Patent Application
20100120778
This invention relates generally to quinoxaline-based modulators of Liver X receptors (LXRs) and related methods.
Atherosclerosis is among the leading causes of death in developed countries. Some of the independent risk factors associated with atherosclerosis include the presence of relatively high levels of serum LDL cholesterol and relatively low levels of serum HDL cholesterol in affected patients. As such, some anti-atherosclerotic therapy regimens include the administration of agents (e.g., statins) to reduce elevated serum LDL cholesterol levels.
Agents that increase patient HDL cholesterol levels can also be useful in anti-atherosclerotic therapy regimens. HDL cholesterol is believed to play a major role in the transport of cholesterol from peripheral tissues to the liver for metabolism and excretion (this process is sometimes referred to as “reverse cholesterol transport”). ABCA1 is a transporter gene involved in HDL production and reverse cholesterol transport. Upregulation of ABCA1 can therefore result in increased reverse cholesterol transport as well as inhibition of cholesterol absorption in the gut. In addition, HDL is also believed to inhibit the oxidation of LDL cholesterol, reduce the inflammatory response of endothelial cells, inhibit the coagulation pathway, and promote the availability of nitric oxide.
Liver X receptors (LXRs), originally identified in the liver as orphan receptors, are members of the nuclear hormone receptor super family and are believed to be involved in the regulation of cholesterol and lipid metabolism. LXRs are ligand-activated transcription factors and bind to DNA as obligate heterodimers with retinoid X receptors. While LXRα is generally found in tissues such as liver, kidney, adipose tissue, intestine and macrophages, LXRβ displays a ubiquitous tissue distribution pattern. Activation of LXRs by oxysterols (endogenous ligands) in macrophages results in the expression of several genes involved in lipid metabolism and reverse cholesterol transport including the aforementioned ABCA1; ABCG1; and ApoE. See, e.g., Koldamova, et al., J. Biol. Chem. 2003, 278, 13244.
Studies have been conducted in LXRα knock-out (k/o), LXRβ k/o and double k/o mice to determine the physiological role of LXRs in lipid homeostasis and atherosclerosis. The data from these studies suggested that in double k/o mice on normal chow diet, increased cholesterol accumulation was observed in macrophages (foam cells) of the spleen, lung and arterial wall. The increased cholesterol accumulation was believed to be associated with the presence of reduced serum HDL cholesterol and increased LDL cholesterol, even though the total cholesterol levels in the mice were about normal. While LXRα k/o mice did not appear to show significant changes in hepatic gene expression, LXRβ k/o mice showed 58% decrease in hepatic ABCA1 expression and 208% increase in SREBP1c expression suggesting that LXRβ may be involved in the regulation of liver SREBP1c expression.
Data obtained from studies employing two different atherosclerotic mouse models (ApoE k/o and LDLR k/o) suggest that agonists of LXRα or β can be relatively effective in upregulating ABCA1 expression in macrophages. For example, inhibition of atherosclerotic lesions could be observed when ApoE k/o and LDLR k/o mice were treated with LXRα or β agonists for 12 weeks. The tested agonists were observed to have variable effects on serum cholesterol and lipoprotein levels and appeared to cause a relatively significant increase in serum HDL cholesterol and triglyceride levels. These in vivo data were found to be consistent with in vitro data obtained for the same agonists in macrophages.
In addition to the lipid and triglyceride effects described above, it is also believed that activation of LXRs results in the inhibition of inflammation and proinflammatory gene expression. This hypothesis is based on data obtained from studies employing three different models of inflammation (LPS-induced sepsis, acute contact dermatitis of the ear and chronic atherosclerotic inflammation of the artery wall). These data suggest that LXR modulators can mediate both the removal of cholesterol from the macrophages and the inhibition of vascular inflammation.
For a review of LXR biology and LXR modulators, see, e.g., Goodwin, et al., Current Topics in Medicinal Chemistry 2008, 8, 781; and Bennett, et al., Current Medicinal Chemistry 2008, 15, 195.
For studies related to atherosclerosis, see, e.g., Scott, J. N. Engl. J. Med. 2007, 357, 2195; Joseph, et al., PNAS 2002, 99, 7604; Tangirala, et. al., PNAS, 2002, 99, 11896; and Bradley, et al., Journal of Clinical Investigation 2007, 117, 2337-2346.
For studies related to inflammation, see, e.g., Fowler, et al., Journal of Investigative Dermatology 2003, 120, 246; and US 2004/0259948.
For studies related to Alzheimer's disease, see, e.g., Koldamova, et al., J. Biol. Chem. 2005, 280, 4079; Sun, et al., J. Biol. Chem. 2003, 278, 27688; and Riddell, et al., Mol. Cell. Neurosci. 2007, 34, 621.
For studies related to diabetes, see, e.g., Kase, et al., Diabetologia 2007, 50, 2171; and Liu, et al., Endocrinology 2006, 147, 5061.
For studies related to skin aging, see, e.g., WO 2004/076418; WO 2004/103320; and US 2008/0070883.
For studies related to arthritis, see, e.g., Chintalacharuvu, et. al., Arthritis a& Rheumatism 2007, 56, 1365; and WO 2008/036239.
This invention relates generally to quinoxaline-based modulators of Liver X receptors (LXRs) and related methods.
In one aspect, this invention features a compound having formula (I):
in which:
each of L1 and L2 is, independently, a bond, —O— or —NH—;
R1 is:
(i) hydrogen; or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra; or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-3 Rb; or
(iv) C3-C7 cycloalkyl optionally substituted with from 1-3 Rc; or
(v) NR7R8, wherein R7 and R8 at each occurrence is, independently, hydrogen, C1-C6 alkyl, or C3-C7 cycloalkyl;
R2 is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is:
(i) substituted with 1 R9, and
(ii) optionally further substituted with from 1-4 Re; wherein:
R9 is WA, wherein:
W at each occurrence is, independently, a bond; —O—; —NR10— wherein R10 is hydrogen, C1-C6 alkyl, or C3-C7 cycloalkyl; C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene; or —(C1-6 alkylene)W1—;
W1 at each occurrence is, independently, —O—, —NH— or —N(C1-6 alkyl)-;
A at each occurrence is, independently, C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is:
(i) substituted with 1 R11, and
(ii) optionally further substituted with from 1-4 Rg;
R11 at each occurrence is, independently:
(i) —W2—S(O)nR12 or —W2—S(O)nNR13R14; or
(ii) —W2—C(O)OR15; or
(iii) —W2—C(O)NR13R14; or
(iv) —W2—CN; or
(v) C1-C8 alkyl or C1-C8 haloalkyl, each of which is:
(vi) —NR16R17;
wherein:
W2 at each occurrence is, independently, a bond; C1-6 alkylene; C2-6 alkenylene; C2-6 alkynylene; C3-6 cycloalkylene; —O(C1-6 alkylene)-; —NH(C1-6 alkylene)-; or —N(C1-C6 alkyl)(C1-6 alkylene)-;
n at each occurrence is, independently, 1 or 2;
R12 at each occurrence is, independently:
(i) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra; or
(ii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-3 Rb; or
(iii) C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C7-C11 aralkyl, or heteroaralkyl including 6-11 atoms, each of which is optionally substituted with from 1-3 Rc; or
(iv) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally substituted with from 1-3 Rd;
R13 and R14 are each, independently, hydrogen; R12 or heterocyclyl including 3-8 atoms or a heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-3 Rc; or
R13 and R14 together with the nitrogen atom to which they are attached form a heterocyclyl including 3-8 atoms or a heterocycloalkenyl including 3-8 atoms, each of which is optionally substituted with from 1-3 Rc;
R15 at each occurrence is, independently, hydrogen or R12;
one of R16 and R17 is hydrogen or C1-C3 alkyl; and the other of R16 and R17 is:
(i) —S(O)nR12; or
(ii) —C(O)R12; or
(iii) —C(O)OR13; or
(iv) —C(O)NR13R14; or
(v) C1-C8 alkyl or C1-C8 haloalkyl, each of which is:
each of R3 and R6 is, independently:
(i) hydrogen; or
(ii) halo; or
(iii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra; or
(iv) nitro; hydroxy; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; cyano; or S(O)z(C1-C3 alkyl), wherein z is 1 or 2;
each of R4 and R5 is, independently:
(i) hydrogen; or
(ii) halo; or
(iii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra;
Ra at each occurrence is, independently:
(i) NRmRn; hydroxy; C1-C6 alkoxy or C1-C6 haloalkoxy; or
(ii) C3-C7 cycloalkyl optionally substituted with from 1-3 substituents independently selected from NRmRn; hydroxy; C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;
Rb at each occurrence is, independently:
(i) halo; NRmRn; hydroxy; C1-C6 alkoxy or C1-C6 haloalkoxy; or
(ii) C3-C7 cycloalkyl optionally substituted with from 1-3 substituents independently selected from NRmRn; hydroxy; C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;
Rc at each occurrence is, independently:
(i) halo; NRmRn; hydroxy; C1-C6 alkoxy or C1-C6 haloalkoxy; or
(ii) C1-C6 alkyl or C1-C6 haloalkyl; or
(iii) C2-C6 alkenyl or C2-C6 alkynyl;
Rd at each occurrence is, independently:
(i) halo; NRmRn; hydroxy; C1-C6 alkoxy or C1-C6 haloalkoxy; or cyano; or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra; or
(iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-3 Rb;
Re at each occurrence is, independently, C1-C6 alkyl; C1-C6 haloalkyl; halo; hydroxy; NRmRn; C1-C6 alkoxy; C1-C6 haloalkoxy; cyano; or phenyl, which is optionally substituted with from 1-4 Rd;
Rg at each occurrence is, independently, C1-C6 alkyl; C1-C6 haloalkyl; halo; hydroxy; NRmRn; C1-C6 alkoxy; C1-C6 haloalkoxy; or cyano;
Rh at each occurrence is, independently, hydroxyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; C3-C8 cycloalkoxy or C3-C8 cycloalkenyloxy, each of which is optionally substituted with from 1-3 Rc; or C6-C10 aryloxy or heteroaryloxy including 5-10 atoms, each of which is optionally substituted with from 1-3 Rd;
each of Rm and Rn at each occurrence is, independently, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
or an N-oxide and/or a pharmaceutically acceptable salt thereof.
In one aspect, this invention features a compound of formula (I-A):
in which R1, R2, R3, R4, R5, and R6 can be as defined anywhere herein.
In one aspect, this invention relates to any subgenera of formula (I) or (I-A) described herein.
In one aspect, this invention relates to any of the specific quinoxaline compounds delineated herein. In some embodiments, the compound of formula (I) or (I-A) can be selected from the title compounds of Examples 1-42 and 44-83; or a pharmaceutically acceptable salt and/or N-oxide thereof.
In one aspect, this invention features a composition (e.g., a pharmaceutical composition), which includes a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof), or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof and a pharmaceutically acceptable carrier. In some embodiments, the composition can include an effective amount of the compound or the salt thereof. In some embodiments, the composition can further include an additional therapeutic agent.
In one aspect, this invention features a dosage form, which includes from about 0.05 milligrams to about 2,000 milligrams (e.g., from about 0.1 milligrams to about 1,000 milligrams, from about 0.1 milligrams to about 500 milligrams, from about 0.1 milligrams to about 250 milligrams, from about 0.1 milligrams to about 100 milligrams, from about 0.1 milligrams to about 50 milligrams, or from about 0.1 milligrams to about 25 milligrams) of formula (I) or (I-A) (including any subgenera or specific compounds thereof), or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof. The dosage form can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.
The invention also relates generally to modulating (e.g., activating) LXRs with the quinoxaline compounds described herein. In some embodiments, the methods can include, e.g., contacting an LXR in a sample (e.g., a tissue, a cell free assay medium, a cell-based assay medium) with a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof. In other embodiments, the methods can include administering a compound of formula (I) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof to a subject (e.g., a mammal, e.g., a human, e.g., a human having or at risk of having one or more of the diseases or disorders described herein).
In one aspect, this invention also relates generally to methods of treating (e.g., controlling, relieving, ameliorating, alleviating, slowing the progression of, delaying the onset of, or reducing the risk of developing) or preventing one or more LXR-mediated diseases or disorders in a subject (e.g., a subject in need thereof). The methods include administering to the subject an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof. LXR-mediated diseases or disorders can include, e.g., cardiovascular diseases (e.g., acute coronary syndrome, restenosis, or coronary artery disease), atherosclerosis, atherosclerotic lesions, type I diabetes, type II diabetes, Syndrome X, obesity, lipid disorders (e.g., dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL), cognitive disorders (e.g., Alzheimer's disease, dementia), inflammatory diseases (e.g., multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, endometriosis, LPS-induced sepsis, acute contact dermatitis of the ear, chronic atherosclerotic inflammation of the artery wall), celiac, thyroiditis, skin aging or connective tissue diseases.
