryl.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXπ), (XXiπ), or (XXIV), R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH2, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)PRC, and— C(O)RC.
In some embodiments, in the compounds represented by formula (XIX), (XX)5 (XXI), (XXII), (XXIIT)3 or (XXIV), Z is N and W is O.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXn). (XXIII), or (XXIV), Y is a covalent bond, O, S, N(Rk), or CH2, and n is O, 1, 2, 3, or 4.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), G is absent.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXTV), G is >C=N-R, -NRkC(O)-, -C(O)NR1S -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NRk-, -NRkC(S)O-, -OC(S)NRk-, -NRkC(NR)NRk~, -NRkC(0)NRk-, -NRkC(S)NRk-, -NRkS(O)2NRk-, -C(NR)NRk-, or -NRkCRgRgC(O)-.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXiπ), or (XXIV), R3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, ORk, SRk, orNRhRj.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXπ), (XXIII), or (XXIV), R3 is optionally substituted aryl or optionally substituted heteroaryl.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXiπ), or (XXIV), R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl. an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted ihiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXm), or (XXIV), R3 is an optionally substituted heterocycloalkyl.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXiπ), or (XXrV), R3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-ρiperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3- dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo- imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXIII), or (XXIV), R3 is -ORk or -NRhRj, and Rf, Rh and Rj are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)RC.
In some embodiments, in the compounds represented by formula (XIX), (XX), (XXI), (XXII), (XXπi), or (XXIV), R3 is -C(O)ORk, -OC(O)Rk, -C(O)NRhRj, -NRkC(O)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(O)NRhRj, -NRkC(S)NRhRj, -C(O)NRhRj, -S(O)2R", -S(O)2NRhRj, -OC(O)NRhRj, or -NRkC(O)ORk.
In some embodiments, in the compounds represented by formula (X), the compound is represented by one of the following structural formulas:
Figure imgf000039_0001
(XI)
Figure imgf000039_0002
(XII)
Figure imgf000039_0003
pan) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:
G, Y, R2, R-3, R4, Rs and n are defined as for formula (I);
R', R", L', X4, U, V, W, Z, and u are defined as for formula (III); w is defined as for formula (X);
X5, Xe and X7 are each, independently, N or CR8; and
X8, X10, and Xn are each, independently, CRgRg, O, S(O)p, or NRk, wherein Rk is defined as for formula (I).
In some embodiments, in the compounds represented by formula (XI), U and
V are N; and X5 and X6 are CRg.
In some embodiments, in the compounds represented by formula (XI), U and
V are N; X5 and X6 are CRg; and X7 is N.
In some embodiments, in the compounds represented by formula (XI), U and
V are N; X5 and X6 are CR8; and X7 is CRε.
In some embodiments, in the compounds represented by formula (Xl), (XII), or (XIII), w is 0, and R' and L' are absent.
In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R" is an optionally substituted aryl or an optionally substituted heteroaryl.
In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH2, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)pRc, and — C(O)RC.
In some embodiments, in the compounds represented by formula (XI), (XII), or (Xπi), Z is N and W is O.
In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), Y is a covalent bond, O, S, N(Rk), or CH2, and n is 0, 1, 2, 3, or 4.
In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), G is absent. In some embodiments, in the compounds represented by formula (XI), (XII), or (Xπi), G is >C=N-R, -NRkC(O)-, -C(O)NRk-, -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NR1S -NRkC(S)O-, -OC(S)NR1X -NRkC(NR)NRk-, -NRkC(O)NRk-, -NRkC(S)NRk-, -NRkS(O)2NRk-, -C(NR)NRk-, or -NRkCRεRsC(O)-.
In some embodiments, in the compounds represented by formula (XI), (XII), or (XHI), R3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, ORk, SRk, orNRhRj.
In some embodiments, in the compounds represented by formula (XI), (XII), or (XIIT), R3 is optionally substituted aryl or optionally substituted heteroaryl. hi some embodiments, in the compounds represented by formula (XI), (XII), or (Xiπ), R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1 -oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadia2olyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
In some embodiments, in the compounds represented by formula (XI), (XII), or (Xπi), R3 is an optionally substituted heterocycloalkyl.
In some embodiments, in the compounds represented by formula (XI), (XH), or (XIII), R3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2-oxopiperazinyl, an optionally substituted 2- oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidiπyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.
In some embodiments, in the compounds represented by formula (XI), (XII), or (Xiπ), R3 is -ORk or -NRhRj, and Rf, Rh and Rj are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R0.
In some embodiments, in the compounds represented by formula (XI), (XII), or (Xni), R3 is -C(O)ORk, -OC(0)Rk, -C(O)NRhRj, -NRkC(0)Rk, -C(S)OR1", -OC(S)Rk, -NRkC(O)NRhRj, -NRkC(S)NRhRj, -C(O)NRhRj, -S(O)2Rk, -S(O)2NRhRj, -OC(O)NRhRj, or-NRkC(O)ORk.
In some embodiments, in the compounds represented by formula (XI), (XII), or (XIII), w is 1; X4 is O, S, or NRj4; and R' and L' are absent.
In some embodiments, in the compounds represented by formula (XIV), the compound is represented by formula (XV):
Figure imgf000043_0001
(XV) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:
Q, U, and V are defined as for formula (I);
R.!6 is defined as for formula (XIV); ring E is optionally substituted with one to four substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl;
X12 is O3 S, S(O), S(O)2, or CR8R8;
X13 is O5 S, S(O), S(O)2, or CH2;
Y1 is O, S, NRk, or CH2;
Ri 7 and Rig, for each occurrence, are independently, H or a lower alkyl; or R17 and R18 taken together with the carbon to which they are attached form a cycloalkyl; and fis O, 1, 2, or 3.
In some embodiments, in the compounds represented by formula (XIV), the compound is represented by formula (XVI):
Figure imgf000044_0001
(XVI) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:
Q, U, and V are defined as for formula (I);
Ri 6 is defined as for formula (XIV);
Yi, Rn5 RiS5 XB, and f are defined as for formula (XV); ring F is optionally substituted with one or two substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl; and
X14 is O, NRk, or CRgRg.
In some embodiments, in the compounds represented by formula (XIV), the compound is represented by formula (XVII):
Figure imgf000045_0001
(xvπ) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:
Q, U, and V are defined as for formula (I);
Ri6 is defined as for formula (XIV);
Y1, Rj7, Ri8, Xi3, and fare defined as for formula (XV); and
X15 is -OH, -NH2 or -SH.
In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVU), Q, U, and V are N.
In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), one of Q, U, or V is CRε, and the other two are N.
In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), V is CRS, Q and U are N.
In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), Q is CRg, V and U are N.
In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), U is CRε, V and Q are N.
In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), one of Q, U, or V is N, and the other two are CRg.
In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), V is N, and Q and U are CRg.
In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVH), Q is N, and V and U are CR8. In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVJI), U is N and Q, and V are CRg.
In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), — NR5R6 is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1 -oxo-thiomorpholino, an optionally substituted 1,1-dioxo-thiomorpholmo, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.
In some embodiments, in the compounds represented by formula (XIV), (XV), (XVI), or (XVn), ring A is a ring system selected from the group consisting of:
Figure imgf000046_0001
wherein:
S represents the point of attachment; rings G, H, I, and J are each, independently, an aryl or a heteroaryl; and each ring system is optionally substituted with one or more substituents.
hi some embodiments, in the compounds represented by formula (XIV), (XV), (XVI), or (XVII), ring A is a ring system selected from the group consisting of:
Figure imgf000046_0002
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
wherein: each ring system is optionally substituted with one or more substituents;
S represents the point of attachment; and R49 is H, an alkyl, an aralkyl, or an alkylcarbonyl.
In some embodiments, in the compounds represented by formula (XIV), (XV), (XVI), or (XVπ), ring A is a ring system selected from the group consisting of:
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
wherein: each ring system is optionally substituted with one or more substituents.
In some embodiments, in the compounds represented by formula (XIV), (XV), (XVI), or (XVII), ring A is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =O, =S, =NR, -ORk, -NRhRj, -SRk, -C(O)Rk, -C(O)NRhRJ, -NRkC(O)Rk, -C(O)ORk, -OC(O)Rk, -NRkC(O)NRhRj, -OC(O)NRhRJ, -NRkC(O)ORk, -C(NR)Rk, -C(NR)NRhR\ -NRkC(NR)Rk, -C(NJR.)OR\ -OC(NR)Rk, -NRkC(NR)NRhRJ, -OC(NR)NRhRJ, -NRkC(NR)ORk, -C(S)Rk, -C(S)NR11RJ. -NRkC(S)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(S)NRhRJ, -OC(S)NRhRJ, -NRkC(S)ORk, -C(O)SRk, -SC(O)Rk, -S(O)pRk, -S(O)pNRhRj, -OS(O)pRk, -S(O)pORk, -OS(O)pORk, -P(O)(ORk)2, -OP(O)(ORk)2, -P(S)(ORk)2, -SP(O)(ORk)2, -P(O)(SRk)(ORk), -OP(O)(SRk)(ORk), -P(O)(SRk)2, or -OP(O)(SRk)2, wherein p is 1 or 2.
In some embodiments, in the compounds represented by formula (XIV), (XV), (XVI), or (XVn), ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, =O, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.
In some embodiments, in the compounds represented by formula (XV), (XVI), Or (XVII)5 Y1 Is O.
In some embodiments, in the compounds represented by formula (XV), (XVI), or (XVII), Y1 is a covalent bond.
In some embodiments, in the compounds represented by formula (XIV), Y is O or CH2,- G is absent; and n is 0, 1, 2, 3 or 4.
In some embodiments, in the compounds represented by formula (XIV), Y is absent, O, S, NRk, or CH2; and n is 0, 1, 2, 3, or 4.
In some embodiments, in the compounds represented by formula (XV), Xi2, Xi3, Yi is O; and Rj7 and R^ are each, independently, H or a lower alkyl.
In some embodiments, in the compounds represented by formula (XVI), Xn, Xi4, and Yi are O; and Rj7 and Ri8 are each, independently, H or a lower alkyl.
In some embodiments, in the compounds represented by formula (XVII), Xn and Yi are O; Xi 5 is -OH; and Rn and Ri8 are each, independently, H or a lower alkyl. In each of the formulae I-XVII disclosed herein, the compound is not a compound disclosed in U.S. Application No. 11/271,704 or U.S. Application No. 11/272,509.
Preferred compounds for use in the method of the invention include the following compounds:
N-(lH-mdol-3-ylmethylene)-N'-[4-moφholin-4-yl-6-(2-pyridin-2-yl-ethoxy)- [l,3,5]triazin-2-yl]-hydrazine;
N-(3-methyl-benzylidene)-N'-[6-morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)- ρyrimidin-4-yI]-hydrazine;
N-(lH-indol-3-ylmethylene)-N'-[4-morpholin-4-yl-6-(2-morpholin-4-yl- ethoxy)-pyridin-2-yl] -hydrazine
N-[3,5-Difluoro-2-morpholin-4-yl-6-(2-morpholm-4-yl-ethoxy)-pyridin-4-yl]- N'-(3-methyl-benzylidene)-hydrazine;
N-(3-methyl-benzylidene)-N'-[4-morpholin-4-yl-6-(2-morpholin-4-yl- ethoxy)-pyridin-2-yl] -hydrazine;
N-methyl-N'-(3-methyl-benzylidene)-N-[4-morpholin-4-yl-6-(2-morpholin-4- yI-ethoxy)-pyridin-2-yl]-hydrazine;
4-methyl-2-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl3- hydrazononomethyl } -phenylamine;
N-(6,7-dimethoxy-2-morpholin-4-yl-quinolin-4-yl)-N'-(3-methyl- benzylidene)-hydrazine;
N-7-Chloro-2-morpholin-4-yl-quninazolin-4-yl)-N'-(3-methyl-benzylidene)- hydrazine;
N-[7-methoxy-2-morpholin-4-yl-6-(2-phenoxy-ethoxy)-quinazolin-4-yl]-N'- (3-methyl-benzylidene)-hydrazine;
N-[6-Morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-ylmethylene]-N'- m-tolyl-hydrazine;
Λr-(3-Chloro-phenyl)- iV-[6-moφholin-4-yl-2-(2-pyridin-2-yl-ethoxy)- pyrimidin-4-yknethylene]- hydrazine;
N-(3-Methoxy-phenyl)- iV-[6-morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)- pyrimidin-4-ylrnethylene]- hydrazine; and
N-(2,5-Dimethyl-phenyl)- -V-[6-morpholin-4-yl-2-(2-pyridin-2-yl-ethoxy)- pyrimidin-4-ylmethylene]- hydrazine. Pharmaceutically acceptable salts, solvates, clathrates and prodrugs of the above compounds of the above compounds are also contemplated for use in the methods of the invention.