In another aspect, this invention relates to methods of modulating (e.g., increasing) serum HDL cholesterol levels in a subject (e.g., a subject in need thereof), which includes administering to the subject an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In another aspect, this invention relates to methods of modulating (e.g., decreasing) serum LDL cholesterol levels in a subject (e.g., a subject in need thereof), which includes administering to the subject an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In another aspect, this invention relates to methods of modulating (e.g., increasing) reverse cholesterol transport in a subject (e.g., a subject in need thereof), which includes administering to the subject an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In another aspect, this invention relates to methods of modulating (e.g., decreasing or inhibiting) cholesterol absorption in a subject (e.g., a subject in need thereof), which includes administering to the subject an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In a further aspect, this invention relates to methods of preventing or treating a cardiovascular disease (e.g., acute coronary syndrome, restenosis, or coronary artery disease), which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In one aspect, this invention relates to methods of preventing or treating atherosclerosis and/or atherosclerotic lesions, which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In another aspect, this invention relates to methods of preventing or treating diabetes (e.g., type I diabetes or type II diabetes), which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In a further aspect, this invention relates to methods of preventing or treating Syndrome X, which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In one aspect, this invention relates to methods of preventing or treating obesity, which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In another aspect, this invention relates to methods of preventing or treating a lipid disorder (e.g., one or more of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and/or high LDL), which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In a further aspect, this invention relates to methods of preventing or treating a cognitive disorder (e.g., Alzheimer's disease or dementia), which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In one aspect, this invention relates to methods of preventing or treating dementia, which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In another aspect, this invention relates to methods of preventing or treating Alzheimer's disease, which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In a further aspect, this invention relates to methods of preventing or treating an inflammatory disease (e.g., multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, endometriosis, LPS-induced sepsis, acute contact dermatitis of the ear, chronic atherosclerotic inflammation of the artery wall), which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In another aspect, this invention relates to methods of preventing or treating rheumatoid arthritis, which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In a further aspect, this invention relates to methods of preventing or treating celiac, which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a pharmaceutically acceptable salt or prodrug thereof.
In a further aspect, this invention relates to methods of preventing or treating thyroiditis, which includes administering to a subject in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof.
In one aspect, this invention relates to methods of treating a connective tissue disease (e.g., osteoarthritis or tendonitis), which includes administering to a subject (e.g., a mammal, e.g., a human) in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof. In embodiments, the compound of formula (I) or (I-A) inhibits (e.g., reduces or otherwise diminishes) cartilage degradation. In embodiments, the compound of formula (I) or (I-A) induces (e.g., increases or otherwise agments) cartilage regeneration. In embodiments, the compound of formula (I) or (I-A) inhibits (e.g., reduces or otherwise diminishes) cartilage degradation and induces (e.g., increases or otherwise agments) cartilage regeneration. In embodiments, the compound of formula (I) or (I-A) inhibits (e.g., reduces or otherwise diminishes) aggrecanase activity. In embodiments, the compound of formula (I) or (I-A) inhibits (e.g., reduces or otherwise diminishes) elaboration of pro-inflammatory cytokines in osteoarthritic lesions.
In another aspect, this invention relates to methods of treating or preventing skin aging, the method comprising administering (e.g., topically administering) to a subject (e.g., a mammal, e.g., a human) in need thereof an effective amount of a compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof. In embodiments, the skin aging can be derived from chronological aging, photoaging, steroid-induced skin thinning, or a combination thereof.
The term “skin aging” includes conditions derived from intrinsic chronological aging (for example, deepened expression lines, reduction of skin thickness, inelasticity, and/or unblemished smooth surface), those derived from photoaging (for example, deep wrinkles, yellow and leathery surface, hardening of the skin, elastosis, roughness, dyspigmentations (age spots) and/or blotchy skin), and those derived from steroid-induced skin thinning. Accordingly, another aspect is a method of counteracting UV photodamage, which includes contacting a skin cell exposed to UV light with an effective amount of a compound of formula (I) or (I-A).
In some embodiments, the compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof does not substantially increase serum and/or hepatic triglyceride levels of the subject.
In some embodiments, the administered compound of formula (I) or (I-A) (including any subgenera or specific compounds thereof) or a salt (e.g., a pharmaceutically acceptable salt), or an N-oxide, or a prodrug thereof can be an LXR agonist (e.g., an LXRα agonist or an LXRβ agonist).
In some embodiments, the subject can be a subject in need thereof (e.g., a subject identified as being in need of such treatment). Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). In some embodiments, the subject can be a mammal. In certain embodiments, the subject is a human.
In a further aspect, this invention also relates to methods of making compounds described herein. Alternatively, the method includes taking any one of the intermediate compounds described herein and reacting it with one or more chemical reagents in one or more steps to produce a compound described herein.
In one aspect, this invention relates to a packaged product. The packaged product includes a container, one of the aforementioned compounds in the container, and a legend (e.g., a label or an insert) associated with the container and indicating administration of the compound for treatment and control of the diseases or disorders described herein.
In embodiments, any compound, composition, or method can also include any one or more of the features below (alone or in combination) and/or delineated in the detailed description and/or in the claims.
Each of L1 and L2 can be a bond. One of L1 and L2 (e.g., L1) can be a bond, and the other of L1 and L2 (e.g., L2) is —O—.
R1 can be C1-C6 alkyl or C1-C6 haloalkyl. In certain embodiments, R1 can be C1-C3 alkyl (e.g., CH3).
In some embodiments, when L1 is —NH— or —O—, then R1 can be other than hydrogen and/or other than NR7R8.
R2 can be C6-C10 aryl, which is (a) substituted with 1 R9; and (b) optionally further substituted with from 1-4 Re.
In certain embodiments, R2 can be phenyl, which is (a) substituted with 1 R9; and (b) optionally further substituted with from 1-4 Re. For example, R2 can have formula (A-2):
in which:
one of R23 and R24 is R9, and the other of R23 and R24 is hydrogen, and each of R22, R25, and R26 is, independently, hydrogen or Re.
R23 can be R9, and R24 can be hydrogen. R24 can be R9, and R23 can be hydrogen. Each of R22, R25, and R26 can be hydrogen. One of R22, R25, and R26 (e.g., R26) can be Re (e.g., halo, e.g., chloro) and the other two are hydrogen.
W can be —O—.
W can be a bond.
A can be C6-C10 aryl, which is (a) substituted with 1 R11; and (b) optionally further substituted with from 1-4 Rg.
In certain embodiments, A can be phenyl, which is (a) substituted with 1 R11; and (b) optionally further substituted with from 1-4 Rg. For example, A can have formula (B-1):
in which:
one of RA3 and RA4 is R11, the other of RA3 and RA4 is hydrogen; and each of RA2, RA5, and RA6 is, independently, hydrogen or Rg.
R11 can be —W2—S(O)nR12. In embodiments, W2 can be a bond, and n is 2. R12 can be C1-C6 alkyl, optionally substituted with from 1-2 Ra. For example, R12 can be CH3.
R2 can have formula (A-2) as described herein, in which:
one of R23 and R24 can have formula (C-1):
in which one of RA2, RA3, RA4, RA5, and RA6 is R11, and the others are each, independently, hydrogen or Rg; and the other of R23 and R24 can be hydrogen; and each of R22, R25, and R26 is, independently, hydrogen or Re.
Embodiments can include, for example, one or more of the following features.
R23 can have formula (C-1), and R24 can be hydrogen. Each of R22, R25, and R26 can be hydrogen. One of R22, R25, and R26 (e.g., R26) can be Re (e.g., halo, e.g., chloro) and the other two are hydrogen.
W can be —O—. W can be a bond.
One of RA3 and RA4 can be R11, and the other of RA3 and RA4 is hydrogen; and each of RA2, RA5, and RA6 is, independently, hydrogen or Rg.
R11 can be —W2—S(O)nR12.
RA3 can be R11, and RA4 is hydrogen. R11 can be —W2—S(O)nR12. W2 can be a bond, and n can be 2. R12 can be C1-C6 alkyl, optionally substituted with from 1-2 Ra. For example, R12 can be CH3. R12 can be C1-C6 alkyl substituted with 1 Ra. Ra can be, e.g., hydroxyl or NRmRn.
Each of RA2, RA5, and RA6 can be hydrogen. RA5 can be Rg (e.g., halo), and each of RA2 and RA6 is hydrogen.
R11 can be —W2—S(O)nNR13R14. W2 can be a bond, and one of R13 and R14 can be C1-C3 alkyl, and the other of R13 and R14 can be hydrogen.
One of R3 and R6 can be:
(i) halo; or (ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra; or (iii) nitro; hydroxy; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; cyano; or S(O)z(C1-C3 alkyl), wherein z is 1 or 2;
and the other of R3 and R6 can be:
(i) hydrogen; or (ii) halo; or (iii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra; or (iv) nitro; hydroxy; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; cyano; or S(O)z(C1-C3 alkyl), wherein z is 1 or 2.
One of R3 and R6 can be:
(i) halo; or (ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra; or (iii) nitro; hydroxy; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; cyano; or S(O)z(C1-C3 alkyl), wherein z is 1 or 2;
and the other of R3 and R6 can be hydrogen.
One of R3 and R6 can be:
(i) halo; or (ii) C1-C6 haloalkyl; or (iii) C1-C6 alkoxy; C1-C6 haloalkoxy; or cyano;
and the other of R3 and R6 can be hydrogen.
One of R3 and R6 can be halo (e.g., chloro), the other of R3 and R6 is hydrogen.
One of R3 and R6 can be C1-C4 haloalkyl (e.g., perfluoroalkyl, e.g., CF3), the other of R3 and R6 can be hydrogen.
Each of R4 and R5 can be hydrogen.
In some embodiment, the compound can have formula (VI):
in which:
R1 is:
(i) hydrogen; or
(ii) C1-C3 alkyl or C1-C3 haloalkyl; or
(iii) NR7R8;
one of R3 and R6 is:
(i) halo; or
(ii) C1-C4 haloalkyl; or
(iii) C1-C6 alkoxy; C1-C6 haloalkoxy; or cyano;
and the other of R3 and R6 is hydrogen;
each of R4 and R5 is hydrogen;
one of R23 and R24 can have formula (C-1) as described herein, in which one of RA2, RA3, RA4, RA5, and RA6 can be R11, and the others can each be, independently, hydrogen or Rg; and W is a bond or —O—;
and the other of R23 and R24 is hydrogen, and
each of R22, R25, and R26 is, independently, hydrogen or Re.
Embodiments can include, for example, one or more of the following features.
R1 can be CH3.
R23 can have formula (C-1), and R24 can be hydrogen. Each of R22, R25, and R26 can be hydrogen. One of R22, R25, and R26 (e.g., R26) can be Re (e.g., halo, e.g., chloro) and the other two are hydrogen.
One of RA3 and RA4 can be R11, and the other of RA3 and RA4 can be hydrogen; and each of RA2, RA5, and RA6 can be, independently, hydrogen or Rg. RA3 can be R11, and RA4 can be hydrogen. R11 can be —W2—S(O)nR12. W2 can be a bond, and n can be 2. R12 can be C1-C6 alkyl, optionally substituted with from 1-2 Ra (e.g., CH3). Each of RA2, RA5, and RA6 can be hydrogen; or RA5 can be Rg, and each of RA2 and RA6 can be hydrogen. R11 can be —W2—S(O)nNR13R14, in which W2 can be a bond, and one of R13 and R14 is C1-C3 alkyl, and the other of R13 and R14 is hydrogen.
R3 can be hydrogen, and R6 can be CF3.
R3 can be CF3, and R6 can be hydrogen.
The term “mammal” includes organisms, which include mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.
“An effective amount” refers to an amount of a compound that confers a therapeutic effect (e.g., treats, inhibits, controls, relieves, ameliorates, prevents, delays the onset of, or reduces the risk of developing a disease, disorder, or condition or symptoms thereof) on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the compound described above may range from about 0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.1 mg/kg to about 100 mg/kg, from about 1 mg/kg to about 100 mg/kg). Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
The term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or iodine.
In general, and unless otherwise indicated, substituent (radical) prefix names are derived from the parent hydride by either (i) replacing the “ane” in the parent hydride with the suffixes “yl,” “diyl,” “triyl,” “tetrayl,” etc.; or (ii) replacing the “e” in the parent hydride with the suffixes “yl,” “diyl,” “triyl,” “tetrayl,” etc. (here the atom(s) with the free valence, when specified, is (are) given numbers as low as is consistent with any established numbering of the parent hydride). Accepted contracted names, e.g., adamantyl, naphthyl, anthryl, phenanthryl, furyl, pyridyl, isoquinolyl, quinolyl, and piperidyl, and trivial names, e.g., vinyl, allyl, phenyl, and thienyl are also used herein throughout. Conventional numbering/lettering systems are also adhered to for substituent numbering and the nomenclature of fused, bicyclic, tricyclic, polycyclic rings.
The term “alkyl” refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C6 alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. Any atom can be optionally substituted, e.g., by one or more substitutents (e.g., such as those delineated in any definition of Ra described herein). Examples of alkyl groups include without limitation methyl, ethyl, n-propyl, isopropyl, and tert-butyl.
The terms “alkylene,” “alkenylene,” “alkynylene,” and “cycloalkylene” refer to divalent straight chain or branched chain alkyl (e.g., —CH2—), alkenyl (e.g., —CH═CH—), alkynyl (e.g., —C≡C—); or cycloalkyl moieties, respectively.
The term “haloalkyl” refers to an alkyl group, in which at least one hydrogen atom is replaced by halo. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) are replaced by halo. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro). “Haloalkyl” also includes alkyl moieties in which all hydrogens have been replaced by halo (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). Any atom can be optionally substituted, e.g., by one or more substituents (e.g., such as those delineated in any definition of Ra described herein).
The term “aralkyl” refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety. Any ring or chain atom can be optionally substituted e.g., by one or more substituents (e.g., such as those delineated in any definition of Rc described herein). Non-limiting examples of “aralkyl” include benzyl, 2-phenylethyl, and 3-phenylpropyl groups.
The term “heteroaralkyl” refers to an alkyl moiety in which an alkyl hydrogen atom is replaced by a heteroaryl group. One of the carbons of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety. Heteroaralkyl includes groups in which more than one hydrogen atom on an alkyl moiety has been replaced by a heteroaryl group. Any ring or chain atom can be optionally substituted e.g., by one or more substituents (e.g., such as those delineated in any definition of Rc described herein). Heteroaralkyl can include, for example, 2-pyridylethyl.
The term “alkenyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon double bonds. Any atom can be optionally substituted, e.g., by one or more substituents (e.g., such as those delineated in any definition of Rb described herein). Alkenyl groups can include, e.g., allyl, 1-butenyl, and 2-hexenyl. One of the double bond carbons can optionally be the point of attachment of the alkenyl substituent. The term “alkynyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carbon-carbon triple bonds. Any atom can be optionally substituted, e.g., by one or more substituents (e.g., such as those delineated in any definition of Rb described herein). Alkynyl groups can include, e.g., ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons can optionally be the point of attachment of the alkynyl substituent.
The term “alkoxy” refers to an —O-alkyl radical. The term “mercapto” refers to an SH radical. The term “thioalkoxy” refers to an —S-alkyl radical. The terms “aryloxy” and “heteroaryloxy” refer to an —O-aryl radical and —O-heteroaryl radical, respectively. The terms “thioaryloxy” and “thioheteroaryloxy” refer to an —S-aryl radical and —S-heteroaryl radical, respectively.
The terms “aralkoxy” and “heteroaralkoxy” refer to an —O-aralkyl radical and —O-heteroaralkyl radical, respectively. The terms “thioaralkoxy” and “thioheteroaralkoxy” refer to an —S-aralkyl radical and —S-heteroaralkyl radical, respectively. The term “cycloalkoxy” refers to an —O-cycloalkyl radical. The terms “cycloalkenyloxy” and “heterocycloalkenyloxy” refer to an —O-cycloalkenyl radical and —O-heterocycloalkenyl radical, respectively. The term “heterocyclyloxy” refers to an —O-heterocyclyl radical. The term “thiocycloalkoxy” refers to an —S-cycloalkyl radical. The terms “thiocycloalkenyloxy” and “thioheterocycloalkenyloxy” refer to an —S-cycloalkenyl radical and —S-heterocycloalkenyl radical, respectively. The term “thioheterocyclyloxy” refers to an —S-heterocyclyl radical.
The term “heterocyclyl” refers to a fully saturated monocyclic, bicyclic, tricyclic or other polycyclic ring system having one or more (e.g., 1-4) heteroatom ring atoms independently selected from O, N, or S. The heteroatom or ring carbon is the point of attachment of the heterocyclyl substituent to another moiety. Any atom can be optionally substituted, e.g., by one or more substituents (e.g., such as those delineated in any definition of Rc described herein). Heterocyclyl groups can include, e.g., tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino), pyrrolinyl, and pyrrolidinyl.
The term “heterocycloalkenyl” refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups having one or more (e.g., 1-4) heteroatom ring atoms independently selected from O, N, or S. A ring carbon (e.g., saturated or unsaturated) or heteroatom is the point of attachment of the heterocycloalkenyl substituent. Any atom can be optionally substituted, e.g., by one or more substituents (e.g., such as those delineated in any definition of Rc described herein). Heterocycloalkenyl groups can include, e.g., tetrahydropyridyl, dihydropyranyl, 4,5-dihydrooxazolyl, 4,5-dihydro-1H-imidazolyl, 1,2,5,6-tetrahydro-pyrimidinyl, and 5,6-dihydro-2H-[1,3]oxazinyl.
The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. Any atom can be optionally substituted, e.g., by one or more substituents (e.g., such as those delineated in any definition of Rc described herein). A ring carbon serves as the point of attachment of a cycloalkyl group to another moiety. Cycloalkyl moieties can include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicycle[2.2.1]heptyl).
The term “cycloalkenyl” refers to partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. A ring carbon (e.g., saturated or unsaturated) is the point of attachment of the cycloalkenyl substituent. Any atom can be optionally substituted e.g., by one or more substituents (e.g., such as those delineated in any definition of Rc described herein). Cycloalkenyl moieties can include, e.g., cyclohexenyl, cyclohexadienyl, or norbornenyl.
The term “aryl” refers to an aromatic monocyclic or bicyclic hydrocarbon ring system, wherein any ring atom can be optionally substituted, e.g., by one or more substituents (e.g., such as those delineated in any definition of Rd described herein). Aryl moieties include phenyl and naphthyl.
The term “heteroaryl” refers to an aromatic monocyclic or bicyclic hydrocarbon groups having one or more (e.g., 1-6) heteroatom ring atoms independently selected from O, N, or S (and mono and dioxides thereof, e.g., N→O−, S(O), SO2). Any atom can be optionally substituted, e.g., by one or more substituents (e.g., such as those delineated in any definition of Rd described herein). Heteroaryl groups include pyridyl, thienyl, furyl (furanyl), imidazolyl, isoquinolyl, quinolyl and pyrrolyl.
The descriptor C(O) refers to a carbon atom that is doubly bonded to an oxygen atom.
The term “substituent” refers to a group “substituted” on, e.g., an alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any atom of that group. In one aspect, the substituent(s) (e.g., Ra) on a group are independently any one single, or any combination of two or more of the permissible atoms or groups of atoms delineated for that substituent. In another aspect, a substituent may itself be substituted with any one of the above substituents.
In general, when a definition for a particular variable includes both hydrogen and non-hydrogen (halo, alkyl, aryl, etc.) possibilities, the term “substituent(s) other than hydrogen” refers collectively to the non-hydrogen possibilities for that particular variable.
Descriptors such as “C1-C6 which is optionally substituted with from 1-5 Ra” (and the like) is intended to include both an unsubstituted C1-C6 alkyl group and a C1-C6 alkyl group that is substituted with from 1-5 Ra. The use of a substituent (radical) prefix names such as alkyl without the modifier “optionally substituted” or “substituted” is understood to mean that the particular substituent is unsubstituted. However, the use of “haloalkyl” without the modifier “optionally substituted” or “substituted” is still understood to mean an alkyl group, in which at least one hydrogen atom is replaced by halo.
In some embodiments, the compounds have agonist activity for genes involved with HDL production and cholesterol efflux (e.g., ABCA1) and antagonist activity for genes involved with triglyceride synthesis (e.g., SREBP-1c).
The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the description and from the claims.
This invention relates generally to quinoxaline-based modulators of Liver X receptors (LXRs) and related methods.
The quinoxaline-based LXR modulators have the general formula (I):
Here and throughout this specification, L1, L2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, W, W1, W2, A, Ra, Rb, Rc, Rd, Re, Rg, Rh, Rm, Rn, z, and n can be as defined anywhere herein.
In some embodiments, the quinoxaline-based LXR modulators have formula (I-A) as described herein. Here and throughout this specification, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, W, W1, W2, A, Ra, Rb, Rc, Rd, Re, Rg, Rh, Rm, Rn, z, and n can be as defined anywhere herein.
For ease of exposition, it is also understood that where in this specification (including the claims), a group is defined by “as defined anywhere herein” (or the like), the definitions for that particular group include the first occurring and broadest generic definition as well as any sub-generic and specific definitions delineated anywhere in this specification.
Variables L1 and L2
In some embodiments, each of L1 and L2 can be a bond.
In some embodiments, one of L1 and L2 can be a bond. In certain embodiments, L1 can be a bond. In certain embodiments, one of L1 and L2 (e.g., L1) can be a bond, and the other of L1 and L2 (e.g., L1) can be —O— or NH (e.g., —O—).
In some embodiments, when L1 is —NH— or —O—, then R1 can be other than hydrogen and/or other than NR7R8.
Variable R1
In some embodiments, R1 can be:
(1-i) hydrogen; or
(1-ii) C1-C6 (e.g., C1-C3) alkyl or C1-C6 (e.g., C1-C4 or C1-C3) haloalkyl, each of which is optionally substituted with from 1-3 (e.g., 1-2, 1) Ra; or
(1-iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-3 (e.g., 1-2, 1) Rb; or
(1-iv) C3-C7 (e.g., C3-C6) cycloalkyl, which is optionally substituted with from 1-3 (e.g., 1-2, 1) Rc; or
(1-v) NR7R8, wherein R7 and R8 at each occurrence is, independently, hydrogen, C1-C6 (e.g., C1-C3) alkyl, or C3-C7 (e.g., C3-C6) cycloalkyl;
In some embodiments, R1 can be:
(1-ii) C1-C6 (e.g., C1-C3) alkyl or C1-C6 (e.g., C1-C4 or C1-C3) haloalkyl, each of which is optionally substituted with from 1-3 (e.g., 1-2, 1) Ra; or
(1-iii) C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with from 1-3 (e.g., 1-2, 1) Rb; or
(1-iv) C3-C7 (e.g., C3-C6) cycloalkyl, which is optionally substituted with from 1-3 (e.g., 1-2, 1) Rc; or
(1-v) NR7R8, wherein R7 and R8 at each occurrence is, independently, hydrogen, C1-C6 (e.g., C1-C3) alkyl, or C3-C7 (e.g., C3-C6) cycloalkyl;
In some embodiments, R1 can be hydrogen.
In certain embodiments, R1 can be (1-i), (1-iia) C1-C6 (e.g., C1-C3) alkyl, which is optionally substituted with from 1-3 (e.g., 1-2, 1) Ra; (1-iii); (1-iv); or (1-v).
In certain embodiments, R1 can be (1-i), (1-iib) C1-C6 (e.g., C1-C3) haloalkyl, which is optionally substituted with from 1-3 (e.g., 1-2, 1) Ra; (1-iii); (1-iv); or (1-v).
In embodiments, R1 can be other than (1-v).
In some embodiments, when L1 is —NH— or —O—, then R1 can be other than hydrogen and/or other than NR7R8.
In some embodiments, R1 can be any one of: (1-i), (1-ii), (1-iia), (1-iib), (1-iii), (1-iv), and (1-v). In certain embodiments, R1 can be hydrogen. In other embodiments, R1 can be a substituent other than hydrogen. For example, R1 can be C1-C6 (e.g., C1-C3) alkyl or C1-C6 (e.g., C1-C4) haloalkyl, each of which is optionally substituted with from 1-3 (e.g., 1-2, 1) Ra; e.g., C1-C6 (e.g., C1-C3) alkyl, which is optionally substituted with from 1-3 (e.g., 1-2, 1) Ra.
In some embodiments, R1 can be any two of: (1-i), (1-ii), (1-iia), (1-iib), (1-iii), (1-iv), and (1-v). In certain embodiments, R1 can be hydrogen and any one of (1-i), (1-ii), (1-iia), (1-iib), (1-iii), (1-iv), and (1-v). In other embodiments, R1 can be any two of (1-ii), (1-iia), (1-iib), (1-iii), (1-iv), and (1-v), e.g., any two of (1-ii), (1-iia), (1-iib), (1-iii), and (1-iv).
In some embodiments, R1 can be any three of: (1-i), (1-ii), (1-iia), (1-iib), (1-iii), (1-iv), and (1-v). In certain embodiments, R1 can be hydrogen and any two of (1-ii), (1-iia), (1-iib), (1-iii), (1-iv), and (1-v); e.g., any two of (1-ii), (1-iia), (1-iib), (1-iii), and (1-iv). In other embodiments, R1 can be any three of (1-ii), (1-iia), (1-iib), (1-iii), (1-iv), and (1-v); any three of (1-ii), (1-iia), (1-iib), (1-iii), and (1-iv).
In some embodiments, R1 can be C1-C6 (e.g., C1-C3) alkyl, which is optionally substituted with from 1-3 (e.g., 1-2, 1) Ra. In certain embodiments, R1 can be C1-C6 (e.g., C1-C3) alkyl. For example, R1 can be methyl (CH3), ethyl (CH2CH3), or isopropyl (CH(CH3)2). In certain embodiments, R1 can be methyl (CH3).
In some embodiments, R1 can be C1-C6 (e.g., C1-C4 or C1-C3) haloalkyl (e.g., perhaloalkyl). For example, R1 can be CF3.
In some embodiments, R1 can be NR7R8, in which R7 and R8 at each occurrence can be, independently, hydrogen or (e.g., C1-C3) C1-C6 alkyl. For example, each of R7 and R8 can be hydrogen.
Variable R2
In some embodiments, R2 can be C6-C10 (e.g., phenyl) aryl, which is (i) substituted with 1 R9 and (ii) optionally substituted with from 1-4 (e.g., 1-3, 1-2, 1) Re. In these and in the following embodiments related to variables R2, R9 and Re can be as defined anywhere herein.
In some embodiments, R2 can be C6-C10 aryl, which is (i) substituted with 1 R9 and (ii) optionally substituted with 1 or 2 Re.
In embodiments, when R2 is aryl and substituted with one (or more) Re, each Re can be independently of one another: halo (e.g., chloro); C1-C3 alkyl; C1-C3 haloalkyl (e.g., C1-C3 fluoroalkyl, e.g., 1-5 fluorines can be present; or C1-C3 perfluoroalkyl); CN; hydroxyl; NRmRn (e.g., NH2, monoalkylamino, or dialkylamino, in which each alkyl portion can independently include, e.g., from 1-3 carbon atoms); C1-C3 alkoxy; C1-C3 haloalkoxy, or C6-C10 aryl (e.g., phenyl) which is optionally substituted with from 1-4 (e.g., 1-3, 1-2, or 1) Rd.
In certain embodiments, when R2 is aryl and substituted with Re, each Re can be independently of one another: C1-C3 alkyl; C1-C3 haloalkyl, e.g., C1-C3 perfluoroalkyl; halo (e.g., fluoro or chloro); CN, or phenyl which is optionally substituted with from 1-5 (e.g., 1-3, 1-2, or 1) Rd.
In certain embodiments, when R2 is aryl and substituted with Re, each Re can be independently of one another: C1-C3 alkyl; C1-C3 haloalkyl, e.g., C1-C3 perfluoroalkyl; halo (e.g., fluoro or chloro), or phenyl which is optionally substituted with from 1-5 (e.g., 1-3, 1-2, or 1) Rd.
In certain embodiments, when R2 is aryl and substituted with Re, each Re can be independently of one another halo (e.g., fluoro or chloro).