In certain embodiments, the compound is a disalt of the form [Compound] 2H+^M", in which [Compound] represents a compound of any of the formulae I — XVII disclosed herein, and each M" is a conjugate base of a Bronsted acid. The term "disalt" refers to an ionic substances of formula A having a cationic, diprotonated IL- 12 production inhibitor compound, (Δ)(2H4), combined with anionic, charge balancing moieties, «(Σ). In general, disalts can be formed by
{[(Δ)(2H+)]2+ • [n(∑)]2 } (A)
contacting IL- 12 production inhibitor compounds of any of Formulae I — XVII ((Δ) in formula A) with Bronsted acids. As used herein, the term "Bronsted acid" includes any chemical species that can be proton (H+) donors. While not wishing to be bound by theory, it is believed that disalt formation occurs when two or more (IT^-acceptor atoms, e.g., nitrogen atoms, of the IL- 12 production inhibitor compounds are protonated by the Bronsted acid. Thus, in some embodiments, the charge balancing moieties («(∑) in formula A) correspond to the conjugate base of the Bronsted acid used to protonate the IL- 12 production inhibitor compounds. In other embodiments, disalt protons ((2H+) in formula A) and charge balancing moieties can be replaced in subsequent exchange reactions. For example, the disalt protons can be exchanged, e.g., for the corresponding isotopic deuterons (2D+) or tritons (2T+), and/or the disalt charge balancing moieties can be exchanged for other negatively charged counterions, e.g., via ion exchange chromatography methods. Disalts prepared via anion and/or cation exchange reactions of disalt starting materials are also within the scope of the present invention.
In one embodiment, the disalt is a disalt of Compound 50 (N-[3- methylbenzylidene]-N'-[6-moφholin-4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]- hydrazine), such as the bis-mesylate salt ((N-[3-methylbenzylidene]-N'-[6-morpholin- 4-yl-2-(2-pyridin-2-yl-ethoxy)-pyrimidin-4-yl]-hydrazine bis-mesylate)). Specific examples of compounds of the invention are set forth below in Table
Table 1
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
3
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
13
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
AU of the features, specific embodiments and particular substituents disclosed herein may be combined in. any combination. Each feature, embodiment or substituent disclosed in this specification may be replaced by an alternative feature, embodiment or substituent serving the same, equivalent, or similar purpose. In the case of chemical compounds, specific values can be combined in any combination resulting in a stable structure. Furthermore, specific values (whether preferred or not) for substituents in one type of chemical structure may be combined with values for other substituents (whether preferred or not) in the same or different type of chemical structure. Thus, unless expressly stated otherwise, each feature, embodiment or substituent disclosed is only an example of a generic series of equivalent or similar features feature, embodiments or substituents.
As used herein, the term "contacting" (i.e., contacting a cell e.g. a cell, with a compound) includes incubating the compound and the cell together in vitro (e.g., adding the compound to cells in culture) as well as administering the compound to a subject such that the compound and cells of the subject are contacted in vivo. The term "contacting" does not include exposure of cells to a compound of the invention (e.g., an IL-12 production inhibitor) that may occur naturally in a subject (i.e., exposure that may occur as a result of a natural physiological process).
In another aspect, this invention features a pharmaceutical composition that includes a pharmaceutically acceptable carrier and at least one compound that is suitable (e.g., safe and effective) for treatment of CVID (e.g., an inhibitor of IL-12 production, a compound of an formula disclosed herein), optionally including a second active compound that is suitable (e.g., safe and effective) for treatment of CVID (e.g., immunoglobulin replacement) or a symptom thereof (e.g., an antibiotic).
The compounds of the invention can be prepared according to a variety of methods, some of which are known in the art, e.g., as disclosed in the patents and patent applications in Table 2, the entire teachings of which are incorporated herein by reference.
Table 2
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Additional compounds useful in the methods and compositions of the invention are disclosed in certain of the patents and patent applications listed in Table 2, supra.
As used herein, the term "alkyl" refers to a straight-chained or branched hydrocarbon group containing 1 to 12 carbon atoms. In certain embodiments, an alkyl can be a lower alkyl; the term "lower alkyl" refers to a C1-CO alkyl chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n- pentyl. Alkyl groups may be optionally substituted with one or more substitueπts.
The term "alkenyl" refers to an unsaturated hydrocarbon chain that may be a straight chain or branched chain, containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Alkenyl groups may be optionally substituted with one or more substituents.
The term "alkynyl" refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing the 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups may be optionally substituted with one or more substituents.
The sp2 or sp carbons of an alkenyl group and an alkynyl group, respectively, may optionally be the point of attachment of the alkenyl or alkynyl groups.
The term "alkoxy," as used herein, refers to an alkyl or a cycloalkyl group which is linked to another moiety though an oxygen atom. Alkoxy groups can be optionally substituted with one or more substituents.
The term "mercapto" refers to a -SH group.
The term "alkyl sulfanyl," as used herein, refers to an alkyl or a cycloalkyl group which is linked to another moiety though a divalent sulfer atom. Alkyl sulfanyl groups can be optionally substituted with one or more substituents.
As used herein, the term "halogen" or "halo" means -F, -Cl, -Br or -I.
As used herein, the term "haloalkyl" means and alkyl group in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from -F, -Cl, -Br, and -L The term "halomethyl" means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichIoroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.
The term "cycloalkyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system which is completely saturated ring. Cycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be substituted by a substituent. Representative examples of cycloalkyl group include cyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and bicyclo[2.1.1]hexyl.
The term "cyclyl" refers to a hydrocarbon 3-8 membered monocyclic or 7-14 membered bicyclic ring system having at least one non-aromatic ring, wherein the non-aromatic ring has some degree of tmsaturation. Cyclyl groups may be optionally substituted with one or more substituents. Ih one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a cyclyl group may be substituted by a substituent. Examples of cyclyl groups include cyclohexenyl, bicyclo[2.2.1]hept-2-enyl, dihydronaphthalenyl, benzocyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl.cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl and the like.
The term "aryl" refers to a hydrocarbon monocyclic, bicyclic or tricyclic aromatic ring system. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.
As used herein, the term "aralkyl" means an aryl group that is attached to another group by a (Ci-Cδ)alkylene group. Aralkyl groups may be optionally substituted, either on the aryl portion of the aralkyl group or on the alkylene portion of the aralkyl group, with one or more substituent. Representative aralkyl groups include benzyl, 2-phenyl-eth.yl, naphth-3-yl-methyl and the like.
As used herein, the term "alkylene" refers to an alkyl group that has two points of attachment. The term "(Ci-Cό)alkylene" refers to an alkylene group that has from one to six carbon atoms. Non-limiting examples of alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), and the like. Alkylene groups may be optionally substituted.
As used herein, the term "cycloalkylene" refers to a cycloalkyl group that has two points of attachment. Cycloalkylene groups may be optionally substituted.
As used herein, the term "cyclylene" refers to a cyclyl group that has two points of attachment. Cyclylene groups may be optionally substituted.
As used herein, the term "arylene" refers to an aryl group that has two points of attachment. Arylene groups may be optionally substituted.
As used herein, the term "aralkylene" refers to an aralkyl group that has two points of attachment. Aralkylene groups may be optionally substituted.
The term "arylalkoxy" refers to an alkoxy substituted with an aryl.
The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon. Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[l,3]dioxolyl, benzo[l,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, and benzo(b)thienyl, 3H- thiazolo[2,3-c] [1 >2,4]thiadiazolyl, imidazo[ 1 ,2-d]- 1,2,4-thiadiazolyl, imidazo[2, 1 -b]- 1,3,4-thiadiazolyl, lH,2H-furo[3,4-d]-l,2,3-thiadiazoryl, lH-pyrazolo[5,l-c]-l,2,4- triazolyl, pyrrolo[3,4-d]-l,2,3-triazolyl, cyclopentatriazolyl, 3H-pyrrolo[3,4- cjisoxazolyl, lH,3H-pyrrolo[l,2-c]oxazolyl, pyrrolo[2,lb]oxazolyl, and the like.
As used herein, the term "heteroaralkyl" or "heteroarylalkyl" means a heteroaryl group that is attached to another group by a (Ct-Cό^lkylene. Heteroaralkyl groups may be optionally substituted, either on the heteroaryl portion of the heteroaralkyl group or on the alkylene portion of the heteroaralkyl group, with one or more substituent. Representative heteroaralkyl groupss include 2-(pyridin-4-yl)- propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl and the like.
As used herein, the term "heteroarylene" refers to a heteroaryl group that has two points of attachment. Heteroarylene groups may be optionally substituted.
As used herein, the term "heteroaralkylene" refers to a heteroaralkyl group that has two points of attachment. Heteroaralkylene groups may be optionally substituted.
The term "heterocycloalkyl" refers to a nonaromatic, completely saturated 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si. Heterocycloalkyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkyl group may be substituted by a substituent. Representative heterocycloalkyl groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4- piperidonyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, an thiirene.
The term "heterocyclyl" refers to a nonaromatic 5-8 membered monocyclic, 7- 12 membered bicyclic, or 10-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S, B, P or Si, wherein the nonaromatic ring system has some degree of unsaturation. Heterocyclyl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocyclyl group may be substituted by a substituent. Examples of these groups include thiirenyl, thiadiazirinyl, dioxazolyl, 1,3-oxathiolyl, 1,3-dioxolyI, 1,3-dithiolyl, oxathiazinyl, dioxazinyl, dithiazinyl, oxadiazinyl, thiadiazinyl, oxazinyl, thiazinyl, l,4-oxathiin,l,4-dioxin, 1,4-dithiin, lH-pyranyl, oxathiepinyl, 5H- 1,4- dioxepinyl, 5H-l,4-dithiepinyl, 6H-isoxazolo[2,3-d]l,2,4-oxadiazolyl, 7H- oxazolo[3,2-d]l,2,4-oxadiazolyl, and the like.
As used herein, the term "heterocycloalkylene" refers to a heterocycloalkyl group that has two points of attachment. Heterocycloalkylene groups may be optionally substituted. As used herein, the term "heterocyclylene" refers to a heterocyclyl group that has two points of attachment. Heterocyclylene groups may be optionally substituted.
When a cycloalkyl, cyclyl, heterocycloalkyl, or heterocyclyl is fused to another ring (e.g., a cycloalkyl, cyclyl, heterocycloalkyl, heterocyclyl, aryl, heteroaryl), it shares two or more ring atoms, preferably two to four ring atoms, with the other ring.
The term "amino" refers to -NH2. The term "alkylamino" refers to an amino in which one hydrogen is replaced by an alkyl group. The term "dialkylamino" refers to an amino in which each of the hydrogens is replaced by an independently selected alkyl group. The term "aminoalkyl" refers to an alkyl substituent which is further substituted with one or more amino groups.
The term "mercaptoalkyl" refers to an alkyl substituent which is further substituted with one or more mercapto groups.
The term "hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl substituent which is further substituted with one or more hydroxy groups.
The term "sulfonylalkyl" refers to an alkyl substituent which is further substituted with one or more sulfonyl groups.
The term "sulfonylaryl" refers to an aryl substituent which is further substituted with one or more sulfonyl groups.
The term alkylcarbonyl refers to an -C(O)-alkyl.
The term "mercaptoalkoxy" refers to an alkoxy substituent which is further substituted with one or more mercapto groups.
The term "alkylcarbonylalkyl" refers to an alkyl substituent which is further substituted with -C(O)-alkyl. The alkyl or aryl portion of alkylamino, aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl, sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionally substituted with one or more substituents.
Suitable substituents for an alkyl, alkoxy, alkyl sulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cyclyl, heterocycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkylene, cyclylene, heterocyclo alkylene, heterocyclylene, arylene, aralkylene, heteroalkylene and heteroaryalkylene groups include any substituent which will form a stable compound of the invention. Examples of substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cyclyl, heterocycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkylene, cyclylene, heterocycloalkylene, heterocyclylene, arylene, aralkyleπe, heteroalkylene and heteroaryalkylene include an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =O, =S, =NR, -ORk, -NRhRj, -SRk, -C(O)Rk, -C(0)NRhRj, -NRkC(O)Rk, -C(O)ORk, -OC(O)Rk, -NRkC(O)NRhRj, -OC(O)NRhRj, -NRkC(O)ORk, -C(NR)Rk, -C(NR)NRhRj, -NRkC(NR)Rk, -C(NR)ORk, -OC(NR)Rk, -NRkC(NR)NRhRj, -OC(NR)NRhRj, -NRkC(NR)ORk, -C(S)Rk, -C(S)NRhRJ, -NRkC(S)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(S)NRhRj, -OC(S)NRhRj, -lSlRkC(S)ORk, -C(O)SRk, -SC(O)Rk, -S(O)pRk, -S(O)pNRhRj, -OS(0)pRk, -S(O)pORk, -OS(O)pORk, -P(O)(ORk)2, -OP(O)(ORk)2, -P(S)(ORk)2, -SP(O)(ORk)2, -P(O)(SRk)(ORk), -OP(O)(SRk)(ORk), -P(O)(SRk)2, or -0P(O)(SRk)2, wherein p is 1 or 2.