In certain embodiments, R2 can be phenyl, which is (i) substituted with 1 R9 and (ii) optionally substituted with from 1-4 (e.g., 1-3, 1-2, or 1) Re (e.g., halo, e.g., fluoro or chloro). In other embodiments, R2 can be phenyl, which is substituted only with 1 R9.
In certain embodiments, R2 can have formula (A), in which R9 (i.e., the moiety —WA) can be attached to a ring carbon that is ortho, meta, or para (e.g., meta or para, e.g., meta) with respect to the ring carbon that connects the phenyl ring to the 2- or 3-position of the quinoxalinering, and Re, when present can be connected to ring carbons that are not occupied by WA. For example, R2 can have formula (A-1), in which R9 (WA) is attached to the ring carbon that is meta with respect to the ring carbon that connects the phenyl ring to the 2- or 3-position of the quinoxalinering in formula (I).
In certain embodiments, R2 can have formula (A-2):
in which one of R23 and R24 (e.g., R23) is R9, and the other of R23 and R24 (e.g., R24) is hydrogen, and each of R22, R25, and R26 is, independently, hydrogen or Re.
In embodiments, each of R22, R25, and R26 can be hydrogen. In other embodiments, each of R22, R25, and R26 can be a substituent other than hydrogen. In still other embodiments, one or two of R22, R25, and R26 can be Re, and the other(s) are hydrogen.
In certain embodiments, one of R22, R25, and R26 can be Re, and the other two are hydrogen. In embodiments, R26 can be Re, and each of R22 and R25 can be hydrogen. In these embodiments, Re can be: halo (e.g., chloro or fluoro, e.g., chloro); C1-C3 alkyl; C1-C3 haloalkyl (e.g., C1-C3 fluoroalkyl, e.g., 1-5 fluorines can be present; or C1-C3 perfluoroalkyl); or C6-C10 aryl (e.g., phenyl) which is optionally substituted with from 1-5 Rd. For example, Re can be halo (e.g., fluoro or chloro). In other embodiments, Re can be phenyl, which is optionally substituted with from 1-4 Rd.
In some embodiments, R2 can be heteroaryl including 5-10 (e.g., 5-6) atoms, which is (i) substituted with 1 R9 and (ii) optionally substituted with from 1-4 (e.g., 1-3, 1-2, 1) Re. In these and in the following embodiments related to variable R2, R9 and Re can be as defined anywhere herein.
In some embodiments, R2 can be heteroaryl including 5-10 atoms, which is (i) substituted with 1 R9 and (ii) optionally substituted with 1 or 2 Re.
In embodiments, when R2 is heteroaryl and substituted with Re, each Re can be independently as defined anywhere herein. For example, each Re can be independently of one another: C1-C3 alkyl; C1-C3 haloalkyl, e.g., C1-C3 perfluoroalkyl; halo (e.g., chloro); e.g., each Re can be halo (e.g., chloro).
In some embodiments, R2 can be heteroaryl including 5-6 atoms, which is (i) substituted with 1 R9 and (ii) optionally substituted with 1 or 2 Re.
In some embodiments, R2 can be heteroaryl including 8-10 atoms, which is (i) substituted with 1 R9 and (ii) optionally substituted with 1 or 2 Re.
In certain embodiments, R2 can be pyridyl, pyrimidinyl, thienyl, furyl, quinolinyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, indolyl, benzo[1,3]-dioxolyl, benzo[1,2,5]-oxadiazolyl, isochromenyl-1-one, 3-H-isobenzofuranyl-1-one (e.g., pyridyl, thienyl, or indolyl, e.g., pyridyl), each of which is (i) substituted with 1 R9 and (ii) optionally substituted with 1 or 2 Re. For example, R2 can be pyridyl substituted with 1 R9.
Variable W
In some embodiments, W can be —O— or a bond.
In other embodiments, W can be —W1(C1-6 alkylene)-. In certain embodiments, W1 can be —O—. For example, W can be —O(C1-3 alkylene)- (e.g., —OCH2—).
In some embodiments, W can be —NR10— (e.g., —NH—).
In some embodiments, W can be —(C1-6 alkylene)W1—. In certain embodiments, W1 is —NH—; or W1 can be —O—. In certain embodiments, W can be —(C1-3 alkylene)NH— (e.g., —CH2NH—). In certain embodiments, W can be —(C1-3 alkylene)O— (e.g., —CH2O—).
In still other embodiments, W can be C2-C4 alkenylene (e.g., —CH═CH—); C2-C4 alkynylene (e.g., —C≡C—); or C1-3 alkylene (e.g., CH2).
In certain embodiments, W is other than NR10. In certain embodiments, is other than —NH— or —N(C1-C6 alkyl).
Variable A
In general, A is an aromatic or heteroaromatic ring system that is (a) substituted with one R11; and (b) optionally substituted with one or more Rg.
In some embodiments, A can be C6-C10 (e.g., phenyl) aryl, which is (a) substituted with 1 R11; and (b) optionally further substituted with from 1-4 (e.g., 1-3, 1-2, 1, e.g., 1-2) Rg. In these and in the following embodiments related to variable A, R11 and Rg can be as defined anywhere herein.
In some embodiments, A can be C6-C10 aryl, which is (i) substituted with 1 R11 and (ii) optionally further substituted with from 1-2 Rg.
In embodiments, when A is aryl and substituted with one or more Rg, each Rg can be independently of one another:
In certain embodiments, Rg can be halo (e.g., chloro).
In some embodiments, A can be phenyl, which is (i) substituted with 1 R11 and (ii) optionally substituted with from 1-4 (e.g., 1-3, 1-2, 1) Rg.
In some embodiments, A can be phenyl, which is (i) substituted with 1 R11 and (ii) optionally substituted with from 1-2 Rg.
In these embodiments, R11 can be attached to a ring carbon that is ortho, meta, or para (e.g., meta or para, e.g., meta) with respect to the ring carbon that connects the phenyl ring to W.
In certain embodiments, A can have formula (B-1):
in which one of RA3 and RA4 is R11, the other of RA3 and RA4 and each of RA2, RA5, and RA6 is, independently, hydrogen or Rg, in which Rg can be as defined anywhere herein.
In embodiments, one of RA3 and RA4 can be R11, the other of RA3 and RA4 can be hydrogen; and each of RA2, RA5, and RA6 can be, independently, hydrogen or Rg.
In certain embodiments, RA3 can be R11. For example, RA3 can be R11, RA4 can be hydrogen, and each of RA2, RA5, and RA6 can be hydrogen. As another example, RA3 can be R11; RA4 can be hydrogen; one of RA2, RA5, and RA6 (e.g., RA5) can be Rg (e.g., halo) and the other two of RA2, RA5, and RA6 can be hydrogen.
In certain embodiments, RA4 can be R11. For example, RA4 can be R11, RA3 can be hydrogen, and each of RA2, RA5, and RA6 can be hydrogen. As another example, RA3 can be R11; RA4 can be hydrogen; one of RA2, RA5, and RA6 can be Rg (e.g., halo) and the other two of RA2, RA5, and RA6 can be hydrogen.
In some embodiments, A can be heteroaryl including 5-10 atoms, which is (a) substituted 1 R11; and (b) is optionally substituted with from 1-3 (e.g., 1-2, 1) Rg. In these and in the following embodiments related to variable, R11 and Rg can be as defined anywhere herein.
In certain embodiments, A can be pyrrolyl, pyridyl, pyridyl-N-oxide, pyrazolyl, pyrimidinyl, thienyl, furyl, quinolinyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, indolyl, benzo[1,3]-dioxolyl, benzo[1,2,5]-oxadiazolyl, isochromenyl-1-one, 3-H-isobenzofuranyl-1-one (e.g., pyridyl, thienyl, or indolyl, e.g., pyridyl), which is (i) substituted with 1 R11 and (ii) optionally substituted with 1-3 (e.g., 1-2, 1) Rg.
In certain embodiments, A can be pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl, thienyl, furyl, quinolyl, oxazolyl, thiazolyl, imidazolyl, or isoxazolyl, each of which is (a) substituted with 1 R11; and (b) is optionally substituted with from 1-3 (e.g., 1-2, 1) Rg.
In certain embodiments, A can be pyridyl, pyrimidinyl, thienyl, furyl, oxazolyl, thiazolyl, imidazolyl, or isoxazolyl, each of which is (a) substituted with 1 R11; and (b) is optionally substituted with from 1-3 (e.g., 1-2, 1) Rg.
In certain embodiments, A can be pyridyl in which W is attached to the 2- or 3-position of the pyridiyl ring. For example, A can be pyridyl in which W is attached to the 2-position of the pyridyl ring, and R11 is attached to the 4- or the 6-position of the pyridyl ring. Such rings can be further substituted with 1, 2 or 3 Rg (e.g., halo, e.g., chloro; or NRmRn, e.g., NH2).
Variable R11
R11 can be:
(11-i) —W2—S(O)nR12 or —W2—S(O)nNR13R14; or
(11-ii) —W2—C(O)OR15; or
(11-iii) —W2—C(O)NR13R14; or
(11-iv) C1-C12 alkyl or C1-C12 haloalkyl, each of which is:
or
(11-v) —NR16R17.
In some embodiments, R11 can be:
(11-i′)—W2—S(O)nR12; or
(11-ii), (11-iii), (11-iv), or (11-v).
In some embodiments, R11 can be any one of: (11-i), (11-i′), (11-ii), (11-iii), (11-iv), or (11-v). In certain embodiments, R11 can be —W2—S(O)nR12or —W2—S(O)nNR13R14 (e.g., —W2—S(O)nR12). In other embodiments, R11 can be —W2—C(O)OR15 or —W2—C(O)NR13R14; or NR16R17.
In some embodiments, R11 can be any two of: (11-i), (11-i′), (11-ii), (11-iii), (11-iv), or (11-v). In certain embodiments, R11 can be —W2—S(O)nR12 or —W2—S(O)nNR13R14 (e.g., —W2—S(O)nR12) and any one of (11-ii), (11-iii), (11-iv), or (11-v). For example, R11 can be:
In other embodiments, R11 can be any two of (11-ii), (11-iii), (11-iv), or (11-v).
In some embodiments, R11 can be any three of: (11-i), (11-i′), (11-ii), (11-iii), (11-iv), or (11-v).
In certain embodiments, R11 can be —W2—S(O)nR12, —W2—S(O)nNR13R14, and —W2—C(O)OR15 or —W2—C(O)NR13R14; or NR16R17.
In certain embodiments, R11 can be:
In other embodiments, R11 can be (11-iii), (11-iv), or (11-v).
In some embodiments, W2 can be a bond.
In some embodiments, R11 can be —W2—S(O)nR12 (e.g., —W2—S(O)nR12, in which n is 2). In embodiments, W2 can be a bond, i.e., R11 is connected to variable A by the sulfur (S) atom of the sulfinyl or the sulfonyl group.
In some embodiments, R12 can be C1-C6 (e.g., C1-C5) alkyl or C1-C6 (e.g., C1-C5 or C1-C3) haloalkyl, optionally substituted with from 1-2 Ra.
In certain embodiments, R12 can be C2-C6 alkyl, that is substituted with from 1-2 (e.g., 1) Ra.
In certain embodiments, R12 can be unsubstituted branched or unbranched C1-C6 (e.g., C1-C2, C1-C3, C1-C5, C2-C6, C3, C4, or C3-C6) alkyl. For example, R12 can be methyl (CH3). As another example, R12 can be ethyl (CH2CH3). As a further example, R12 can be isopropyl (CH(CH3)2).
In certain embodiments, R12 can be branched or unbranched C2-C6 (e.g., C3-C6 or C3-C5) alkyl, which is substituted with 1 Ra. In embodiments, Ra can be: hydroxyl; C1-C6 (e.g., C1-C3) alkoxy; NRmRn. For example, Ra can be hydroxyl, C1-C6 (e.g., C1-C3) alkoxy, or NRmRn. In certain embodiments, Ra (e.g., hydroxyl) can be attached to a secondary or tertiary carbon atom of the alkyl group or a primary carbon of the alkyl group. In embodiments, R12 can be hydroxyl substituted C3-C6 (e.g., C3-C5) alkyl. In other embodiments, R12 can be C3-C6 (e.g., C3-C5) alkyl that is substituted with an amino group (NH2) or a secondary or tertiary amino group.
In certain embodiments, R12 can be branched or unbranched C1-C6 haloalkyl (e.g., having from 1-3, 1-2, or 1 halo).
In certain embodiments, R12 can be C7-C11 aralkyl (e.g., benzyl), optionally substituted with from 1-3 (e.g., 1-2, 1) Rc.
In certain embodiments, R12 can be C6-C10 aryl, optionally substituted with from 1-2 Rd.
In some embodiments, R11 can be —W2—S(O)nNR13R14 (e.g., —W2—S(O)2NR13R14, in which n is 2). In embodiments, W2 can be a bond, i.e., R11 is connected to variable A by the sulfur (S) atom of the sulfinamide or sulfonamide group.
In certain embodiments, one or both of R13 and R14 can be hydrogen. In certain embodiments, R11 can be —S(O)2NH2.
In other embodiments, one of R13 and R14 can be hydrogen, and the other of R13 and R14 can be C1-C6 (e.g., C1-C3) alkyl optionally substituted with 1 Ra; C3-C7 cycloalkyl optionally substituted with 1 Rc; or heterocyclyl including 3-8 atoms or a heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-3 Rc.
In certain embodiments, R13 and R14 can each be, independently of one another: C1-C6 (e.g., C1-C3) alkyl optionally substituted with 1 Ra; C3-C7 cycloalkyl optionally substituted with 1 Rc; or heterocyclyl including 3-8 atoms or a heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted with from 1-3 Rc.
In still other embodiments, R13 and R14 together with the nitrogen atom to which they are attached can form a heterocyclyl including 3-8 (e.g., 3-6) atoms or a heterocycloalkenyl including 3-8 (e.g., 3-6) atoms, each of which is optionally substituted with from 1-3 (1-2, 1) Rc. In some embodiments, the heterocyclyl can further include one or more additional ring heteroatoms (e.g., N, O, or S).
In certain embodiments, R13 and R14 together with the nitrogen atom to which they are attached can form a heterocyclyl including 3-8 (e.g., 3-6, or 5-6) atoms, which is optionally substituted with from 1-3 (1-2, 1) Rc. For example, R13 and R14 together with the nitrogen atom to which they are attached can form a morpholinyl, piperidyl, pyrrolidinyl, or piperazinyl ring, each of which is optionally substituted with from 1-3 (1-2, 1) Rc.
In some embodiments, R11 can be —W2—C(O)OR15. In some embodiments, W2 can be C1-C6 alkylene; or a bond. In certain embodiments, W2 can be C1-C6 alkylene. For example, W2 can be C1-C3 alkylene, such as CH2 or CH2CH2. In other embodiments, W2 can be a bond. In some embodiments, R15 can be: (i) hydrogen; or (ii) C1-C6 (e.g., C1-C3) alkyl.
In some embodiments, R11 can be —W2—C(O)NR13R14
Embodiments can include, for example, any one or more of the features described above in conjunction with —W2—S(O)nNR13R14 and/or —W2—C(O)OR15.
In some embodiments, R11 can be: C1-C6 alkyl or C1-C6 haloalkyl, each of which is (a) substituted with from 1 Rh, and (b) optionally further substituted with from 1 or 2 Ra; or
In certain embodiments, Rh at each occurrence can be, independently, hydroxyl, C1-C6 alkoxy, C1-C6 haloalkoxy; C3-C8 cycloalkoxy, which is optionally substituted with from 1-3 Rc; or C6-C10 aryloxy or heteroaryloxy including 5-10 atoms, each of which is optionally substituted with from 1-3 Rd.
In certain embodiments, R11 can have the following formula: —C(R111)(R112)(Rh), in which each of R111 and R112 is, independently, C1-C7 alkyl or C1-C7 haloalkyl, each of which is optionally further substituted with from 1 or 2 Ra (e.g., Ra can be C3-C7 cycloalkyl, which is optionally substituted with from 1-5 Rc); and Rh can be as defined anywhere herein.
In some embodiments, R11 can be —NR16R17, one of R16 and R17 is hydrogen or C1-C3 alkyl (e.g., hydrogen); and the other of R16 and R17 can be:
(i) —S(O)nR12; or
(ii) —C(O)OR15; or
(iii) —C(O)NR13R14; or
(iv) C1-C12 alkyl or C1-C12 haloalkyl, each of which is:
In certain embodiments, one of R16 and R17 is hydrogen, and the other of R16 and R17 is —S(O)nR12.
In embodiments, each of n, R12, R13, R14, R15, Rh, Ra, and Rd can be, independently, as defined anywhere herein.
Variables R4 and R5
In some embodiments, each of R4 and R5 can be, independently:
(i) hydrogen; or
(ii) halo; or
(iii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra; or
In certain embodiments, each of R4 and R5 can be, independently:
(i) hydrogen; or
(ii) halo; or
(iii) C1-C3 alkyl or C1-C3 haloalkyl (e.g., perhaloalkyl, e.g., perfluoroalkyl), each of which is optionally substituted with from 1-3 Ra.
In certain embodiments, each of R4 and R5 can be, independently, hydrogen or halo (e.g., fluoro).
In certain embodiments, each of R4 and R5 can be hydrogen.
In certain embodiments, each of R4 and R5 can be a substituent other than hydrogen (e.g., halo, e.g., fluoro).
Variable R3 and R6
In some embodiments, one of R3 and R6 can be:
(i) halo; or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra (e.g., C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra); or
(iii) nitro; hydroxy; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; cyano; or S(O)z(C1-C3 alkyl), wherein z is 1 or 2;
and the other of R3 and R6 can be:
(i) hydrogen; or
(ii) halo; or
(iii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra (e.g., C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra); or
(iv) nitro; hydroxy; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; cyano; or S(O)z(C1-C3 alkyl), wherein z is 1 or 2.
In certain embodiments, one of R3 and R6 can be:
(i) halo; or
(ii) C1-C6 haloalkyl; or
(iii) C1-C6 alkoxy; C1-C6 haloalkoxy; or; cyano;
and the other of R3 and R6 can be:
(i) hydrogen; or
(ii) halo; or
(iii) C1-C6 haloalkyl; or
(iv) C1-C6 alkoxy; C1-C6 haloalkoxy; or cyano.
In some embodiments, one of R3 and R6 can be:
(i) halo; or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra; or
(iii) nitro; hydroxy; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; cyano; or S(O)z(C1-C3 alkyl), wherein z is 1 or 2;
and the other of R3 and R6 can be hydrogen.
In certain embodiments, one of R3 and R6 can be:
(i) halo; or
(ii) C1-C6 haloalkyl; or
(iii) C1-C6 alkoxy; C1-C6 haloalkoxy; or cyano;
and the other of R3 and R6 can be hydrogen.
In certain embodiments, one of R3 and R6 can be halo (e.g., chloro), the other of R3 and R6 can be hydrogen.
In certain embodiments, one of R3 and R6 can be C1-C4 haloalkyl (e.g., C1-C4 perfluoroalkyl, CF3), the other of R3 and R6 is hydrogen.
In certain embodiments, R3 can be hydrogen, and R6 can be CF3.
In certain embodiments, R3 can be CF3, and R6 can be hydrogen.
In some embodiments, each of R3 and R6 can be, independently:
(i) halo; or
(ii) C1-C6 alkyl or C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra (e.g., C1-C6 haloalkyl, each of which is optionally substituted with from 1-3 Ra); or
(iii) nitro; hydroxy; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; cyano; or S(O)z(C1-C3 alkyl), wherein z is 1 or 2.
In certain embodiments, each of R3 and R6 can be, independently:
(i) halo; or
(ii) C1-C6 haloalkyl; or
(iii) C1-C6 alkoxy; C1-C6 haloalkoxy; or cyano;
For example, each of R3 and R6 can be, independently, halo (e.g., chloro).
In some embodiments, each of R3 and R6 can be hydrogen.
A subset of compounds includes those in which R2 has formula (A-2):
in which:
one of R23 and R24 can be R9 (e.g., one of R23 and R24 can have formula (C-1):
in which one of RA2, RA3, RA4, RA5, and RA6 is R11, and the others are each, independently, hydrogen or Rg);
and the other of R23 and R24 is hydrogen;
and each of R22, R25, and R26 is, independently, hydrogen or Re.
In these and in the following embodiments, R22, R23, R24, R25, R26, W, RA2, RA3, RA4, RA5, RA6, R9, R11, Re, and Rg can be, independently, as defined anywhere herein. By way of example, the compounds can include one or more of the following features.
R23 can have formula (C-1), and R24 can be hydrogen.
R23 can be hydrogen, and R24 can have formula (C-1).
Each of R22, R25, and R26 can be hydrogen.
One of R22, R25, and R26 can be Re, and the other two can each be hydrogen. For example, R26 can be Re, and each of R22 and R25 can be hydrogen. Re can be: halo (e.g., chloro or fluoro); C1-C3 alkyl; or C1-C3 haloalkyl (e.g., C1-C3 fluoroalkyl, e.g., 1-5 fluorines can be present; or C1-C3 perfluoroalkyl). In certain embodiments, Re can be halo (e.g., chloro or fluoro, e.g., chloro).
W can be —O—.
W can be a bond.
One of RA3 and RA4 (e.g., RA3) can be R11, and the other of RA3 and RA4 (e.g., RA4) can be hydrogen; and each of RA2, RA5, and RA6 is, independently, hydrogen or Rg.
R11 can be —W2—S(O)nR12. W2 can be a bond. n can be 2. R12 can be C1-C6 alkyl, optionally substituted with from 1-2 Ra. For example, R12 can be C1-C3 alkyl (e.g., CH3). As another example, R12 can be C1-C6 alkyl substituted with 1 Ra, in which Ra is hydroxyl or NRmRn.
Each of RA2, RA5, and RA6 can be hydrogen.
RA5 can be hydrogen or Rg, and each of RA2 and RA6 is hydrogen. RA5 can be Rg (e.g., halo).
RA3 can be R11, RA4 can be hydrogen, and each of RA2, RA5, and RA6 can be hydrogen; or RA3 can be R11; RA4 can be hydrogen; one of RA2, RA5, and RA6 (e.g., RA5) can be Rg (e.g., halo, e.g., fluoro) and the other two of RA2, RA5, and RA6 can be hydrogen.
RA4 can be R11, RA3 can be hydrogen, and each of RA2, RA5, and RA6 can be hydrogen. RA3 can be R11; RA4 can be hydrogen; one of RA2, RA5, and RA6 can be Rg (e.g., halo) and the other two of RA2, RA5, and RA6 can be hydrogen.
R11 can be —W2—S(O)nNR13R14. W2 can be a bond, and one of R13 and R14 can be C1-C3 alkyl, and the other of R13 and R14 can be hydrogen.
Other embodiments can include one of more other features described herein and present in combination with the features delineated above.
In some embodiments, the compounds can have formula (II):
in which each of R1 and R2 can be, independently, as defined anywhere herein (generically, subgenerically, or specifically), and R6 is a substituent other than hydrogen (e.g., halo, e.g., chloro; or C1-C4 haloalkyl, e.g., C1-C4 perfluoroalkyl, e.g., CF3).
In some embodiments, the compounds can have formula (III):
in which each of R1 and R2 can be, independently, as defined anywhere herein (generically, subgenerically, or specifically), and R3 is a substituent other than hydrogen (e.g., halo, e.g., chloro; or C1-C4 haloalkyl, e.g., C1-C4 perfluoroalkyl, e.g., CF3).
In some embodiments, the compounds can have formula (IV):
in which each of R1 and R2 can be, independently, as defined anywhere herein (generically, subgenerically, or specifically).
In some embodiments, the compounds can have formula (VI):
in which each of R1, R3, R4, R5, R6, R22, R23, R24, W, and A can be, independently, as defined anywhere herein (generically, subgenerically, or specifically).
In embodiments, the compounds of formulas (II), (III), (IV), and (VI) can include any one or more of the following features.
R1 can be (i) hydrogen; or (ii) C1-C3 alkyl or C1-C3 haloalkyl; or (iii) NR7R8. For example, R1 can be C1-C3 alkyl (e.g., CH3).
One of R3 and R6 can be (i) halo; or (ii) C1-C4 haloalkyl; or (iii) C1-C6 alkoxy; C1-C6 haloalkoxy; or cyano; and the other of R3 and R6 is hydrogen. For example, one of R3 and R6 can be halo, e.g., chloro; or C1-C4 haloalkyl, e.g., C1-C4 perfluoroalkyl, e.g., CF3; and the other of R3 and R6 can be hydrogen.
Each of R4 and R5 can be hydrogen.
R2 can have formula (A), (A-1), (A-2), or (C-1) as defined anywhere herein.
W can be —O—.
W can be a bond.
In some embodiments, A can be phenyl, which is (i) substituted with 1 R11 and (ii) optionally substituted with from 1-4 (e.g., 1-3, 1-2, 1) Rg, in which Rg can be as defined anywhere herein.
A can have formula (B-1). In embodiments, one of RA3 and RA4 is R11, and the other of RA3 and RA4 is hydrogen; and each of RA2, RA5, and RA6 is, independently, hydrogen or Rg, in which R11 and Rg can be as defined anywhere herein.
Each of Re, R11, and Rg can be, independently, as defined anywhere herein.
R11 can be —W2—S(O)nR12 or —W2—S(O)nNR13R14 (e.g., —W2—S(O)nR12).
Each of R12, R13, R14, and R15 can be, independently, as defined anywhere herein (e.g., as defined in conjunction with formula (C-1)).
W2, n, R22, R23, R24, RA2, RA3, RA4, RA5, and RA6 can be as defined in conjunction with formula (C-1).
It is understood that the actual electronic structure of some chemical entities cannot be adequately represented by only one canonical form (i.e. Lewis structure). While not wishing to be bound by theory, the actual structure can instead be some hybrid or weighted average of two or more canonical forms, known collectively as resonance forms or structures. Resonance structures are not discrete chemical entities and exist only on paper. They differ from one another only in the placement or “localization” of the bonding and nonbonding electrons for a particular chemical entity. It can be possible for one resonance structure to contribute to a greater extent to the hybrid than the others. Thus, the written and graphical descriptions of the embodiments of the present invention are made in terms of what the art recognizes as the predominant resonance form for a particular species.
The compounds described herein can be synthesized according to methods described herein (or variations thereof) and/or conventional, organic chemical synthesis methods from commercially available starting materials and reagents or from starting materials and reagents that can be prepared according to conventional organic chemical synthesis methods. The compounds described herein can be separated from a reaction mixture and further purified by a method such as column chromatography, high-performance liquid chromatography (HPLC), or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those skilled in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. C. Larock, Comprehensive Organic Transformations, 2d. ed., Wiley-VCH Publishers (1999); P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4th Ed., John Wiley and Sons (2007); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.
The compounds of this invention can be readily prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. The schemes show the preparation of representative compounds of this invention. It is also possible to make use of variants of these process steps, which in themselves are known to and well within the preparatory skill of the skilled artisan. In the following reaction schemes, R1 to R6, and A are selected from groups defined above.