In addition, alkyl, cycloalkyl, alkylene, a heterocycloalkyl, a and any saturated portion of a alkenyl, a cyclyl, alkynyl, heterocyclyl, aralkyl, and heteroaralkyl groups, may also be substituted with =O, =S, or =NR.
When a heterocyclyl. heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent the nitrogen may be a quaternary nitrogen.
Choices and combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). Typically, such compounds are stable at a temperature of 400C or less, in the absence of excessive moisture, for at least one week. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.
As used herein, the term "lower" refers to a group having up to six atoms. For example, a "lower alkyl" refers to an alkyl radical having from 1 to 6 carbon atoms, and a "lower alkenyl" or "lower alkynyl" refers to an alkenyl or alkynyl radical having from 2 to 6 carbon atoms, respectively. A "lower alkoxy" or "lower alkyl sulfanyl" group refers to an alkoxy or alkyl sulfanyl group that has from 1 to 6 carbon atoms.
The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
The compounds of this invention include the compounds themselves, as well as their salts, solvate, clathrate, hydrate, polymorph, or prodrugs, if applicable. As used herein, the term "pharmaceutically acceptable salt," is a salt formed from, for example, an acid and a basic group of a compound of any one of the formulae disclosed herein. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,/>-toluenesulfonate, and pamoate {i.e., 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of any one of the formulae disclosed herein having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylarnine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris- (hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N- methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of any one of the formulae disclosed herein having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid. Suitable acids include hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, furαaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and/?-toluenesulfonic acid.
Salts of the compounds disclosed herein can be prepared by several methods, some of which are known in the art. Exemplary methods for making certain salts are disclosed in U.S. Application No. 11/105,818, filed April 13, 2005, and U.S. Provisional Application No. 60/731,038, filed October 27, 2005 and PCT Application No. PCT/US06/42211, filed October 27, 3006, the contents of which are incorporated herein by reference.
As used herein, the term "polymorph" means solid crystalline forms of a compound of the present invention or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it.
As used herein, the term "hydrate" means a compound of the present invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. As used herein, the term "clathrate" means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule {e.g. , a solvent or water) trapped within.
As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydro lyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of any one of the formulae disclosed herein that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of any one of the formulae disclosed herein that comprise -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-
178, 949-982 (Manfred E. Wolff ed., 5th ed).
As used herein and unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide" and "biohydrolyzable phosphate analogue" mean an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylaminσ alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amxnoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines. In addition, some of the compounds of this invention have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms. AU such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also be represented in multiple tautomeric forms, in such instances, the invention expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the invention expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present invention. All crystal forms of the compounds described herein are expressly included in the present invention.
Further, the aforementioned compounds also include their iV-oxides. The term 'W-oxides" refers to one or more nitrogen atoms, when present in a heterocyclic or heteroaryl compound, are in iV-oxide form, i.e., N→O. For example, in compounds of any one of the formula d or Table 1 when one of Q, U, or V is N, also included are compounds in which Q, U, or V, respectively, is N→O.
As used herein, the term "pharmaceutically acceptable solvate," is a solvate formed from the association of one or more solvent molecules to one of the compounds of any of the formulae disclosed herein. The term solvate includes hydrates (e.g., hemi-hydrate, mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).
The method can also include the step of identifying that the subject is in need of treatment for CVID. The identification can be in the judgment of a subject or a health professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or a diagnostic method).
As noted above, one embodiment of the present invention is directed to treating subjects with CVID. "Treating a subject with a CVID" includes achieving, partially or substantially, one or more of the following: ameliorating or improving a clinical symptom or indicator associated with CVID (such as hypogammaglobulinemia, bacterial infection, autoimmune diseases (i.e., autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, and pernicious anemia), and increased risk for lymphoproliferation and/or neoplasia). An "effective amount" is the quantity of compound in which a beneficial clinical outcome is achieved when the compound is administered to a subject with CVID. A "beneficial clinical outcome" includes increase in gamma globulin level, and/or a reduction in the severity of the symptoms associated with CVID and/or an increase in the longevity of the subject compared with the absence of the treatment. The precise amount of compound administered to a subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree and severity of CVDD. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compounds typically range between about 1 mg per day to 100 mgper day, or between 10 mg/day and 500 mg/day, or between 50 to 250 mg/day, or between 50 to 150 mg/day. The disclosed compounds can be administered once daily or in divided doses. When co-administered with another anti-CVID agent, an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for existing agents used for the thereapy of CVID and can be adjusted by the skilled artisan according to the condition of the subject, the severity of CVID and the amount of the compound of the invention being used.
To practice a method of the present invention, a compound of the invention- alone, or as a component of a pharmaceutical composition, can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
A sterile injectable composition, for example, a sterile injectable aqueous or oleaginous suspension, can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
A composition for oral administration can be any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. A nasal aerosol or inhalation composition can be prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. A compound of this invention can also be administered in the form of suppositories for rectal administration.
The carrier in the pharmaceutical composition must be "acceptable" in the sense of being compatible with the active ingredient of the formulation (and preferably, capable of stabilizing it) and not deleterious to the subject to be treated. For example, solubilizing agents such as cyclodextrins, which form specific, more soluble complexes with the compounds of this invention, or one or more solubilizing agents, can be utilized as pharmaceutical excipients for delivery of the compounds of the invention. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
As used herein, the terms "animal", "subject," "mammal" and "patient", include, but are not limited to, a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human (preferably, a human). The methods for treating CVID in a patient in need thereof can further comprise administering, to the patient being administered a compound of this invention, an effective amount of one or more other therapeutic agents. Such therapeutic agents may include other therapeutic agents such as those conventionally used to treat CVED or the symptoms thereof. For example, the compounds of the invention can be co-administered with immunoglobulin (Ig), immunosupresants such as steroids or cyclosporin A5 anti-CD20 monclonal antibody, IL-2, antibiotics (for treatment of infection), inhaled corticosteroids and other asthma medications for treatment of lung disease, anti-neoplastic agents (for prevention and/or treatment of cancers associated with CVID), and the like.
The foregoing and other useful combination therapies will be understood and appreciated by those of skill in the art. Potential advantages of such combination therapies include the ability to use less of each of the individual active ingredients to minimize toxic side effects, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound preparation or formulation.
Without further elaboration, it is believed that the above description has adequately enabled the present invention. The following specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All of the references and publications cited herein are hereby incorporated by reference in their entirety.
EXAMPLES
Example 1
The IL- 12 production inhibitory activity of the compounds disclosed herein can be tested according to methods known in the art, for example, by the representative method described below.
Reagents. Staphylococcus aureus Cowan I (SAC) is obtained from Calbiochem (La Jolla, CA), and lipopolysaccharide (LPS, Serratia marscencens) is obtained from Sigma (St. Louis, MO). Human and mouse recombinant IFNγ are purchased from Boehringer Mannheim (Mannheim, Germany) and Pharmingen (San Diego, CA), respectively. Human In Vitro Assay. Human PBMC are isolated by centrifiigation using Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden) and prepared in RPMI medium supplemented with 10% fetal calf serum (FCS), 100 U/mL penicillin, and 100 μg/mL streptomycin. PBMC are plated in wells of a 96-well plate at a concentration of 5 x 105 cells/well, and primed by adding IFNy (30 U/mL) for 22 h and stimulated by adding LPS (1 μg/mL), or by adding IFNγ (100 U/mL) and then stimulated by adding SAC (0.01%). A test compound is dissolved in DMSO, and added to wells of the 96- well plate. The final DMSO concentration is adjusted to 0.25% in all cultures, including the compound-free control. Human THP-I cells are plated in wells, primed by adding IFNγ (100 U/mL) for 22 h and stimulated by adding SAC (0.025%) in the presence of different concentrations of the test compound. Cell-free supernatants are taken 18 h later for measurement of cytokines. Cell viability is assessed using the bioreduction of MTS. Cell survival is estimated by determining the ratio of the absorbance in compound-treated groups versus compound-free control.
The supernatant is assayed for the amount of EL-12p40, IL-12p70, or IL-10 by using a sandwich ELISA with anti-human antibodies, i.e., a Human IL-12 p40 ELISA kit from R&D Systems (Berkeley, CA), and a Human IL-12 p70 or IL-10 ELISA kit from Endogen (Cambridge, MA). Assays are based on the manufacturer's instructions.
Example 2
Certain compounds disclosed herein are tested for the ability to inhibit IL-12 production as described in Example 1, and some of the results are shown below.
Figure imgf000167_0001
Figure imgf000168_0001
The IL-12 production inhibitory activity of certain other compounds useful in the present invention is described, e.g., in certain of the patents and patent applications of Table 2, supra.
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OTHER EMBODIMENTS
From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. For example, compounds structurally analogous to a heterocyclic compound described in the specification also can be made, screened for their ability to inhibit EL-12, and used to practice this invention. Thus, other embodiments are also within the claims.

Claims

WHAT IS CLAIMED IS:
A method of treating common variable immunodeficiency in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I):
Figure imgf000173_0001
(I) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, wherein:
Ri is optionally substituted aryl, optionally substituted heteroaryl, or a group represented by the following formula:
Figure imgf000173_0002
R2 and R4, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)R0, -OC(O)R0, -SC(O)RC, -NRkC(O)Rc, -C(S)RC, -OC(S)R0, -SC(S)RC, -NRkC(S)Rc, -C(NR)RC, -OC(NR)R0, -SC(NR)RC, -NRkC(NR)R°, -SO2R0, -S(O)R0, -NRkSO2Rc, -OS(O)2R0, -OP(O)R0R0, -P(O)R0R0, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl. an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R2 and R4 taken together are =0, =S, or =NR;
R3 is Rg;
R5 and Rβ are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl. an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R3 and Rg taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
X is O, S, S(O), S(O)2, or NRk;
Yis (CH(Rg))m, C(O), C(NR), O, S, S(O), S(O)2, N(Rk), or absent;
G is a bond, -C(O)NRkNRk-, -NRkNRkC(O)-, -NRkN=CRk-, - CRk=NNRk-, -NRkNRk-, -N(OH)-, -NR1O-, -ONRk-, -C(O)-, -C(NR)-, -NRkC(O)-, -C(O)NR1S -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NR1S -NRkC(S)O-, -OC(S)NRk-, -NRk-C(NR)-NRk-, - NR1^-C(O)-NR1S -NR1^C(S)-NR1S -NRk-S(O)2-NRk-, -P(O)(RC)-, -P(O)(RC)O-, -OP(O)(RC)-, -OP(O)(RC)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NRk-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(0Rk)2-, -B(ORk)-, -C(NR)-NR1S -NRk-CRsRs-C(O)-, -C(O)-ONR1S -C(O)-NRkO-, -C(S)-0NRk-, -C(S)-NRkO-, -C(NR)-ONRk-, -C(NR)-NRkO-, -OS(O)2-NRkNRk-, -OC(O)-NRkNRk-, -OC(S)-NRkNRk-, -OC(NR)-NRkNRk-, -NRkNRkS(O)2O-, -NRkNRkC(S)O-, -NRkNRkC(NR)O-, -OP(0)(Rc)O-, -NRkP(O)(Rc)O-, -OP(O)(Rc)NRk-, -NRkP(0)(Rc)NRlS -P(0)(Rc)NRk-, -NRkP(O)(Rc)-,
-O-alkylene-heterocycloalkylene-NR.'S -NRk-CHRg-C(O)-NRk-CHRε-C(O)-, -NRk-CHRs-C(O)-, -NRk-C(O)-CHRs-, or -C(O)-NRk-CHRg-C(0)-; and each of Q5 U, and V are independently N or CRε, wherein at least one of Q5 U, or V is N; and each CRε may be the same or different;
R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)RC, -ORk, -SRk, -NRhRJ, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)2R0; each of Ra and Rb, independently, is H, optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
Rc, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRJ, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;
R8, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R0, -OC(O)RC, -SC(O)R0, -NRkC(O)Rc, -C(S)R0, -OC(S)R0, -SC(S)Rc.-NRkC(S)R°, -C(NR)R0, -OC(NR)R0, -SC(NR)R0, -NRkC(NR)Rc, -SO2RC, -S(O)R0, -NRkSO2R°, -OS(O)2R0, -OP(O)R0R0, -P(O)R0R0, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;
Rh and Rj, for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or Rh and R* taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
Rk, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; n is 0, 1, 2, 3, 4, 5, 6 or 7; and m is 0, 1, 2, 3, or 4.