According to Scheme 1, quinoxalines can be prepared by condensation of 1,2-dioxoalkanes 1 with 1,2-diaminobenzenes 2, typically in a solvent such as ethanol at temperatures, typically 0 to 120° C. These reaction conditions typically provide a mixture of regioisomers 3 and 4 which can be separated by a method such as column chromatography, high-performance liquid chromatography (HPLC), or recrystallization. The structure of 3 and 4 can be assigned by NMR techniques such as 1H-13C HMBC, 1H-1H nOe. In compounds 3 and 4, in which T is a protected hydroxyl group such as a methoxy or benzyloxy, deprotection of the hydroxyl group leads to compounds 5 and 6, respectively. Typical conditions for deprotection when T is a methoxy include treatment with HBr or treatment with BBr3 at elevated temperatures, typically 60-150° C., for 0.1 to 24 h, or other methods known to those skilled in the art. Phenols 5 and 6 can be converted to triflates 7 and 8, respectively, using triflic anhydride or N-phenylbis(trifluoromethanesulfonamide) in the presence of a base such as triethylamine or potassium carbonate. The resulting triflates 7 and 8 can be coupled to an aryl boronic acid or ester under catalysis with a palladium catalyst, a reaction known as a Suzuki reaction to those skilled in the art, to give the biaryl derivatives 9 and 10, respectively.
Alternatively, according to Scheme 2, the phenol 5 and 6 can be treated with a halogenated aromatic ring-containing compound X-A (where X is a halogen) to provide biarylether 11 and 12, respectively. If the halogen is a fluorine or chlorine atom, the formation of the biarylether can be accomplished by treatment with a base such as potassium carbonate, typically in a polar solvent such as dimethylformamide or dimethylsulfoxide, at elevated temperatures, typically 100° C. to 150° C. for 1 to 48 hours. Alternatively, where the halogen is a bromine or iodine, the formation of the biarylether can be accomplished with a coupling reaction using a metal catalyst such as a copper salt or a palladium salt in the presence of a base and a solvent such as dioxane at elevated temperatures.
Alternatively, according to Scheme 3, quinoxalines can be prepared by condensation of biaryl 1,2-dioxoalkanes such as 13 with 1,2-diaminobenzenes 2, typically in a solvent such as ethanol at temperatures, typically 0 to 120° C.
Alternatively, according to Scheme 4, quinoxalines can be prepared by amination of aldehydes such as 14 with 1,2-diaminobenzenes 2, typically in a solvent such as ethanol at temperatures, typically 0 to 120° C. Treatment of the resulting imine 15 with a reagent such as potassium cyanide in a solvent like methanol provides amino quinoxalines 16. This can then be coupled to an aryl boronic acid or ester under catalysis with a palladium catalyst, a reaction known as a Suzuki reaction to those skilled in the art, to give the biaryl derivatives 17.
According to Scheme 5 condensation of diamine 2 with bis-carbonyls such as pyruvates or glyoxalates gives quinoxalinones such as 18, along with the undesired isomer. 18 can be treated with chlorinating agents under standard conditions to provide the chloro-quinoxalines 19. Under basic conditions these can be treated with phenols to provide quinoxaline ethers such as 20 which can be substituted using an aryl boronic acid or ester under catalysis with a palladium catalyst to provide 21. Quinoxaline amines (analogs of 21 in which the —O— linkage is replaced with —NH—) can be made by analogous procedures using anilines in place of phenols.
The compounds of this invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of this invention may also contain linkages (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring or double bond. Accordingly, all cis/trans and E/Z isomers and rotational isomers 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, even though only a single tautomeric form may be represented (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.
The compounds of this invention include the compounds themselves, as well as their salts and their prodrugs, if applicable. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. Examples of prodrugs include C1-6 alkyl esters of carboxylic acid groups, which, upon administration to a subject, are capable of providing active compounds.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)4+ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Salt forms of the compounds of any of the formulae herein can be amino acid salts of carboxy groups (e.g. L-arginine, -lysine, -histidine salts).
The term “pharmaceutically acceptable carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a subject (e.g., a patient), together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
In general, the compounds described herein can be used for, treating (e.g., controlling, relieving, ameliorating, alleviating, slowing the progression of, delaying the onset of, or reducing the risk of developing) or preventing one or more diseases, disorders, conditions or symptoms mediated by LXRs (e.g., cardiovascular diseases (e.g., acute coronary syndrome, restenosis, or coronary artery disease), atherosclerosis, atherosclerotic lesions, type I diabetes, type II diabetes, Syndrome X, obesity, lipid disorders (e.g., dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL), cognitive disorders (e.g., Alzheimer's disease, dementia), inflammatory diseases (e.g., multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, endometriosis, LPS-induced sepsis, acute contact dermatitis of the ear, chronic atherosclerotic inflammation of the artery wall), celiac, thyroiditis, skin aging (e.g., skin aging is derived from chronological aging, photoaging, steroid-induced skin thinning, or a combination thereof), or connective tissue disease (e.g., osteoarthritis or tendonitis).
A disorder or physiological condition that is mediated by LXR refers to a disorder or condition wherein LXR can trigger the onset of the condition, or where inhibition of a particular LXR can affect signaling in such a way so as to treat, control, ameliorate, alleviate, prevent, delay the onset of, slow the progression of, or reduce the risk of developing the disorder or condition. Examples of such disorders include, but are not limited to cardiovascular diseases (e.g., acute coronary syndrome, restenosis, or coronary artery disease), atherosclerosis, atherosclerotic lesions, type I diabetes, type II diabetes, Syndrome X, obesity, lipid disorders (e.g., dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL), cognitive disorders (e.g., Alzheimer's disease, dementia), inflammatory diseases (e.g., multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, endometriosis, LPS-induced sepsis, acute contact dermatitis of the ear, chronic atherosclerotic inflammation of the artery wall), celiac, thyroiditis, skin aging (e.g., skin aging is derived from chronological aging, photoaging, steroid-induced skin thinning, or a combination thereof), or connective tissue disease (e.g., osteoarthritis or tendonitis).
While not wishing to be bound by theory, it is believed that LXR modulators that activate cholesterol efflux (e.g., upregulate ABCA1), but do not substantially increase SREBP-1c expression and triglyceride synthesis in liver, can both reduce atherosclerotic risk and minimize the likelihood of concommitantly increasing serum and hepatic triglyceride levels. Candidate compounds having differential activity for regulating ABCA1 (ABCG1) vs. SREBP-1c can be can be evaluated using conventional pharmacological test procedures, which measure the affinity of a candidate compound to bind to LXR and to upregulate the gene ABCA1.
In some embodiments, LXR ligands can be identified initially in cell-free LXR beta and LXR alpha competition binding assays. LXR ligands can be further characterized by gene expression profiling for tissue selective gene regulation.
In some embodiments, the compounds described herein have agonist activity for ABCA1 transactivation but do not substantially affect (e.g., inhibit) SREBP-1c gene expression in differentiated THP-1 macrophages. Gene expression analysis in an antagonist mode can be used to further delineate differential regulation of ABCA1 and SREBP-1c gene expression. In certain embodiments, the compounds described herein preferentially antagonize SREBP-1c activation (a marker for genes involved in cholesterol and fatty acid homeostasis) but do not substantially affect (e.g., have relatively minimal or additive effects) on ABCA1 gene expression or genes known to enhance HDL biogenesis (based on a competition assay with known potent synthetic LXR agonists). Cell type or tissue specificity may be further evaluated in additional cell lines, intestinal, CaCo2 or liver, HepG2 and Huh-7 cells where ABCA1 activity is believed to influence net cholesterol absorption and reverse cholesterol transport. The test procedures performed, and results obtained therefrom are described in the Examples section.
In some embodiments, the compounds described herein have agonist activity for ABCA1 and antagonist activity for SREBP-1c (e.g., as determined by gene specific modulation in cell based assays). In certain embodiments, the compounds described herein (in the agonist mode) have at least about 20% efficacy for ABCA1 activation by LXR and do not substantially agonize SREBP-1c (at most about 25% efficacy relative to a reference compound N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-benzenesulfonamide (Schultz, Joshua R., Genes & Development (2000), 14(22), 2831-2838)). In certain embodiments, the compounds described herein (in the antagonist mode) do not substantially antagonize ABCA1 gene expression. While not wishing to be bound by theory, it is believed that there may be an additive effect on ABCA1 gene expression relative to the reference compound at their EC50 concentration. In certain embodiments, the compounds described herein (in the antagonist mode) inhibited agonist-mediated SREBP-1c gene expression in a dose dependent fashion.
In some embodiments, to study the effect of the compounds of formula (I) on skin aging, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of TIMP1, ABCA12, decorin, TNFα, MMP1, MMP3, and/or IL-8. The levels of gene expression (i.e., a gene expression pattern) can be quantified, for example, by Northern blot analysis or RT-PCR, by measuring the amount of protein produced, or by measuring the levels of activity of TIMP1, ABCA12, decorin, TNFα, MMP1, MMP3, and/or IL-8, all by methods known to those of ordinary skill in the art. In this way, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the compounds of formula (I). Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the compounds of formula (I).
In one embodiment, expression levels of cytokines and metalloproteases described herein can be used to facilitate design and/or identification of compounds that treat skin aging through an LXR-based mechanism. Accordingly, the invention provides methods (also referred to herein as “screening assays”) for identifying modulators, i.e., LXR modulators, that have a stimulatory or inhibitory effect on, for example, TIMP1, ABCA12, decorin, TNFα, MMP1, MMP3, and/or IL-8 expression.
An exemplary screening assay is a cell-based assay in which a cell that expresses LXR is contacted with a test compound, and the ability of the test compound to modulate TIMP1, ABCA12, decorin, TNFα, MMP1, MMP3, and/or IL-8 expression through an LXR-based mechanism. Determining the ability of the test compound to modulate TIMP1, ABCA12, decorin, TNFα, MMP1, MMP3, and/or IL-8 expression can be accomplished by monitoring, for example, DNA, mRNA, or protein levels, or by measuring the levels of activity of TIMP1, ABCA12, decorin, TNFα, MMP1, MMP3, and/or IL-8, all by methods known to those of ordinary skill in the art. The cell, for example, can be of mammalian origin, e.g., human.
In some embodiments, to study the effect of the compounds of formula (I) on osteoarthritis, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of ApoD and other genes implicated in osteoarthritis (for example, TNFα). The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, by measuring the amount of protein produced, or by measuring the levels of activity of ApoD or other genes, all by methods known to those of ordinary skill in the art. In this way, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the LXR modulator. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the LXR modulator.
An exemplary screening assay is a cell-based assay in which a cell that expresses LXR is contacted with a test compound, and the ability of the test compound to modulate ApoD expression and/or aggrecanase activity and/or cytokine elaboration through an LXR-based mechanism. Determining the ability of the test compound to modulate ApoD expression and/or aggrecanase activity and/or cytokine elaboration can be accomplished by monitoring, for example, DNA, mRNA, or protein levels, or by measuring the levels of activity of ApoD, aggrecanase, and/or TNFα, all by methods known to those of ordinary skill in the art. The cell, for example, can be of mammalian origin, e.g., human.
In some embodiments, the compounds described herein can be coadministered with one or more other therapeutic agents. In certain embodiments, the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention (e.g., sequentially, e.g., on different overlapping schedules with the administration of one or more compounds of formula (I) (including any subgenera or specific compounds thereof)). In other embodiments, these agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. In still another embodiment, these agents can be given as a separate dose that is administered at about the same time that one or more compounds of formula (I) (including any subgenera or specific compounds thereof) are administered (e.g., simultaneously with the administration of one or more compounds of formula (I) (including any subgenera or specific compounds thereof)). When the compositions of this invention include a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent can be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
The compounds and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intraarterially, intrasynovially, intrasternally, intrathecally, intralesionally and by intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, by injection, subdermally, intraperitoneally, transmucosally, or in an ophthalmic preparation, with a dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg, from about 1 to about 10 mg/kg) every 4 to 120 hours, or according to the requirements of the particular drug. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep. 50, 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). In certain embodiments, the compositions are administered by oral administration or administration by injection. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.
Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.
Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
The compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
The compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may 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 may 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 may 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. For this purpose, any bland fixed oil may be employed including 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 may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The compositions of this invention may be orally administered in 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 and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation.
In some embodiments, topical administration of the compounds and compositions described herein may be presented in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution. By the term “a semi-solid composition” is meant an ointment, cream, salve, jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970) and in Chapter 67 of Remington's Pharmaceutical Sciences, 21st Edition (2005) published by Mack Publishing Company, which is incorporated herein by reference in its entirety.
Topically-transdermal patches are also included in this invention. Also within the invention is a patch to deliver active chemotherapeutic combinations herein. A patch includes a material layer (e.g., polymeric, cloth, gauze, bandage) and the compound of the formulae herein as delineated herein. One side of the material layer can have a protective layer adhered to it to resist passage of the compounds or compositions. The patch can additionally include an adhesive to hold the patch in place on a subject. An adhesive is a composition, including those of either natural or synthetic origin, that when contacted with the skin of a subject, temporarily adheres to the skin. It can be water resistant. The adhesive can be placed on the patch to hold it in contact with the skin of the subject for an extended period of time. The adhesive can be made of a tackiness, or adhesive strength, such that it holds the device in place subject to incidental contact, however, upon an affirmative act (e.g., ripping, peeling, or other intentional removal) the adhesive gives way to the external pressure placed on the device or the adhesive itself, and allows for breaking of the adhesion contact. The adhesive can be pressure sensitive, that is, it can allow for positioning of the adhesive (and the device to be adhered to the skin) against the skin by the application of pressure (e.g., pushing, rubbing,) on the adhesive or device.
The compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may 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 composition having the compound of the formulae herein and an additional agent (e.g., a therapeutic agent) can be administered using any of the routes of administration described herein. In some embodiments, a composition having the compound of the formulae herein and an additional agent (e.g., a therapeutic agent) can be administered using an implantable device. Implantable devices and related technology are known in the art and are useful as delivery systems where a continuous, or timed-release delivery of compounds or compositions delineated herein is desired. Additionally, the implantable device delivery system is useful for targeting specific points of compound or composition delivery (e.g., localized sites, organs). Negrin et al., Biomaterials, 22(6):563 (2001). Timed-release technology involving alternate delivery methods can also be used in this invention. For example, timed-release formulations based on polymer technologies, sustained-release techniques and encapsulation techniques (e.g., polymeric, liposomal) can also be used for delivery of the compounds and compositions delineated herein.
The invention will be further described in the following examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
The following describes the preparation of representative compounds of this invention. Compounds described as homogeneous are determined to be of 90% or greater purity (exclusive of enantiomers) by analytical reverse phase chromatographic analysis with 254 nM UV detection. Melting points are reported as uncorrected in degrees centigrade. Mass spectral data is reported as the mass-to-charge ratio, m/z; and for high resolution mass spectral data, the calculated and experimentally found masses, [M+H]+, for the neutral formulae M are reported. All reactions are stirred and run under a nitrogen atmosphere unless otherwise noted. Eluents for chromatography are indicated by E for ethyl acetate and H for hexanes. Thus, for example, the expression “30:70 E:H” refers to a mixture of 30% ethyl acetate and 70% hexanes by volume.
Step 1: A mixture of 2-nitro-3-(trifluoromethyl)aniline (2.6 g, 12.6 mmol), ethanol (20 mL) and 10% Pd/C (1.0 g) was pressurized with 25 psi H2 for 1.5 hours. The catalyst was then removed by filtering through a short pad of celite. The filtrate was used for the next reaction with out any purification.
Step 2: 1-(4-Methoxyphenyl)propane-1,2-dione (2.5 g, 14.0 mmol) was added to the solution of 3-(trifluoromethyl)benzene-1,2-diamine in ethanol which was obtained from Step 1. The mixture was stirred at room temperature for 1 hour and the solvent was removed. The residue was purified by flash chromatography eluted with EtOAc/hexane to give 2-(4-methoxyphenyl)-3-methyl-5-(trifluoromethyl)quinoxaline as a pale yellow solid (1.4 g, 35% for two steps); MS (ES) m/z 319.1. The regio isomer 3-(4-methoxyphenyl)-2-methyl-5-(trifluoromethyl)quinoxaline (2.0 g, 50%) was also isolated from the reaction mixture.
Step 3: A mixture of 2-(4-methoxyphenyl)-3-methyl-5-(trifluoromethyl)quinoxaline (1.4 g, 4.39 mmol), HBr (48% in water, 20 mL) in 20 mL of acetic acid was heated to 90° C. over night. 7 mL of HBr (45%) in acetic acid was added and the reaction mixture was heated to reflux for 5 hours. The reaction mixture was poured into ice, extracted with EtOAc. The organic was concentrated and purified by flash chromatography eluted with EtOAc/hexane to give 4-[3-methyl-5-(trifluoromethyl)quinoxalin-2-yl]phenol (1.20 g, 90%) as a gummy solid; MS (ESI) m/z 305.1; HRMS: calcd for C16H11F3N2O+H+, 305.08962. found (ESI, [M+H]+Obs'd), 305.0894.
Step 4: A mixture of 4-[3-methyl-5-(trifluoromethyl)quinoxalin-2-yl]phenol (1.20 g, 3.93 mmol), anhydrous THF (40 mL), and N-phenylbis(trifluoromethanesulphonimide) (2.11 g, 5.93 mmol) was cooled to 0° C. upon which potassium tert-butoxide (0.62, 5.53 mmol) was added. The resulting mixture was stirred at 0° C. for 1 hour. Another portion of N-phenylbis(trifluoromethanesulphonimide) (2.11 g, 5.93 mmol) and potassium tert-butoxide (0.62, 5.53 mmol) was added. After 1 more hour the reaction was quenched with water, partitioned between water and EtOAc, and the organic was dried over MgSO4. The residue was subjected to flash silica gel chromatography (hexane:EtOAc) to afford 4-[3-methyl-5-(trifluoromethyl)quinoxalin-2-yl]phenyl trifluoromethanesulfonate (1.2 g, 65%) as a colored solid; MS (ES) m/z 436.9.
Step 5: A mixture of 4-[3-methyl-5-(trifluoromethyl)quinoxalin-2-yl]phenyl trifluoromethanesulfonate (1.2 g, 2.75 mmol), 3-methylsulfonylphenyl boronic acid (2.4 g, 12 mmol), K3PO4 (5.0 g, 23.6 mmol), Pd(PPh3)4 (0.5 g, 0.43 mmol) in 40 mL of dioxane was heated to 80° C. for 1 hour. The reaction mixture was poured into water, extracted with EtOAc. The organic was concentrated and purified by flash chromatography eluted with EtOAc/hexane to give the title compound (0.59 g, 48%) as a white solid; MS (ES) m/z 443.0; HRMS: calcd for C23H17F3N2O2S+H+, 443.10356. found (ESI, [M+H]+Obs'd), 443.1040.
Step 1: In a reaction flask equipped with a magnetic stir bar under CaSO4 tube was placed 3-(trifluoromethyl)benzene-1,2-diamine (750 mg, 4.261 mmol) and 1-(3-methoxyphenyl)propane-1,2-dione (910 mg, 5.114 mmol) in 2-propanol (50 ml). The resulting dark red solution was heated at reflux for 1.5 h. Cooling to room temperature upon which the dark red solution was concentrated in vacuo to a dark red powder. To this same power purification by SiO2 chromatography (Hex:EtOAc) and concentration in vacuo of the cleanest fractions afforded two regio isomers. The second isolated product being 2-(3-methoxyphenyl)-3-methyl-5-(trifluoromethyl)quinoxaline as a red powder (0.512 g, 38% yield). MS (ES) m/z 319.0.
Step 2: In a reaction vial equipped with a magnetic stir bar was placed 2-(3-methoxyphenyl)-3-methyl-5-(trifluoromethyl)quinoxaline (400 mg, 1.258 mmol) and Hydrobromic acid 48% in HOAc (10 ml). The vial was tightly capped and heated at 90° C. for 2 h. Cooling to room temperature upon which pouring into H2O (20 ml) and EtOAc (10 ml). Neutralization with solid NaHCO3 until pH<7. Extraction, separation and extraction of the aqueous layer with EtOAc (20 ml). All organics combined, dried MgSO4, filtration concentration in vacuo to a red powder. To this same power purification by SiO2 chromatography (Hex:EtOAc) and concentration in vacuo of the cleanest fractions afforded 3-[3-methyl-5-(trifluoromethyl)quinoxalin-2-yl]phenol as a red powder (346 mg, 90% yield). MS (ES) m/z 304.7; HRMS: calcd for C16H11F3N2O+H+, 305.08962. found (ESI, [M+H]+ Obs'd), 305.0899.
Step 3: To a reaction vial suitable for microwave reactions containing a magnetic stir bar was placed 3-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenol (50 mg, 0.164 mmol), 1-fluoro-3-(methylsulfonyl)benzene (57 mg, 0.328 mmol) and K2CO3 (68 mg, 0.493 mmol) in DMA (4 ml). The vial was capped put in a microwave reactor (Personal Chemistry unit) and the sample was irradiated at 180° C. for 1 h. Cooling to room temperature and partition between EtOAc and H2O (5 ml each), extraction, separation, extraction of the aqueous layer with EtOAc (4 ml). All organics combined, dried MgSO4, filtration concentration in vacuo to a brown powder. To this same powder was purified by RP-HPLC (H2O:AcCN) to afford the title compound as a red powder (36 mg, 48% yield). MS (ES) m/z 459.0; HRMS: calcd for C23H17F3N2O3S+H+, 459.09847. found (ESI, [M+H]+ Obs'd), 459.0984.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 3-(3-methyl-8-(trifluoromethyl)quinoxalin-2-yl)phenol in place of 3-[3-methyl-5-(trifluoromethyl)quinoxalin-2-yl]phenol; MS (ES) m/z 459.0; HRMS: calcd for C23H17F3N2O3S+H+, 459.09847. found (ESI, [M+H]+ Obs'd), 459.0988.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-(4-methoxyphenyl)-2-methyl-5-(trifluoromethyl)quinoxaline in place of 2-(4-methoxyphenyl)-3-methyl-5-(trifluoromethyl)quinoxaline; MS (ES) m/z 443.0; HRMS: calcd for C23H17F3N2O2S+H+, 443.10356. found (ESI, [M+H]+ Obs'd), 443.1034.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 3-chlorobenzene-1,2-diamine in place of 3-(trifluoromethyl)benzene-1,2-diamine; MS (ES) m/z 390.6; HRMS: calcd for C22H17ClN2O3S+H+, 425.07212. found (ESI, [M+H]+ Obs'd), 425.0719.
Step 1: 3-(2-fluoro-4-methoxyphenyl)-2-methyl-5-(trifluoromethyl)quinoxaline was prepared using a procedure analogous to that described in Example 1 Step 2 but using 1-(2-fluoro-4-methoxyphenyl)propane-1,2-dione in place of 1-(4-methoxyphenyl)propane-1,2-dione; MS (ESI) m/z 337.1; HRMS: calcd for C17H12F4N2O+H+, 337.09585. found (ESI, [M+H]+ Obs'd), 337.0963.
Step 2: 3-fluoro-4-[3-methyl-8-(trifluoromethyl)quinoxalin-2-yl]phenol was prepared using a procedure analogous to that described in Example 1 Step 3 but using 3-(2-fluoro-4-methoxyphenyl)-2-methyl-5-(trifluoromethyl)quinoxaline in place of 2-(4-methoxyphenyl)-3-methyl-5-(trifluoromethyl)quinoxaline; MS (ESI) m/z 323.1; HRMS: calcd for C16H10F4N2O+H+, 323.08020. found (ESI, [M+H]+ Obs'd), 323.0802.
Step 3: The title compound was prepared using procedures analogous to those described in Example 1 Step 4 and Step 5 but using 3-fluoro-4-[3-methyl-8-(trifluoromethyl)quinoxalin-2-yl]phenol in place of 4-[3-methyl-5-(trifluoromethyl)quinoxalin-2-yl]phenol; MS (ESI) m/z 461.1; HRMS: calcd for C23H16F4N2O2S+H+, 461.09414. found (ESI, [M+H]+ Obs'd), 461.0943.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 4-(3-methyl-8-(trifluoromethyl)quinoxalin-2-yl)phenol in place of 3-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenol; MS (ES) m/z 459.0.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 2-(4-methoxyphenyl)-2-oxoacetaldehyde in place of 1-(4-methoxyphenyl)propane-1,2-dione; HRMS: calcd for C21H15ClN2O3S+H+, 411.05647. found (ESI, [M+H]+ Obs'd), 411.0569.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 2-(4-methoxyphenyl)-2-oxoacetaldehyde in place of 1-(4-methoxyphenyl)propane-1,2-dione; MS (ES) m/z 444.9.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 3-(8-chloro-3-methylquinoxalin-2-yl)phenol in place of 3-(3-methyl-5-(trifluoromethyl)-quinoxalin-2-yl)phenol; HRMS: calcd for C22H17ClN2O3S+H+, 425.07212. found (ESI, [M+H]+ Obs'd), 425.0719.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 4-(8-(trifluoromethyl)quinoxalin-2-yl)phenol and 3-(3-fluorophenylsulfonyl)propan-1-ol in place of 3-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenol and 1-fluoro-3-(methylsulfonyl)-benzene; MS (ES) m/z 488.9.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 4-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenol in place of 3-(3-methyl-5-(trifluoro-methyl)quinoxalin-2-yl)phenol; MS (ES) m/z 458.9.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 3-(8-chloroquinoxalin-2-yl)phenol in place of 3-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenol; MS (ES) m/z 410.5.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 3-(5-(trifluoromethyl)quinoxalin-2-yl)phenol in place of 3-(3-methyl-5-(trifluoromethyl)-quinoxalin-2-yl)phenol; MS (ES) m/z 445.0.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 4-(3-methyl-8-(trifluoromethyl)quinoxalin-2-yl)phenol and 1-(ethylsulfonyl)-3-fluorobenzene in place of 3-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenol and 1-fluoro-3-(methylsulfonyl)-benzene; MS (ES) m/z 473.0.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 3-(8-(trifluoromethyl)quinoxalin-2-yl)phenol and 1-(ethylsulfonyl)-3-fluorobenzene in place of 3-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenol and 1-fluoro-3-(methylsulfonyl)benzene; MS (ES) m/z 459.0.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 3-(8-(trifluoromethyl)quinoxalin-2-yl)phenol and 1-fluoro-3-(isobutylsulfonyl)benzene in place of 3-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenol and 1-fluoro-3-(methylsulfonyl)benzene; MS (ES) m/z 487.0.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 4-methylsulfonylphenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ES) m/z 443.0; HRMS: calcd for C23H17F3N2O2S+H+, 443.10356. found (ESI, [M+H]+ Obs'd), 443.1039.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 1-(3-methoxyphenyl)propane-1,2-dione in place of 1-(4-methoxyphenyl)propane-1,2-dione; MS (ES) m/z 443.0; HRMS: calcd for C23H17F3N2O2S+H+, 443.10356. found (ESI, [M+H]+ Obs'd), 443.1037.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 1-(3-methoxyphenyl)propane-1,2-dione and 4-methylsulfonylphenylboronic acid in place of 1-(4-methoxyphenyl)propane-1,2-dione and 3-methylsulfonylphenylboronic acid; HRMS: calcd for C23H17F3N2O2S+H+, 443.10356. found (ESI, [M+H]+ Obs'd), 443.1038.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 1-(4-methoxyphenyl)propane-1,2-dione and 2-methylsulfonylphenylboronic acid in place of 1-(3-methoxyphenyl)propane-1,2-dione and 3-methylsulfonylphenylboronic acid; HRMS: calcd for C23H7F3N2O2S+H+, 443.10356. found (ESI, [M+H]+ Obs'd), 443.1043.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 2-(4-methoxyphenyl)-2-oxoacetaldehyde in place of 1-(3-methoxyphenyl)propane-1,2-dione; HRMS: calcd for C22H15F3N2O2S+H+, 429.08791. found (ESI, [M+H]+ Obs'd), 429.0883.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 2-(4-methoxyphenyl)-2-oxoacetaldehyde and 4-methylsulfonylphenylboronic acid in place of 1-(3-methoxyphenyl)propane-1,2-dione and 3-methylsulfonylphenylboronic acid; HRMS: calcd for C22H15F3N2O2S+H+, 429.08791. found (ESI, [M+H]+ Obs'd), 429.0873.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 2-(4-methoxyphenyl)-2-oxoacetaldehyde and 2-methylsulfonylphenylboronic acid in place of 1-(3-methoxyphenyl)propane-1,2-dione and 3-methylsulfonylphenylboronic acid; HRMS: calcd for C22H15F3N2O2S+H+, 429.08791. found (ESI, [M+H]+ Obs'd), 429.0873.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 2-(4-methoxyphenyl)-2-oxoacetaldehyde in place of 1-(3-methoxyphenyl)propane-1,2-dione; HRMS: calcd for C22H15F3N2O2S+H+, 429.08791. found (ESI, [M+H]+ Obs'd), 429.0874.