2. The method of Claim 1 , wherein Q, U, and V are N.
3. The method of Claim 1, wherein one of Q, U, or V is CRg, and the other two are N.
4. The method of Claim 3, wherein V is CRε, Q and U are N.
5. The method of Claim 3, wherein Q is CRg, V and U are N.
6. The method of Claim 3, wherein U is CR8, V and Q are N.
7. The method of Claim 1, wherein one of Q, U, or V is N, and the other two are CRS.
8. The method of Claim 7, wherein V is N, and Q and U are CRε.
9. The method of Claim 7, wherein Q is N, and V and U are CRε.
10. The method of Claim 7, wherein U is N and Q5 and V are CRε.
11. The method of Claim 2, 3, or 7 wherein -NR5R6 is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1-oxo-thiomorpholino, an optionally substituted 1,1-dioxo- thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.
12. The method of Claim 11, wherein X is -NRk-.
13. The method of Claim 12, wherein the Rk of group X is -H or a lower alkyl.
14. The method of Claim 13, wherein Ri is an optionally substituted aryl or an optionally substituted heteroaryl.
15. The method of claim 14, wherein Ri is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4-tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]ρyrirnidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
16. The method of Claim 15, wherein Ri is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro- carbazolyl.
17. The method of Claim 13, wherein Ri is a group represented by the following formula:
Figure imgf000178_0001
18. The method of claim 17, wherein one of Ra or Rb is — H or a lower alkyl, and the other is an optionally substituted aryl or an optionally substituted heteroaryl.
19. The method of claim 18, wherein one of Ra or Rb is — H or a lower alkyl, and the other is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4-tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
20. The method of claim 18, wherein one of Ra or Rb is — H or a lower alkyl, and the other is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro-carbazolyl.
21. The method of Claim 11 , wherein Y is O.
22. The method of Claim 11 , wherein Y is a covalent bond.
23. The method of Claim 11 , wherein R3 is H.
24. The method of Claim 11 , wherein R3 is an optionally substituted aryl or an optionally substituted heteroaryl.
25. The method of Claim 24, wherein R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyi, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl. an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
26. The method of claim 11, wherein R3 is a hydroxy, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
27. The method of Claim 26, wherein R3 is a hydroxy, an optionally substituted pyridinyl, an optionally substituted morpholino, or an optionally substituted oxazolidin-2-one.
28. The method of Claim 11, wherein each of R2 and R4 is, independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl.
29. The method of Claim 28, wherein n is 1 , 2, or 3, and R2 and R4, for each occurrence are, independently, H or a lower alkyl.
30. The method of Claim 11, wherein G is absent.
31. The method of Claim 11 , wherein G is an optionally substituted heteroaryl or an optionally substituted heterocyclyl.
32. The method of Claim 11 , wherein G is -C(O)NHNH-, -NHNHC(O)-, -CH=N- NH-, -NH-N=CH- -NHNH-,-NHO-, -O-NH-, -NRk-O-, -CH=N-O-, -0- N=CH-, -0-C(S)-NH-, or -NH-C(S)-O-.
33. The method of Claim 11 , wherein G is -0-C(O)-NH-, -NH-C(NH)-NH-, -NRk-C(NH)-NH-, -NRk-C(NRk)-NH-, -NH-C(N(CN))-NH-, -NH- C(NSO2RC)-NH-, -NRk-C(NSO2Rc)-NH-, -NH-C(NNOa)-NH-, NH- C(NC(O)RC)-NH-, -NH-C(O)-NH-, or -NH-C(S)-NH-.
34. The method of Claim 11 , wherein G is -NH-S(O)2-NH-, -NRk-S(O)2-0-, -P(O)(RC)-, -P(O)(RC)-O-, or -P(O)(Rc)-NRk-.
35. The method of Claim 11, wherein G is an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.
)
36. The method of Claim 35, wherein G is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted cycloheptyl, an optionally substituted aziridinyl, an optionally substituted oxiranyl, an optionally substituted azetidinyl, an optionally substituted oxetanyl, an optionally substituted morpholinyl, an optionally substituted piperazinyl or an optionally substituted piperidinyl.
37. The method of Claim 11, wherein G is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, - C(N-CN)-NH-, -Si(OH)2-, -C(NH)-NRk-, or -NRk-CH2-C(O)-.
38. The method of Claim 37, wherein G is an optionally substituted imidazolyl, an optionally substituted imidazolidinone, an optionally substituted imidazolidineamine, an optionally substituted pyrrolidinyl, an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted thienyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazolyl, an optionally substituted tetrazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted indolyl, or an optionally substituted benzothiazolyl.
39. The method of Claim 11, wherein:
Y is O or CH2; G is absent; and n is O, 1, 2, 3 or 4.
40. The method of Claim 11, wherein:
Y is absent, O, S, NRk, or CH2; and n is 0, 1, 2, 3, or 4.
41. Amethod of treating common variable immunodeficiency in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (III):
Figure imgf000183_0001
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrug or polymorph thereof, wherein:
X3 is -C(Rg)=N-A-;
A is O, S, S(O), S(O)2, C(CRε)2, orNRk;
R2 and R4, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)RC, -OC(O)RC, -SC(O)RC, -NRkC(O)Rc, -C(S)RC, -OC(S)RC, -SC(S)R0, -NRkC(S)Rc, -C(NR)R0, -OC(NR)RC, -SC(NR)RC, -NRkC(NR)R°, -SO2R0, -S(O)RC, -NRkSO2Rc, -OS(O)2R0, -OP(O)R0R0, -P(O)R0R0, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R2 and R4 taken together are =O, =S, or =NR;
R3 is Rg;
R5 and Rg are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or R5 and Re taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaiyl;
R7 is an optionally substituted aryl or an optionally substituted heteroaryl;
Y is (CH(Rs))m, C(O), C(NR), O, S, S(O), S(O)2, N(Rk), or absent;
G is a bond, -C(O)NRkNRk-, -NRkNRkC(O)-, -NRkN=CRk-, - CR1^=NNR1S -NRkNRk-, -N(OH)-, -NRkO-, -ONR1S -C(O)-, -C(NR)-, -NRkC(O)-, -C(O)NRk-, -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NR1S -NRkC(S)O-, -OC(S)NRk-, -NRk-C(NR)-NRk-, - NRk-C(O)-NRk-, -NRk-C(S)-NRk-, -NRk-S(O)2-NRk-, -P(O)(RC)-, -P(O)(RC)O-, -OP(O)(R>, -OP(O)(RC)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NR -, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(ORk)2-, -B(ORk)-, -C(NR)-NRk-, -NRk-CRgR8-C(O)-, -C(O)-ONRk-, -C(O)-NRkO-, -C(S)-ONRk-, -C(S)-NRkO-, -C(NR)-ONR1S -C(NR)-NRkO-, -OS(O)2-NRkNRk-, -OC(O)-NRkNRk-, -OC(S)-NRkNRk-, -OC(NR)-NRkNRk-, -NRkNRkS(O)2O-, -NRkNRkC(S)O-, -NRkNRkC(NR)O-, -OP(O)(RC)O-, -NRkP(O)(Rc)O-, -OP(O)(Rc)NRk-, -NRkP(O)(Rc)NRk-3 -P(O)(Rc)NRk-, -NRkP(O)(Rc)-,
-O-alkylene-heterocycloalkylene-NRk-, -NRk-CHRg-C(O)-NRk-CHRg-C(O)-, -NRk-CHRs-C(O)-, -NRk-C(O)-CHRε-, or -C(O)-NRk-CHRg-C(O)-; and each of Q, U, and V are independently N orCRg, wherein at least one of Q, U, or V is N; and each CRS may be the same or different;
R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)RC, -ORk, -SRk, -NRhRJ', hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)2RC; R°, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;
Rβ, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)RC, -OC(O)R0, -SC(O)R0, -NRkC(0)Rc, -C(S)RC, -OC(S)RC, -SC(S)Rc,-NRkC(S)Rc, -C(NR)R0, -OC(NR)R0, -SC(NR)R0, -NRkC(NR)Rc, -SO2R0, -S(O)R0, -NRkSO2R°, -OS(O)2R0, -OP(O)R0R0, -P(O)R0R0, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;
Rh and R", for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or Rh and RJ taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
Rk, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an . optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; n is 0, 1, 2, 3, 4, 5, 6 or 7; and m is 0, 1, 2, 3, or 4.
42. The method of Claim 41 , wherein Q, U, and V are N.
43. The method of Claim 41, wherein one of Q, U, or V is CRS, and the other two are N.
44. The method of Claim 43, wherein V is CRS, Q and U are N.
45. The method of Claim 43, wherein Q is CRg, V and U are N.
46. The method of Claim 43, wherein U is CRε, V and Q are N.
47. The method of Claim 41, wherein one of Q5 U, or V is N, and the other two are CRε.
48. The method of Claim 47, wherein V is N, and Q and U are CR8.
49. The method of Claim 47, wherein Q is N, and V and U are CRg.
50. The method of Claim 47, wherein U is N and Q, and V are CRe.
51. The method of Claim 42, 43, or 47 wherein -NRsR6 is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1-oxo-thiomorpholino, an optionally substituted 1,1- dioxo-thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.
52. The method of Claim 51 , wherein X3 is -C(Rs)=N-NRk-, wherein Rs and Rk of X3 are each, independently, -H or a lower alkyl.
53. The method of claim 52, wherein R7 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]ciioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted carbazolyl, an optionally substituted 1,2,3,4-tetrahydro-carbazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl. an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyL
54. The method of claim 53, wherein R7 is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted indanyl, an optionally substituted carbazolyl, or an optionally substituted 1,2,3,4-tetrahydro- carbazolyl.
55. The method of Claim 52, wherein R7 is a group represented by the following formula:
Figure imgf000188_0001
wherein: the dashed line indicates a double or a single bond;
X2 is -O-, -S(O)p-, -N(Rk)-, or -C(RS)(R8)-;
R8 and R9 are each, independently, Rg, -C(O)RC, -C(S)R0, -C(NR)R0, -NRkC(O)Rc, -OC(O)R0, -SC(O)RC, -NRkC(S)Rc, -OC(S)R0, -SC(S)RC, -NRkC(NR)Rc, -OC(NR)R0, or -SC(NR)R0; or R8 and R9, taken together with the carbons to which they are attached, form a 5- to 7-membered optionally substituted cycloalkyl, a 5- to 7-membered optionally substituted cyclyl, a 5- to 7-membered optionally substituted aryl, a 5- to 7-membered optionally substituted heterocycloalkyl, a 5- to 7-membered optionally substituted heterocyclyl, a 5- to 7-membered optionally substituted heteroaryl;
Rio, for each occurrence, is, independently, R8, -C(O)R0, -C(S)RC, -C(NR)RC, -NRkC(O)Rc, -OC(O)R0, -SC(O)RC, -NRkC(S)Rc, -OC(S)RC, -SC(S)R0, -NRkC(NR)R°, -OC(NR)RC, or -SC(NR)R0; p is 0, 1, or 2; and t is 0, 1, 2, or, 3.
56. The method of claim 55, wherein R7 is (2,3-dimethyl-li7-indol-5-yl), (IH- indol-5-yl), or (6,7,8,9-tetrahydro-5H/-carbazol-3-yl).
57. The method of Claim 52, wherein R7 is a group represented by the following formula: W
Figure imgf000189_0001
wherein:
R11 and R12, for each occurrence, are, independently, Rε, -C(O)RC, -C(S)RC, -C(NR)R0, -NRkC(O)Rc, -OC(O)RC, -SC(O)R0, -NRkC(S)R°, -OC(S)RC, -SC(S)R0, -NRkC(NR)Rc, -OC(NR)R0, or -SC(NR)R0; and s is 0, 1, 2, 3, or 4.
58. The method of Claim 52, wherein Y is O.
59. The method of Claim 52, wherein Y is a covalent bond.
60. The method of Claim 52, wherein R3 is H.
61. The method of Claim 52, wherein R3 is an optionally substituted aryl or an optionally substituted heteroaryl.
62. The method of Claim 61, wherein R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l33]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
63. The method of claim 62, wherein R3 is a hydroxy, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
64. The method of Claim 63, wherein R3 is a hydroxy, an optionally substituted pyridinyl, an optionally substituted morpholino, or an optionally substituted oxazolidin-2-one.
65. The method of Claim 52, wherein each of R2 and R4 is, independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl.
66. The method of Claim 65, wherein n is 1, 2, or 3, and R2 and R4, for each occurrence are, independently, H or a lower alkyl.
67. The method of Claim 52, wherein G is absent.
68. The method of Claim 52, wherein G is an optionally substituted heteroaryl or an optionally substituted heterocyclyl.
69. The method of Claim 52, wherein G is -C(O)NHNH-, -NHNHC(O)-, -CH=N- NH-, -NH-N=CH-,-NHNH-,-NHO-, -0-NH-, -NRk-O-, -CH=N-O-, -O- N=CH-, -0-C(S)-NH-, or -NH-C(S)-O-.
70. The method of Claim 52, wherein G is -0-C(O)-NH-, -NH-C(NH)-NH-, -NRk-C(NH)-NH-, -NRk-C(NRk)-NH-, -NH-C(N(CN))-NH-, -NH- C(NS02Rc)-NH-, -NRk-C(NSO2Rc)-NH-, -NH-C(NNO2)-NH-, NH- C(NC(O)RC)-NH-, -NH-C(O)-NH-, Or-NH-C(S)-NH-.
71. The method of Claim 52, wherein G is -NH-S(O)2-NH-, -NRk-S(O)2-O-, -P(O)(R0)-, -P(O)(RC)-O-, or -P(O)(Rc)-NRk-.
72. The method of Claim 52, wherein G is an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.
73. The method of Claim 72, wherein G is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted cycloheptyl, an optionally substituted aziridinyl, an optionally substituted oxiranyl, an optionally substituted azetidinyl, an optionally substituted oxetanyl, an optionally substituted morpholinyl, an optionally substituted piperazinyl or an optionally substituted piperidinyl.
74. The method of Claim 52, wherein G is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, - C(N-CN)-NH-, -Si(OH)2-, -C(NH)-NRk-, or -NRk-CH2-C(O)-.
75. The method of Claim 74, wherein G is an optionally substituted imidazolyl, an optionally substituted imidazolidinone, an optionally substituted imidazolidineamine, an optionally substituted pyrrolidinyl, an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted thienyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazolyl, an optionally substituted tetrazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted indolyl, or an optionally substituted benzothiazolyl.
76. The method of Claim 52, wherein: Y is O or CH2; G is absent; and n is 0, 1 , 2, 3 or 4.
77. The method of Claim 52, wherein: Y Y iiss aabbsseenntt,, OO,, SS,, I NRk, or CH2; and n is O, 1, 2, 3, or 4.
78. A method of treating common variable immunodeficiency in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (III)
Figure imgf000192_0001
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrugs thereof, wherein:
U and V are each, independently, N or CRS;
Ring D is a 5 to 9-membered aryl, 3 to 9-membered cycloalkyl, 3 to 9- membered cyclyl, 5 to 9-membered heteroaryl, 3 to 9-membered heterocycloalkyl, or a 3 to 9-membered heterocyclyl, each of which may be further substituted with one or more substituents; one of Ai and A2 is - X4-R' -L'-R" and the other is a group represented by the following formula:
Figure imgf000193_0001
Z is N or CH;
W is O, S, S(O), S(O)2, NRm, or NC(O)R"1, wherein Rm, for each occurrence, is independently -H7 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylcarbonyl; u is O, 1, 2, 3, or 4;
X4 is O, S, S(O), S(O)2, N(Rk), C(O)5 C(S), C(S)NRk, C(NR), C(NR)NRk, C(O)NRk, C(O)NRkNRk, C(O)ONRk, C(O)NRkO, C(O)O, OC(O), OC(O)O, (C(Rs)(Rg))q, (C(R'0(Rβ))qNRk, (C(Rg)(Rs))qO, (C(R8)(R8))qS(O)p, (C(Rg)(Rg))qN=C(R8), C(Rg)=N, C(R8)=N-O, C(RS)=N-S(O)P, C(Rg)=N-NRk, C(Rg)=N-C(CRg)2 , (C(Rg)(Rg))qC(Rg)=N, (C(Rε)(Rg))qN=N, (C(Rg)(Rg))qC(Rg)=C(Rε), C(Rg)=C(Rg), N=C(R8), N(Rk)N=C(Rg), N(Rk)C(Rg)=N, N(Rk)C(Rs)=C(Rg), N=N, N(Rk)N=N, NRkC(0)NRk, NRkC(S)NRk, NRkC(O), NRkC(O)O, NRkC(NR)NRk, NRkC(S)0, NRkS(O)pNRk,
Figure imgf000193_0002
0C(S)NRk, OC(NR)NRk, OS(O)pNRk, C(NR)O, S(O)pNRk, or S(O)pNRkNRk;
R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)RC, -ORk, -SRk, -NRhRJ, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)2R0;
R1 is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or absent;
L' is O, S, S(O), S(O)2, N(Rk), C(O), C(S), C(S)NRk, C(NR), C(NR)NRk, C(O)NRk, C(0)NRkNRk, C(O)ONRk, C(O)NRkO, C(O)O, OC(O), W
OC(O)O, (C(Rg)(Rε))q, (C(R8XRg))CNR1*, (C(Rg)(RE))qO, (C(Rg)(Rg))qS(O)p, (C(R8)(Rg))qN=C(Rg), C(RS)=N, C(Rg)=N-O, C(Rg)=N-S(O)p, C(Rg)=N-NRk, C(Rs)=N-C(CRe)2 , (C(Rg)(Rs))qC(Rs)=N, (C(Rg)(Rβ))qN=N, (C(Rg)(Rg))qC(Rg)=C(Rg), C(Rg)=C(Rg), N=C(R8), N(R1^N=C(R8), N(Rk)C(Rg)=N, N(Rk)C(Rs)=C(Rg), N=N, N(Rk)N=N, NRkC(O)NRk, NRkC(S)NRk, NRkC(O), NRkC(O)O, NRkC(NR)NRk, NRkC(S)O, NRkS(O)pNRk, OC(O)NRk, OC(S)NRk, OC(NR)NRk, OS(O)pNRk, C(NR)O, S(O)pNRk, S(O)pNRkNRk or absent; and
R" is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(Rk)(CH2)qRg, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)R0, -C(S)RC, -C(NR)R0, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, -S(O)RC, -S(O)2R0, -P(O)R0R0, -P(S)RCRC, or an optionally substituted alkylcarbonylalkyl;
R°, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;
Rg, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)R0, -OC(O)R0, -SC(O)R0, -NRkC(O)Rc, -C(S)RC, -OC(S)R0, -SC(S)Rc,-NRkC(S)R°, -C(NR)R0, -OC(NR)R0, -SC(NR)R0, -NRkC(NR)R°, -SO2R0, -S(O)R0, -NRkSO2Rc, -OS(O)2RC > -OP(O)RCRC, -P(O)RCRC, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;
Rh and RJ, for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocyeloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or Rh and RJ taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocyeloalkyl, or an optionally substituted heteroaryl;
Rk, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocyeloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; q, for each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, or S; and p, for each occurrence, is independently 0, 1, or 2.
The method of Claim 78, wherein the compound is represented by formula (V):
Figure imgf000195_0001
(V) wherein:
Ring D is a 5- or 6-membered cycloalkyl, 5- or 6-membered cyclyl, 5- or 6-membered aryl, 5- or 6-membered heterocyeloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which optionally may be further substituted with one or more substituent; R2 and R4, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)RC, -OC(O)RC, -SC(O)R0, -NRkC(O)Rc, -C(S)R0, -OC(S)R0, -SC(S)R0, -NRkC(S)Rc, -C{NR)RC, -OC(NR)RC, -SC(NR)R0, -NRkC(NR)Rc, -SO2R0, -S(O)R0, -NRkSO2Rc, -OS(O)2R0, -OP(O)R0R0, -P(O)R0R0, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R2 and R4 taken together are =O, =S, or =NR;
R3 is Rε;
Y is (CH(Rs))m> C(O), C(NR), O, S, S(O), S(O)2, N(Rk), or absent;
G is a bond, -C(O)NRkNRk-, -NRkNRkC(O)-, -NRkN=CRk-, - CRk=NNRk-, -NRkNRk-, -N(OH)-, -NRkO-, -ONRk-, -C(O)-, -C(NR)-, -NRkC(O)-, -C(O)NRk-, -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NRk-, -NRkC(S)O-, -OC(S)NRk-, ~NRk-C(NR)-NRk-, - NRk-C(O)-NRk-, -NRk-C(S)-NRk-, -NRk-S(O)2-NRk-, -P(O)(R0)-, -P(O)(R°)O-, -OP(O)(R0)-, -OP(O)(RC)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NRk-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(ORk)2-, -B(ORk)-, -C(NR)-NR1S -NRk-CRgRg-C(O)-, -C(O)-ONRk-, -C(O)-NRkO-, -C(S)-ONRk-, -C(S)-NRkO-, -C(NR)-ONRk-, -C(NR)-NRkO-, -OS(O)2-NRkNRk-, -OC(O)-NRkNRk-, -OC(S)-NRkNRk-, -OC(NR)-NRkNRk-, -NRkNRkS(O)2O-, -NRkNRkC(S)O-, -NRkNRkC(NR)O-, -OP(O)(R°)O-, -NRkP(O)(Rc)O-, -OP(O)CR°)NRk-, -NRkP(O)(Rc)NRk-, -P(O)(R°)NRk-, -NRkP(O)(R°)-,
-O-alkylene-heterocycloalkylene-NR1*-, -NRk-CHRg-C(O)-NRk-CHR8-C(O)-:> -NRk-CHRs-C(O)-, -NR1^C(O)-CHR8-, or -C(O)-NRk-CHRs-C(O)-; and n is 0, 1, 2, 3, 4, 5, 6, or 7; and m is 0, 1, 2, 3, or 4.
The method of Claim 79, wherein the compound is represented by one of the following structural formulas:
Figure imgf000197_0001
(VI)
Figure imgf000197_0002
(vπ)
Figure imgf000197_0003
(VIII)
Figure imgf000198_0001
(IX) wherein:
X5, X6 and X7 are each, independently, N or CRg;
X8 is CRsRg, O, S(O)p, or NRk.
81. The method of Claim 80, wherein the compound is represented by formula (VI) or formula (VII); and wherein:
U and V are N; and X5, X6 and X7 are CRg.
82. The method of Claim 81 , wherein R' and L' are absent.
83. The method of Claim 82, wherein R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
84. The method of Claim 83, wherein R" is an optionally substituted aryl or an optionally substituted heteroaryl.
85. The method of Claim 84, wherein R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH2, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)PRC, and-C(O)Rc.
86. The method of claim 83, wherein Z is N and W is O.
87. The method of claim 83, wherein Y is a covalent bond, O, S, N(Rk), or CH2, and n is 0, I, 2, 3, or 4.
88. The method of Claim 87, wherein G is absent.
89. The method of Claim 87, wherein G is >C=N-R, -NRkC(O)-, -C(O)NR1S -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NR1S -NRkC(S)O-, -OC(S)NR1S -NRkC(NR)NRk-, -NRkC(O)NRk-, -NRkC(S)NRk-, -NRkS(O)2NRk-, -C(NR)NR1S or -NRkCRgReC(O)-.
90. The method of claim 88, wherein R3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, ORk, SRk, or NRhRJ.
91. The method of claim 90, wherein R3 is optionally substituted aryl or optionally substituted heteroaryl.
92. The method of claim 91, wherein R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyi, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadϊazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
93. The method of claim 90, wherein R3 is an optionally substituted heterocycloalkyl.
94. The method of claim 93, wherein R3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2- oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted rnorpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.
95. The method of claim 90, wherein R3 is -ORk or -NRhRJ, and Rf, Rh and RJ are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R0.
96. The method of Claim 88, wherein R3 is -C(O)ORk, -OC(O)Rk, -C(O)NRhRj, -NRkC(O)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(O)NRhRj, -NRkC(S)NRhRj, -C(O)NRIiRj, -S(O)2R\ -S(O)2NRhRj, -OC(O)NRhRj, or -NRkC(O)ORk.
97. The method of claim 78, wherein the compound is represented by one of the followin structural formulas:
Figure imgf000201_0001
wherein;
X9 is CRgRg, O, S(O)P, orNRk; one of R13, R14 and R15 is a group represented by the following structural formula:
Figure imgf000201_0002
and the remainder of Ro, Rw and R15 are independently selected from H, Rs, or isothionitro;
R2 and R4, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)RC, -OC(O)R0, -SC(O)RC, -NRkC(O)Rc, -C(S)RC, -OC(S)R0, -SC(S)RC, -NRkC(S)Rc, -C(NR)R0, -OC(NR)R0, -SC(NR)RC, -NRkC(NR)Rc, -SO2R0, -S(O)R°, -NRkSO2Rc, -OS(O)2R0, -OP(O)R0R0, -P(O)RCRC, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R2 and R4 taken together are =0, =S, or =NR;
R3 is Rs;
Y is (CH(Rg))m, C(O), C(NR)3 O, S, S(O), S(O)2, N(Rk), or absent;
G is a bond, -C(O)NRkNRk-, -NRkNRkC(O)-, -NRkN=CRk-, - CRk=NNRk-, -NRkNRk-, -N(OH)-, -NRkO-3 -ONRk-, -C(O)-, -C(NR)-, -NRkC(O)-, -C(O)NR14-, -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NRk-, -NRkC(S)O-, -OC(S)NRk-, ~NRk-C(NR)-NRk-, - NRk-C(O)-NRk-, -NRk-C(S)-NRk-, -NRk-S(O)2-NRk-, -P(O)(RC)-, -P(O)(RC)O-, -OP(O)(R0)-, -OP(O)(R°)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted hetero arylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NRk-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(ORk)2-, -B(ORk)-, -C(NR)-NRk-, -NRk-CR8Rg-C(O)-, -C(O)-ONRk-, -C(O)-NRkO-, -C(S)-ONRk-, -C(S)-NRkO-, -C(NR)-ONRk-, -C(NR)-NRkO-> -OS(O)2-NRkNRk-, -OC(O)-NRkNRk-, -OC(S)-NRkNRk-, -0C(NR)-NRkNRk-, -NRkNRkS (O)2O-, -NRkNRkC(S)O-, -NRkNRkC(NR)O-, -OP(O)(RC)O-, -NRkP(O)(R°)O-, -OP(O)(Rc)NRk-, -NRkP(O)(Rc)NRk-, -P(O)(R°)NRk-, -NRkP(O)(Rc)-,
-O-alkylene-heterocycloalkylene-NR1'-, -NRk-CHRg-C(O)-NRk-CHRg-C(O)-, -NRk-CHRg-C(O)-, -NRk-C(O)-CHRs-5 or -C(O)-NRk-CHRg-C(O)-; and n is O, 1, 2, 3, 4, 5, 6, or 7.
98. The method of Claim 97, wherein U and V are N.
99. The method of Claim 97, wherein R' and L' are absent.
100. The method of Claim 99, wherein R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
101. The method of Claim 100, wherein R" is an optionally substituted aryl or an optionally substituted heteroaryl.
102. The method of Claim 101, wherein R" is substituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH2, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)PRC, and~C(O)Rc.
103. The method of claim 100, wherein Z is N and W is O.
104. The method of claim 100, wherein Y is a covalent bond, O, S, N(Rk), or CH2, and n is 0, 1, 2, 3, or 4.
105. The method of Claim 104, wherein G is absent.
106. The method of Claim 104, wherein G is >C=N-R, -NRkC(O)-, -C(O)NR1S -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NRk-, -NRkC(S)O-, -OC(S)NR15-, -NRkCCNR)NRk-, -NRkC(O)NRk-, -NRkC(S)NRk-, -NRkS(O)2NRk-, -C(NR)NRk-, or -NRkCRgRsC(O)-.
107. The method of claim 105, wherein R3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloaikyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, ORk, SRk, orNRhRj.
108. The method of claim 107, wherein R3 is optionally substituted aryl or optionally substituted heteroaryl.
109. The method of claim 108, wherein R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluoreπyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxmyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
110. The method of claim 107, wherein R3 is an optionally substituted heterocycloalkyl.
111. The method of claim 110, wherein R3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2- oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomoφholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1 ,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.
112. The method of claim 107, wherein R3 is -ORk or -NRhRj, and Rf, Rh and Rj are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocyclo alkyl, or -C(O)R0.
113. The method of Claim 105, wherein R3 is -C(O)ORk, -OC(O)Rk, -C(O)NRhRj, -NRkC(O)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(O)NRhRj, -NRkC(S)NRhRj, -C(O)NRhRj, -S(O)2Rk, -S(O)2NRhRj, -OC(O)NRhRj, or -NRkC(O)ORk.
114. A method of treating common variable immunodeficiency in a subject in need thereof, comprising administering to the subject an effective amount of a
com ound of formula X :
Figure imgf000206_0001
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, prodrug thereof, wherein:
Ring D is a 5 to 9-membered aryl, 3 to 9-membered cycloalkyl, 3 to 9- membered cyclyl, 5 to 9-membered heteroaryl, 3 to 9-membered heterocycloalkyl, or a 3 to 9-membered heterocyclyl, each of which maybe further substituted with one or more substituents;
U and V are each, independently, N or CRS;
Z is N or CH;
W is O, S, S(O), S(O)2, NRm, or NC(O)Rm, wherein Rm is H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkylcarbonyl; u is O, 1, 2, 3, or 4;
X4 is O, S, S(O), S(O)2, N(Rk), C(O), C(S), C(S)NRk, C(NR), C(NR)NRk, C(O)NRk, C(O)NRkNRk, C(O)ONRk, C(O)NRkO, C(O)O, OC(O), OC(O)O, (C(Rs)(Rs))q, (C(Rg)(Rg))qNRk, (C(Rε)(Rg))qO, (C(Rg)(Rg))qS(O)p> (C(Rg)(Rg))qN=C(Rg), C(Rg)=N, C(R8)=N-O, C(Rg)=N-S(O)p, C(Rg)=N-NRk, C(Rg)=N-C(CRg)2 , (C(Rg)(Rg))qC(Rg)=N, (C(Rg)(Rs))qN=N, (C(Rg)(Rg))qC(Rg)=C(Rg), C(Rg)=C(R8), N=C(Rg), N(Rfc)N=C(Rg), N(Rk)C(Rg)=N, N(Rk)C(Rg)=C(Rg), N=N, N(Rk)N=N, NRkC(O)NRk, NRkC(S)NRk, NRkC(O), NRkC(O)0, NRkC(NR)NRk, NRkC(S)O, NRkS(O)pNRk, OC(O)NRk, OC(S)NRk, OC(NR)NRk, OS(O)pNRk, C(NR)O, S(O)pNRk, or S(O)pNRkNRk; w is 0 or 1 ;
R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)RC, -ORk, -SRk, -NRhRj, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)2RC;
R' is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, or absent;
L' is O, S, S(O), S(O)2, N(Rk), C(O), C(S), C(S)NRk, C(NR), C(NR)NRk,
Figure imgf000207_0001
C(O)NRkNRk, C(O)ONRk, C(O)NRkO, C(O)O, OC(O), OC(O)O, (C(RS)(RS))C1, (C(Rs)(Rg))qNRk, (C(Rs)(Rg))qO, (C(R8)(Rs))qS(O)p, (C(Rs)(Rg))qN=C(RB), C(Re)=N, C(R8)=N-O, C(RS)=N-S(O)P, C(Rg)=N-NRk, C(R8)=N-C(CRS)2 , (C(Rs)(Rs))qC(Rg)=N, (C(Rg)(Rε))qN=N, (C(Rs)(Rg))<)C(R8)=C(Rs), C(R8)=C(RS), N=C(R8), N(Rk)N=C(Rg), N(Rk)C(Rg)=N, N(Rk)C(Rg)=C(Rg), N=N, N(Rk)N=N, NRkC(O)NRk, NRkC(S)NRk, NRkC(O), NRkC(O)O, NRkC(NR)NRk, NRkC(S)O, NRkS(O)pNRk, OC(O)NRk, OC(S)NRk, OC(NR)NRk, OS(O)pNRk, C(NR)O, S(O)pNRk, S(O)pNRkNRk or absent;
R" is H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, N(Rk)(CH2)qR8, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)R0, -C(S)RC, -C(NR)RC, halo, haloalkyl, aminoalkyl, rnercaptoalkyl, cyano, nitro, -S(O)RC, -S(O)2R0, -P(O)RCRC, -P(S)RCRC, or an optionally substituted alkylcarbonylalkyl;
R2 and R4, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)R0, -OC(O)R0, -SC(O)RC, -NRkC(O)Rc, -C(S)RC, -OC(S)R0, -SC(S)R0, -NRkC(S)R°, -C(NR)RC, -OC(NR)R0, -SC(NR)R0, -NRkC(NR)Rc, -SO2RC, -S(O)R0, -NRkSO2Rc, -OS(O)2RC 5 -OP(O)RCRC, -P(O)R0R0, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyaπo, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R2 and R4 taken together are =0, =S, or =NR;
R3 is Rg;
Y is (CH(Rg))m, C(O), C(NR), O, S, S(O), S(O)2, N(Rk), or absent;
G is a bond, -C(O)NRkNRk-, -NRkNRkC(O)-> -NRkN=CRk-, - CRk=NNRk-, -NRkNRk-, -N(OH)-, -NRkO-, -ONRk-, -C(O)-, -C(NR)-, -NRkC(O)-, -C(O)NRk-5 -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NRk-, -NRkC(S)O-, -OC(S)NRk-, -NRk-C(NR)-NRk-, - NRk-C(O)-NRk-, -NRk-C(S)-NRk-, -NRk-S(O)2-NRk-, -P(O)(R0)-, -P(O)(RC)O-, -OP(O)(R0)-, -OP(O)(RC)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NRk-. an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(0Rk)2-> -B(ORk)-, -C(NR)-NR1S -NRk-CRsRs-C(O)-, -C(O)-ONRk-, -C(O)-NRkO-, -C(S)-ONRk-, -C(S)-NRkO-, -C(NR)-ONRk-, -C(NR)-NRkO-, -OS(O)2-NRkNRk-, -OC(O)-NRkNRk-, -OC(S)-NRkNRk-, -OC(NR)-NRkNRk-, -NRkNRkS(O)2O-, -NRkNRkC(S)O-, -NRkNRkC(NR)O-, -OP(O)(RC)O-, -NRkP(0)(R°)O-, -OP(O)(R°)NRk-, -NRkP(O)(Rc)NRk-, -P(O)(R°)NRk-, -NRkP(O)(R°)-,
-O-alkylene-heterocycloalkylene-NRk~, -NRk-CHRg-C(O)-NRk-CHRg-C(O)-, -NRk-CHRg-C(O)-, -NRk-C(O)-CHRg-, or -C(O)-NRk-CHRs-C(0)-;
R°, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;
R8, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, thioalkoxy, -C(O)RC, -OC(O)R0, -SC(O)RC, -NRkC(O)Rc, -C(S)RC, -OC(S)R*, -SC(S)Rc,-NRkC(S)Rc, -C(NR)RC, -OC(NR)RC, -SC(NR)RC, -NRkC(NR)Rc, -SO2RC, -S(O)R0, -NRkSO2Rc 5 -OS(O)2R0, -OP(O)RCRC, -P(0)RcRc, halo, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, or azide;
Rh and Rj, for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or Rh and RJ taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
Rk, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; m, for each occurrence, is independently 1, 2, 3, or 4; n, for each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, or 7; p, for each occurrence, is independently 0, 1, or 2; and q, for each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, or 8.
The method of Claim 114, wherein the compound is represented by one of the following structural formulas:
Figure imgf000210_0001
(XI)
Figure imgf000210_0002
(XII)
Figure imgf000211_0001
(XIII) wherein:
X5, X6 and X7 are each, independently, N or CR8; and Xg, X10, and Xn are each, independently, CRgRg, O, S(O)P, or NRk.
116. The method of Claim 115, wherein the compounds are represented by formula (XI); and wherein:
U and V are N; and X5 and X6 are CRg.
117. The method of Claim 116, wherein X7 is N.
118. The method of Claim 116, wherein X7 is CRε.
119. The method of Claim 116, wherein w is 0, and R' and L' are absent.
120. The method of Claim 119, wherein R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
121. The method of Claim 120, wherein R" is an optionally substituted aryl or an optionally substituted heteroaryl.
122. The method of Claim 121, wherein R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH2, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, -S(O)PRC, and -C(O)R0.
123. The method of claim 120, wherein Z is N and W is O.
124. The method of claim 120, wherein Y is a covalent bond, O, S, N(Rk), or CH2, and n is O, 1, 2, 3, or 4.
125. The method of Claim 124, wherein G is absent.
126. The method of Claim 124, wherein G is >C=N-R, -NRkC(O)-, -C(O)NRk-, -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NR1S -NRkC(S)O~, -OC(S)NR1S -NR1^(NR)NR1S -NRkC(O)NRk-, -NRkC(S)NRk-, -NRkS(O)2NRk-, -C(NR)NR1S or -NRkCRgR8C(O)-.
127. The method of claim 125, wherein R3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, ORk, SRk, orNRhRj.
128. The method of claim 127, wherein R3 is optionally substituted aryl or optionally substituted heteroaryl.
129. The method of claim 128, wherein R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted qumolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrirnidinyl, or an optionally substituted benzo(b)thienyl.
130. The method of claim 127, wherein R3 is an optionally substituted heterocycloalkyl.
131. The method of claim 130, wherein R3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2- oxopiperazinyl, an optionally substituted 2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted tbiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.
132. The method of claim 127, wherein R3 is -ORk or -NRhRj, and Rf, Rh and Rj are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R0.
133. The method of Claim 125, wherein R3 is -C(O)ORk, -OC(O)Rk, -C(O)NRhRj, -NRkC(O)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(O)NRhRj, -NRkC(S)NRhRj, -C(O)NRhRj, -S(O)2Rk, -S(O)2NRhRj, -OC(O)NRhRj, or -NRkC(O)ORk.
134. The method of Claim 116, wherein: w is 1;
X4 is O, S, or NRk; and
R' and L' are absent.
135. The method of Claim 134, wherein R" is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl.
136. The method of Claim 135, wherein R" is an optionally substituted aryl or an optionally substituted heteroaryl.
137. The method of Claim 136, wherein R" is substitituted with one or more substituent selected from the group consisting of a lower alkyl, cyano, halo, nitro, -NH2, a lower alkylamino, a lower dialkylamino, a lower alkoxy, a lower haloalkyl, or-C(O)Ry, wherein Ry is a lower alkyl.
138. The method of claim 135, wherein Z is N and W is O.
139. The method of claim 135, wherein Y is a covalent bond, O, S, N(Rk), or CH2, and n is 0, 1, 2, 3, or 4.
140. The method of Claim 139, wherein G is absent.
141. The method of Claim 139, wherein G is >C=N-R, -NRkC(O)-, -C(0)NRk-, -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NRk-, -NRkC(S)O-, -OC(S)NRk-, -NRkC(NR)NRk-, -NRkC(O)NRk-, -NRkC(S)NRk-, -NRkS(O)2NRk-, -C(NR)NRk-, or -NRkCRgRgC(O)-.
142. The method of claim 140, wherein R3 is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, nitro, cyano, halo, ORk, SRk, orNRhRj.
143. The method of claim 142, wherein R3 is optionally substituted aryl or optionally substituted heteroaryl.
144. The method of claim 143, wherein R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl., an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrirnidinyl, ^n optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
145. The method of claim 142, wherein R3 is an optionally substituted heterocycloalkyl.
146. The method of claim 145, wherein R3 is an optionally substituted piperidinyl, an optionally substituted piperazinyl, an optionally substituted 2- oxopiperazinyl, an optionally substituted 2-oxopiperidinyl. an optionally substituted 2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, an optionally substituted tetrahydropyranyl, an optionally substituted oxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, an optionally substituted tetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, an optionally substituted thiomorpholinyl, an optionally substituted thiomorpholinyl sulfoxide, an optionally substituted thiomorpholinyl sulfone, an optionally substituted 1,3-dioxolanyl, an optionally substituted [l,4]dioxanyl, an optionally substituted 2-oxo-imidazoIidinyl, tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl.
147. The method of claim 142, wherein R3 is -ORk or -NRhRj, and Rf, Rh and Rj are each, independently, H, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl, or -C(O)R0.
148. The method of Claim 140, wherein R3 is -C(O)ORk, -OC(O)Rk, -C(O)NRhRJ, -NRkC(O)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(O)NRhRj, -NRkC(S)NRhRj, -C(O)NRhRj, -S(O)2Rk, -S(O)2NRhRj, -0C(O)NRhRj, or -NRkC(O)ORk. A method of treating common variable immunodeficiency in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (XIV):
Figure imgf000217_0001
(XTV) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein: ring A is an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl, wherein the cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclycl are optionally fused to an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; each of Q, U, and V are independently N orCRg, wherein at least one of Q, U, or V is N; and each CRg may be the same or different;
Yis a covalent bond, (CH(Rs))m, C(O), C(NR), O, S, S(O), S(O)2, NRk, or absent;
G is a bond, -C(0)NRkNRk-, -NRkNRkC(O)-, -NRkN=CRk-, - CRk=NNRk-, -NRkNRk-, -N(OH)-, -NRkO-, -ONRk-, -C(O)-, -C(NR)-, -NRkC(O)-, -C(O)NR1S -OC(O)-, -C(O)O-, -OC(O)O-, -NRkC(O)O-, -OC(O)NR1S -NRkC(S)0-, -OC(S)NR1S -NRk-C(NR)-NRk-, - NRk-C(O)-NRk-, -NRk-C(S)-NRk-, -NRk-S(O)2-NRk-, -P(O)(R>, -P(O)(RC)O-, -OP(O)(R>, -OP(O)(RC)O-, an optionally substituted cycloalkylene, an optionally substituted cyclylene, an optionally substituted heterocycloalkylene, an optionally substituted heterocyclylene, an optionally substituted arylene, an optionally substituted aralkylene, an optionally substituted heteroarylene, an optionally substituted heteroaralkylene, an optionally substituted heteroarylene-NRk-, an optionally substituted heteroarylene-S-, an optionally substituted heteroaralkylene-O-, -Si(ORk)2-, -B(ORk)-, -C(NR)-NRk-, -NRk-CR8Rg-C(O)-, -C(O)-ONRk-, -C(O)-NRkO-, -C(S)-ONRk-, -C(S)-NR1O-, -C(NR)-ONRk-, -C(NR)-NR1O-, -OS(O)2-NRkNRk-, -OC(O)-NRkNRk-, -OC(S)-NRkNRk-, -OC(NR)-NRkNRk-, -NRkNRkS(O)20-5 -NRkNRkC(S)O-, -NRkNRkC(NR)O-, -OP(O)(RC)O-, -NRkP(O)(R°)O-, -OP(O)(Rc)NRk-, -NRkP(O)(Rc)NRk-, -P(O)(Rc)NRk-, -NRkP(O)(Rc)-,
-O-alkylene-heterocycloalkylene-NR1'-, -NRk-CHRs-C(O)-NRk-CHRg-C(O)-, -NRk-CHR8-C(OK -NRk-C(O)-CHR8-, or -C(O)-NRk-CHRg-C(O)-, provided that G is not -NRkN=CRk- or -CRk=NNRfc-, when n is 0 and Y is a covalent bond;
R, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -C(O)R0, -ORk, -SRk, -NRhRj, hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or -S(O)2R0;
R16, for each occurrence, is independently, H or a lower alkyl;
R2 and R4, for each occurrence, are independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, -C(O)R0, -OC(O)RC, -SC(O)RC, -NRkC(O)Rc, .-C(S)RC, -OC(S)R0, -SC(S)R0, -NRkC(S)Rc, -C(NR)R0, -OC(NR)RC, -SC(NR)R0, -NRkC(NR)Rc, -SO2R0, -S(O)R0, -NRkSO2Rc, -OS(O)2R0, -OP(O)R0R0, -P(O)R°RC, halo, haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, an optionally substituted alkylcarbonylalkyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, or isothionitro; or R2 and R4 taken together are -O, =S, or =NR;
R3 is R5; Rs and Re are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or Rs and R^ taken together with the N to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
Rc, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRj, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or mercaptoalkoxy;
Rg, for each occurrence, is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl, haloalkyl, -ORk, -SRk, -NRhRJ, hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, mercaptoalkoxy, -C(O)R0, -OC(O)R0, -SC(O)RC, -NRkC(O)Rc, -C(S)RC, -OC(S)RC, -SC(S)Rc,-NRkC(S)R°, -C(NR)RC, -OC(NR)R0, -SC(NR)R0, -NRkC(NR)Rc, -S(O)2R0, -S(O)R0, -NRkS(O)2R°, -OS(O)2R0, -OP(O)R0R0, -P(O)R0R0, halo, cyano, nitro, nitroso, or azide;
Rh and RJ, for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, an optionally substituted heteroaryl; or Rh and RJ taken together with the nitrogen to which they are attached is an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl;
Rk, for each occurrence, is independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; m is O, 1, 2, 3, or 4; and n is O, 1, 2, 3, 4, 5, 6, or 7.
150. The method of Claim 149, wherein Q, U, and V are N.
151. The method of Claim 149, wherein one of Q, U, or V is CR8, and the other two are N.
152. The method of Claim 151, wherein V is CRε, Q and U are N.
153. The method of Claim 151, wherein Q is CRg, V and U are N.
154. The method of Claim 151, wherein U is CRS, V and Q are N.
155. The method of Claim 149, wherein one of Q, U, or V is N, and the other two are CRS.
156. The method of Claim 145, wherein V is N, and Q and U are CRg.
157. The method of Claim 145, wherein Q is N, and V and U are CRg.
158. The method of Claim 145, wherein U is N and Q, and V are CRE.
159. The method of Claim 150, 151 , or 155 wherein -NR5R6 is an optionally substituted morpholino, an optionally substituted thiomorpholino, an optionally substituted 1-oxo-thiomorpholino, an optionally substituted 1,1- dioxo-thiomorpholino, an optionally substituted piperidinyl, or an optionally substituted piperazinyl.
160. The method of Claim 159, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000221_0001
wherein: it C. »
S represents the point of attachment; rings G, H, I, and J are each, independently, an aryl or a heteroaryl; and each ring system is optionally substituted with one or more substituents.
161. The method of Claim 159, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000221_0002
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
wherein: each ring system is optionally substituted with one or more substituents;
S represents the point of attachment; and Ri9 is H, an alkyl, an aralkyl, or an alkylcarbonyl.
162. The method of Claim 161, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
wherein: each ring system is optionally substituted with one or more substituents.
163. The method of Claim 162, wherein ring A is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =O, =S, =NR, -ORk, -NRhRj, -SRk, -C(O)Rk, -C(O)NRhRj, -NRkC(O)Rk, -C(O)ORk, -0C(O)Rk, -NRkC(0)NRhRj, -OC(O)NRhRj, -NRkC(O)ORk, -C(NR)Rk, -C(NR)NRhRj, -NRkC(NR)Rk, -C(NR)ORk, -OC(NR)Rk, -NRkC(NR)NRhRj, -OC(NR)NRhRj, -NRkC(NR)ORk, -C(S)Rk, -C(S)NRhRj, -NRkC(S)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(S)NRhRj, -OC(S)NRhRj, -MtkC(S)ORk, -C(O)SRk, -SC(O)Rk, -S(O)pRk, -S(O)pNRhRj, -OS(0)pRk, -S(O)pORk, -OS(O)pORk, -P(O)(ORk)2, -OP(O)(ORk)2, -P(S)(ORk)2, -SP(O)(ORk)2, -P(O)(SR^(OR"), -OP(O)(SRk)(ORk), -P(O)(SRk)2, or -OP(O)(SRk)2, wherein p is 1 or 2.
164. The method of Claim 163, wherein ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, =O, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.
165. The method of Claim 159, wherein Y is O.
166. The method of Claim 159, wherein Y is a covalent bond.
167. The method of Claim 159, wherein R3 is H.
168. The method of Claim 159, wherein R3 is an optionally substituted aryl or an optionally substituted heteroaryl.
169. The method of claim 168, wherein R3 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted anthracenyl, an optionally substituted fluorenyl, an optionally substituted indenyl, an optionally substituted azulenyl, an optionally substituted pyridyl, an optionally substituted 1-oxo-pyridyl, an optionally substituted furanyl, an optionally substituted benzo[ 1 ,3]dioxolyl, an optionally substituted benzo[l,4]dioxinyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted quinolinyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted indolizinyl, an optionally substituted imidazopyridyl, an optionally substituted tetrazolyl, an optionally substituted benzimidazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted indazolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl, an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionally substituted benzo(b)thienyl.
170. The method of claim 159, wherein R3 is a hydroxy, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.
171. The method of Claim 170, wherein R3 is a hydroxy, an optionally substituted morpholino, or an optionally substituted oxazolidin-2-one.
172. The method of Claim 159, wherein each of R2 and R4 is, independently, H, an optionally substituted alkyl, an optionally substituted alkylcarbonyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocycloalkyl, or an optionally substituted heterocyclyl.
173. The method of Claim 172, wherein n is 1, 2, or 3, and R2 and R4, for each occurrence are, independently, H or a lower alkyl.
174. The method of Claim 159, wherein G is absent.
175. The method of Claim 159, wherein G is an optionally substituted heteroaryl or an optionally substituted heterocyclyl.
176. The method of Claim 159, wherein G is -C(O)NHNH-, -NEINHC(O)-, - CH=N-NH-, -NH-N=CH- -NHNH-.-NHO-, -O-NH-, -NRk-O-, -CH=N-O-. - 0-N=CH-, -0-C(S)-NH-, Or -NH-C(S)-O-.
177. The method of Claim 159, wherein G is -0-C(O)-NH-, -NH-C(NH)-NH-, -NR^C(NH)-NH-, -NRk-C(NRk)-NH-, -NH-C(N(CN))-NH-, -NH- C(NSO2RC)-NH-, -NRk-C(NSO2R°)-NH-, -NH-C(NNO2)-NH-, NH- C(NC(O)RC)-NH-, -NH-C(O)-NH-, Or -NH-C(S)-NH-.
178. The method of Claim 159, wherein G is -NH-S(O)2-NH-, -NRk-S (O)2-O-, -P(O)(RC)-, -P(O)(RC)-O-, or -P(O)(Rc)-NRk-.
179. The method of Claim 159, wherein G is an optionally substituted cyclyl, an optionally substituted cycloalkyl, an optionally substituted heterocycloalkyl or an optionally substituted heterocyclyl.
180. The method of Claim 179, wherein G is an optionally substituted cyclopropyl, an optionally substituted cyclobutyl, an optionally substituted cyclopentyl, an optionally substituted cyclohexyl, an optionally substituted cycloheptyl, an optionally substituted aziridinyl, an optionally substituted oxiranyl, an optionally substituted azetidinyl, an optionally substituted oxetanyl, an optionally substituted morpholinyl, an optionally substituted piperazinyl or an optionally substituted piperidinyl.
181. The method of Claim 159, wherein G is an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heteroaralkyl, - C(N-CN)-NH-, -Si(OH)2-, -C(NH)-NR1S or -NRk-CH2-C(O)-.
182. The method of Claim 181, wherein G is an optionally substituted imϊdazolyl, an optionally substituted imidazolidinone, an optionally substituted imidazolidineamine, an optionally substituted pyrrolidinyl, an optionally substituted pyrrolyl, an optionally substituted furanyl, an optionally substituted tbienyl, an optionally substituted thiazolyl, an optionally substituted triazolyl, an optionally substituted oxadiazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazolyl, an optionally substituted tetrazolyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidyl, an optionally substituted indolyl, or an optionally substituted benzothiazolyl.
183. The method of Claim 159, wherein:
Y is O or CH2; G is absent; and n is 0, 1, 2, 3 or 4.
184. The method of Claim 159, wherein:
Y is absent, O, S3 NRk, or CH2; and n is O, 1, 2, 3, or 4.
185. The method of Claim 149, wherein the compound is represented by formula (XV):
Figure imgf000231_0001
(XV) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein: ring E is optionally substituted with one to four substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl;
Xi2 is O, S, S(O), S(O)2, or CRgRg;
Xi3 is O, S, S(O), S(O)2, or CH2;
Y1 Is O, S7 NRk, or CH2;
R17 and Rig, for each occurrence, are independently, H or a lower alkyl; or Rn and Ri8 taken together with the carbon to which they are attached form a cycloalkyl; and fis O, 1, 2, or 3.
186. The method of Claim 185, wherein Q, U, and V are N.
187. The method of Claim 185, wherein one of Q, U, or V is CRg, and the other two are N.
188. The method of Claim 187, wherein V is CRε, Q and U are N.
189. The method of Claim 187, wherein Q is CRg, V and U are N.
190. The method of Claim 187, wherein U is CR8, V and Q are N-
191. The method of Claim 185, wherein one of Q, U, or V is N, and the other two are CRg.
192. The method of Claim 191, wherein V is N, and Q and U are CRg.
193. The method of Claim 191, wherein Q is N, and V and U are CRε.
194. The method of Claim 191, wherein U is N and Q, and V are CR8.
195. The method of Claim 186, 187, or 191, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000233_0001
wherein:
S represents the point of attachment; rings G, H, I, and J are each, independently, an aryl or a heteroaryl; and each ring system is optionally substituted with one or more substituents.
196. The method of Claim 186, 187, or 191, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000233_0002
Figure imgf000234_0001
Figure imgf000234_0003
Figure imgf000234_0004
Figure imgf000234_0005
Figure imgf000234_0002
Figure imgf000235_0001
Figure imgf000236_0001
wherein: each ring system is optionally substituted with one or more substituents;
*3 represents the point of attachment; and R19 is H, an alkyl, an aralkyl, or an alkylcarbonyl.
197. The method of Claim 196, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
wherein: each ring system is optionally substituted with one or more substituents.
198. The method of Claim 197, wherein ring A is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =O, =S, =NR, -ORk, -NRhRj, -SR\ -C(O)Rk, -C(O)NRhRj, -NRkC(O)Rk, -C(O)ORk, -OC(O)Rk, -NRkC(0)NRhRj, -OC(O)NRhRJ, -NRkC(O)ORk, -C(NR)Rk, -C(NR)NRhRj, -NRkC(NR)Rk, -C(NR)ORk, -OC(NR)Rk, -NRkC(NR)NRhRj, -OC(NR)NRhRj, -NRkC(NR)ORk, -C(S)Rk, -C(S)NRhRj, -NRkC(S)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(S)NRhRj, -OC(S)NRhRj, -NRkC(S)ORk, -C(O)SRk, -SC(O)Rk, -S(O)pRk, -S(O)pNRhRJ, -OS(0)pRk, -S(O)pORk, -OS(O)pORk, -P(O)(ORk)2, -OP(O)(ORk)2, -P(S)(ORk)2, -SP(O)(ORk)2, -P(O)(SRk)(ORk), -OP(O)(SRk)(ORk), -P(O)(SRk)2j or -OP(O)(SRk)2, wherein p is 1 or 2.
199. The method of Claim 198, wherein ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, =0, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.
200. The method of Claim 198, wherein:
Figure imgf000240_0001
Ri7 and Rig are each, independently, H or a lower alkyl.
201. The method of Claim 149, wherein the compound is represented by formula (XVI):
Figure imgf000240_0002
(XVI) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein: ring F is optionally substituted with one or two substituents selected from a lower alkyl, a halo, an amino, a lower alkyl amino, a lower dialkyl amino, a cyano, a nitro, a lower haloalkyl, a hydroxyl, and a lower hydroxyalkyl;
X13 is O, S, S(O), S(O)2, or CH2;
Xi4 is O, NRk, or CRgRg;
Yi is O, S, NRk, or CH2; Rj7 and R^, for each occurrence, are independently, H or a lower alkyl; or Ri 7 and Rj s taken together with the carbon to which they are attached form a cycloalkyl; and fis O, 1, 2, or 3.
202. The method of Claim 201 , wherein Q, U, and V are N.
203. The method of Claim 201 , wherein one of Q, U, or V is CRg, and the other two are N.
204. The method of Claim 203, wherein V is CRe, Q and U are N.
205. The method of Claim 203, wherein Q is CRS, V and U are N.
206. The method of Claim 203, wherein U is CRg, V and Q are N.
207. The method of Claim 201, wherein one of Q, U, or V is N, and the other two are CRg.
208. The method of Claim 207, wherein V is N, and Q and U are CRg.
209. The method of Claim 207, wherein Q is N, and V and U are CR8.
210. The method of Claim 207, wherein U is N and Q, and V are CRg.
211. The method of Claim 212, 213, or 217, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000241_0001
wherein: S represents the point of attachment; rings G, H, I, and J are each, independently, an aryl or a heteroaryl; and each ring system is optionally substituted with one or more substituents.
212. The method of Claim 202, 203, or 207, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
wherein: each ring system is optionally substituted with one or more substituents;
5 represents the point of attachment; and Ri9 is H, an alkyl, an aralkyl, or an alkylcarbonyl.
213. The method of Claim 212, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000245_0002
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
wherein: each ring system is optionally substituted with one or more substituents.
214. The method of Claim 213, wherein ring A is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocyclo alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =O, =S, =NR, -ORk, -NRhRJ, -SRk, -C(O)Rk, -C(O)NRhRj, -NRkC(O)Rk, -C(O)ORk, -OC(O)Rk, -NRkC(O)NRhRj, -OC(O)NRhRj, -NRkC(O)ORk, -C(NR)Rk, -C(NR)NRhRj, -NRkC(NR)Rk, -C(3SlR)ORk, -OC(NR)Rk, -NRkC(NR)NRhRj, -OC(NR)NRhRj, -NRkC(NR)ORk, -C(S)Rk, -C(S)NRhRj, -NRkC(S)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(S)NRhRj, -OC(S)NRhRj, -NRkC(S)ORk, -C(O)SRk, -SC(O)Rk, -S(O)pRk, -S(O)pNRhRj, -OS(O)pRk, -S(O)pORk, -OS(O)POR\ -P(O)(ORk)2, -OP(O)(ORk)2, -P(S)(ORk)2, -SP(O)(ORk)2, -P(O)(SRk)(ORk), -OP(O)(SRk)(ORk), -P(O)(SRk)2, or -OP(O)(SRk)2> wherein p is 1 or 2.
215. The method of Claim 214, wherein ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, =O, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.
216. The method of Claim 214, wherein:
Xi3, X14, and Y1 are O;
R17 and R1S are each, independently, H or a lower alkyl.
217. The method of Claim 149, wherein the compound is represented by formula (XVII):
Figure imgf000249_0001
(XVII) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, or prodrug thereof, wherein:
X13 is O, S, S(O), S(O)2, or CH2;
Figure imgf000249_0002
Rn and R1S, for each occurrence, are independently, H or a lower alkyl; or Ri7 and R1S taken together with the carbon to which they are attached form a cycloalkyl; and fis O, 1, 2, or 3.
218. The method of Claim 217, wherein Q, U, and V are N.
219. The method of Claim 217, wherein one of Q, U, or V is CRg, and the other two are N.
220. The method of Claim 219, wherein V is CR8, Q and U are N.
221. The method of Claim 219, wherein Q is CR8, V and U are N.
222. The method of Claim 219, wherein U is CR8, V and Q are N.
223. The method of Claim 217, wherein one of Q, U, or V is N, and the other two are CR8.
224. The method of Claim 223, wherein V is N, and Q and U are CRg.
225. The method of Claim 223, wherein Q is N, and V and U are CRS.
226. The method of Claim 223, wherein U is N and Q, and V are CRg.
227. The method of Claim 218, 219, or 213, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000250_0001
wherein:
M C «
** represents the point of attachment; rings G, H, I, and J are each, independently, an aryl or a heteroaryl; and each ring system is optionally substituted with one or more substituents.
228. The method of Claim 218, 219, or 223, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
wherein: each ring system is optionally substituted with one or more substituents;
S represents the point of attachment; and R49 is H, an alkyl, an aralkyl, or an alkylcarbonyl.
229. The method of Claim 228, wherein ring A is a ring system selected from the group consisting of:
Figure imgf000254_0002
Figure imgf000255_0001
Figure imgf000256_0001
wherein: each ring system is optionally substituted with one or more substituents.
230. The method of Claim 229, wherein ring A is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkyl sulfanyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cyclyl, an optionally substituted heterocyclyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, halo, cyano, nitro, haloalkoxy, =O, =S, =NR, -ORk, -NRhRj, -SRk, -C(O)Rk, -C(O)NRhRj, -NRkC(O)Rk, -C(O)ORk, -OC(O)Rk, -NRkC(O)NRhRj, -OC(O)NRhRj, -]MRkC(O)ORk, -C(NR)Rk, -C(NR)NRhRj, -NRkC(NR)Rk, -C(NR)ORk, -OC(NR)Rk, -NRkCCNR)NRhRJ, -OC(NR)NRhRj, -NRkC(NR)ORk, -C(S)Rk, -C(S)NRhRj, -NRkC(S)Rk, -C(S)ORk, -OC(S)Rk, -NRkC(S)NRhRj, -OC(S)NRhRj, -NRkC(S)ORk, -C(O)SRk, -SC(O)Rk, -S(O)pRk, -S(O)pNRhRj, -OS(O)pRk, -S(O)pORk, -OS(O)pORk, -P(O)(ORk)2, -OP(0)(ORk)2, -P(S)(ORk)2, -SP(O)(ORk)2, -P(O)(SRk)(ORk), -OP(O)(SRk)(ORk), -P(O)(SRk)2, or -OP(O)(SRk)2, wherein p is 1 or 2.
231. The method of Claim 230, wherein ring A is optionally substituted with from one to three substituents selected from the group consisting of a lower alkyl, a lower alkoxy, =O, nitro, cyano, hydroxy, amino, lower alkyl amino, lower dialkyl amino, mercapto, lower alkyl sulfanyl, halo, or haloalkyl.
232. The method of Claim 230, wherein:
Figure imgf000257_0001
X15 is -OH; and
R17 and R18 are each, independently, H or a lower alkyl.
233. A method of treating common variable immunodeficiency (CVID) in a subject, the method comprising administering to the subject an effective amount of N-(3-methyl-benzylidene)-N' -[6-morpholin-4-yl-2-(2-pyridin-2 -yl- ethoxy)-pyrimidin-4-yl]-hydrazine, or a pharmaceutically acceptable salt thereof.
234. The method of claim 233, wherein , the pharmaceutically acceptable salt is a mesylate salt.
235. The method of any one of claims 1, 41, 78, 114, 149, or 233, wherein the subject is a human.
236. The method of any one of claims 1, 41, 78, 114, 149, or 233, wherein the compound is a disalt.
237. Use of a compound of any one of claims 1, 41, 78, 114, 149, or 233 for the manufacture of a medicament for the treatment of common variable immunodeficiency.
PCT/US2007/004913 2006-02-22 2007-02-22 Method for treating common variable immunodeficiency WO2007100759A2 (en)

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RU2568853C1 (en) * 2014-09-30 2015-11-20 Федеральное бюджетное учреждение науки "Федеральный научный центр медико-профилактических технологий управления рисками здоровью населения" (ФБУН "ФНЦ медико-профилактических технологий управления рисками здоровью населения") Method for preventing variable immunodeficiency with predominant variance of b-cell count and functional activity in children of three years and more using drinking water with residual amount of hyperchlorination products
RU2574003C1 (en) * 2014-10-24 2016-01-27 Федеральное бюджетное учреждение науки "Федеральный научный центр медико-профилактических технологий управления рисками здоровью населения" (ФБУН "ФНЦ медико-профилактических технологий управления рисками здоровью населения") Method for prevention of variable immunodeficiency primarily involving monocytes and macrophages of immune system in children aged 3 years and older, consuming drinking water with residual amounts of hyperchlorination products
WO2023107689A1 (en) * 2021-12-09 2023-06-15 X4 Pharmaceuticals, Inc. Methods for treating primary immunodeficiency

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