Step 1: Benzene-1,2-diamine (1.08 g, 10 mmol) and methyl 3,3,3-trifluoro-2-oxopropanoate (1.70 g, 10 mmol) were heated in ethanol (10 mL) to reflux for 1 hour. The reaction was cooled to room temperature and the product was filtered to give 3-(trifluoromethyl)quinoxalin-2-ol as a pale yellow solid (1.50 g); HRMS: calcd for C9H5F3N2O+H+, 215.04267. found (ESI, [M+H]+ Obs'd), 215.0426.
Step 2: 3-(Trifluoromethyl)quinoxalin-2-ol (1.0 g, 4.67 mmol) and PCl5 (2 g) was heated to reflux in phosphorus oxychloride (30 mL) for 1 hour. The reaction was concentrated and purified by column chromatography, eluting with a gradient of 0-100% ethyl acetate in hexane to afford 2-chloro-3-(trifluoromethyl)quinoxaline as a white solid (0.6 g).
Step 3: A mixture of 2-chloro-3-(trifluoromethyl)quinoxaline (0.6 g, 2.59 mmol), 4-hydroxylphenyl boronic acid (1.2 g, 8.7 mmol), K3PO4 (3.0 g, 14.2 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.4 g, 0.98 mmol), Pd(OAc)2 (0.2 g, 0.90 mmol) in 10 mL of 1-butanol was heated to 80° C. for 30 minutes. The reaction mixture was concentrated and purified by flash chromatography eluted with EtOAc/hexane to give 4-(3-(trifluoromethyl)quinoxalin-2-yl)phenol (0.35) as a pale yellow solid; MS (ESI) m/z 291.1; HRMS: calcd for C15H9F3N2O+H+, 291.07397. found (ESI, [M+H]+ Obs'd), 291.0745.
Step 4: The title compound was prepared using a procedure analogous to that described in Example 1 but using 4-(3-(trifluoromethyl)quinoxalin-2-yl)phenol in place of 4-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenol; MS (ESI) m/z 429.1; HRMS: calcd for C22H15F3N2O2S+H+, 429.08791. found (ESI, [M+H]+ Obs'd), 429.0877.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 4-(3-(trifluoromethyl)quinoxalin-2-yl)phenol in place of 3-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenol; MS (ESI) m/z 445.1; HRMS: calcd for C22H15F3N2O3S+H+, 445.08282. found (ESI, [M+H]+ Obs'd), 445.0828.
Step 1: 1-(2-Fluoro-4-methoxyphenyl)propan-2-one was oxidized with pyridinium chlorochromate in the presence of pyridine in CH2Cl2 to give 1-(2-fluoro-4-methoxyphenyl)propane-1,2-dione (55%).
Step 2: The title compound was prepared using a procedure analogous to that described in Example 1 but using 1-(2-fluoro-4-methoxyphenyl)propane-1,2-dione in place of 1-(4-methoxyphenyl)propane-1,2-dione; MS (ESI) m/z 461.1; HRMS: calcd for C23H16F4N2O2S+H+, 461.09414. found (ESI, [M+H]+ Obs'd), 461.0943.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-fluoro-4-methoxyphenyl)propane-1,2-dione in place of 1-(3-methoxyphenyl)propane-1,2-dione; MS (ESI) m/z 477.1; HRMS: calcd for C23H16F4N2O3S+H+, 477.08905. found (ESI, [M+H]+ Obs'd), 477.0898.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-fluoro-4-methoxyphenyl)propane-1,2-dione in place of 1-(3-methoxyphenyl)propane-1,2-dione; MS (ESI) m/z 477.1; HRMS: calcd for C23H16F4N2O3S+H+, 477.08905. found (ESI, [M+H]+ Obs'd), 477.0895.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-ethylsulfonylphenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ESI) m/z 457.2; HRMS: calcd for C24H19F3N2O2S+H+, 457.11921. found (ESI, [M+H]+ Obs'd), 457.1199.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 1-(4-methoxyphenyl)butane-1,2-dione in place of 1-(4-methoxyphenyl)propane-1,2-dione; MS (ESI) m/z 457.1; HRMS: calcd for C24H19F3N2O2S+H+, 457.11921. found (ESI, [M+H]+ Obs'd), 457.1191.
Step 1: 3-(Trifluoromethyl)benzene-1,2-diamine (1.28 g, 1.46 mmol) and 4-bromobenzaldehyde (0.257 g, 1.46 mmol) were warmed in anhydrous ethanol (30 mL) to 50° C., under a nitrogen atmosphere, for 8 hours. The solvent was removed, in vacuo, to give an amber colored oil (468 mg, 93% Yield). This crude imine was used, as is, in the next reaction.
Step 2: E,Z—N1-(4-Bromobenzylidene)-3-(trifluoromethyl)benzene-1,2-diamine (150 mg, 0.437 mmol) and potassium cyanide (43 mg, 0.656 mmol) were stirred in anhydrous dimethylformamide at room temperature in a sealed vial for 18 hours. The reaction was partitioned between ethyl acetate and water and the organic phase dried (MgSO4), filtered and the solvent removed, in vacuo, to give a tan solid which was adsorbed onto silica and purified by column chromatography, eluting with a gradient of 0% to 100% CH2Cl2/hexane to afford a light yellow solid (16 mg, 10% Yield). HRMS: calcd for C15H9BrF3N3+H+, 368.0005. found (ESI, [M+H]+, 368.0004.
Step 3: 3-(4-Bromophenyl)-8-(trifluoromethyl)quinoxalin-2-amine (11 mg, 0.030 mmol), 3-(methylsulfonyl)phenylboronic acid (18 mg, 0.090 mmol), potassium phosphate (19 mg, 0.090 mmol), and tetrakis(triphenylphosphine) palladium (0) (10 mg, 0.090 mmol) were heated in anhydrous 1,4-dioxane in a sealed vial to 80° C. for 18 hours. The reaction was allowed to cool to room temperature and adsorbed onto silica and purified by column chormatography, eluting with a gradient of 0-50% ethyl acetate in hexane to afford an off white solid (5 mg, 38% Yield); MS (ESI) m/z 444.1; HRMS: calcd for C22H16F3N3O2S+H+, 444.09881. found (ESI, [M+H]+ Obs'd), 444.0996.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 1-(4-methoxyphenyl)butane-1,2-dione in place of 1-(4-methoxyphenyl)propane-1,2-dione; MS (ESI) m/z 457.1; HRMS: calcd for C24H19F3N2O2S+H+, 457.11921. found (ESI, [M+H]+ Obs'd), 457.1200.
Step 1: To a solution of 1-(4-chlorophenyl)propane-1,2-dione (0.2 g, 1.1 mmol) in THF (10 mL) under N2 was added potassium fluoride (0.19 g, 3.3 mmol), palladium (II) acetate (0.024 g, 0.11 mmol), 2-(dicyclohexylphosphino)biphenyl (0.08 g, 0.22 mmol) and 3-methylsulfonylphenyl boronic acid (0.33 g, 1.65 mmol). The reaction mixture was allowed to stir at room temperature for 18 then diluted with EtOAc, washed with water then dried (Na2SO4), filtered and chromatographed on silica (EtOAc/hexane gradient) to give 1-(3′-(methylsulfonyl)biphenyl-4-yl)propane-1,2-dione (0.07 g, 20%) as a yellow oil. MS (ES) m/z 302.9.
Step 2: To a solution of 3,6-dichlorobenzene-1,2-diamine (0.04 g, 0.23 mmol) in EtOH (3 mL) was added 1-(3′-(methylsulfonyl)biphenyl-4-yl)propane-1,2-dione, from step 1, and the reaction mixture allowed to stir for 18 h at room temperature. The reaction was concentrated and chromatographed on silica (EtOAC/hexane gradient) giving 5,8-dichloro-2-methyl-3-[3′-(methylsulfonyl)biphenyl-4-yl]quinoxaline (0.025 g, 25%) as a foamy solid; HRMS: calcd for C22H16O2N2O2S+H+, 443.03823; found (ESI, [M+H]+ Obs'd), 443.0381;
Step 1: A mixture of 1-(3-methoxyphenyl)propan-2-one (4.0 g, 24.4 mmol), Oxone (44.9 g, 73.2 mmol), KCl (5.46 g, 73.2 mmol) in 150 mL of acetonitrile was stirred over night. The solid was filtered off the liquid residue was purified by silica gel chromatropraphy (0 to 70% EtOAc/Hex) to give 1-(2-chloro-5-methoxyphenyl)propan-2-one as an oil (3.4 g, 70%); MS (ESI) m/z 199.0520; HRMS: calcd for C10H11ClO2+H+, 199.05203. found (ESI, [M+H]+), 199.0520.
Step 2: 1-(2-chloro-5-methoxyphenyl)propan-2-one was oxidized with pyridinium chlorochromate in the presence of pyridine in CH2Cl2 to give 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione.
Step 3: The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione in place of 1-(3-methoxyphenyl)propane-1,2-dione; MS (ESI) m/z 493.1; HRMS: calcd for C23H16ClF3N2O3S+H+, 493.05950. found (ESI, [M+H]+ Obs'd), 493.0592.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione in place of 1-(3-methoxyphenyl)propane-1,2-dione; MS (ESI) m/z 493.1; HRMS: calcd for C23H16ClF3N2O3S+H+, 493.05950. found (ESI, [M+H]+ Obs'd), 493.0592.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 2-(4-fluorophenylsulfonyl)acetonitrile in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 518.1; HRMS: calcd for C24H15ClF3N3O3S+H+, 518.05475. found (ESI, [M+H]+ Obs'd), 518.0548.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione in place of 1-(3-methoxyphenyl)propane-1,2-dione; MS (ESI) m/z 493.1.
A mixture of 2-{2-chloro-5-[3-(methylsulfonyl)phenoxy]phenyl}-3-methyl-5-(trifluoromethyl)-quinoxaline (0.017 g, 0.03 mmol), phenyl boronic acid (0.015 g, 0.12 mmol), K3PO4 (0.05 g, 0.23 mmol), Pd(OAc)2 (5 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (10 mg) in 4 mL of 1-butanol was heated to 80° C. for 30 min. The reaction mixture was purified by flash chromatography eluted with EtOAc/hexane to give the title compound (6 mg) as a white solid; MS (ESI) m/z 535.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 2-(3-fluorophenylsulfonyl)acetonitrile in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 518.1; HRMS: calcd for C24H15ClF3N3O3S+H+, 518.05475. found (ESI, [M+H]+ Obs'd), 518.0544.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1-fluoro-4-(methylsulfonyl)benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 493.1; HRMS: calcd for C23H16ClF3N2O3S+H+, 493.05950. found (ESI, [M+H]+ Obs'd), 493.0594.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1-fluoro-2-(methylsulfonyl)benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 493.1.
Treatment of 2-{3-[(3-{4-chloro-3-[3-methyl-5-(trifluoromethyl)quinoxalin-2-yl]phenoxy}phenyl)sulfonyl]propyl}-1H-isoindole-1,3(2H)-dione with hydrazine in ethanol gave the title compound; MS (ESI) m/z 535.9.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1-fluoro-2-(methylsulfonyl)benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 493.1.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-(methylsulfonamido)phenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ESI) m/z 458.1; HRMS: calcd for C23H18F3N3O2S+H+, 458.11446. found (ESI, [M+H]+ Obs'd), 458.1144.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-(N-methylsulfamoyl)phenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ESI) m/z 458.2; HRMS: calcd for C23H18F3N3O2S+H+, 458.11446. found (ESI, [M+H]+ Obs'd), 458.1143.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-(methylsulfonamido)phenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ESI) m/z 458.1; HRMS: calcd for C23H18F3N3O2S+H+, 458.11446. found (ESI, [M+H]+ Obs'd), 458.1140.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-carbamoylphenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ESI) m/z 408.1; HRMS: calcd for C23H16F3N3O+H+, 408.13182. found (ESI, [M+H]+ Obs'd), 408.1318.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-acetamidophenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ESI) m/z 422.2; HRMS: calcd for C24H18F3N3O+H+, 422.14747. found (ESI, [M+H]+ Obs'd), 422.1475.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-(methylcarbamoyl)phenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ESI) m/z 422.2; HRMS: calcd for C24H18F3N3O+H+, 422.14747. found (ESI, [M+H]+ Obs'd), 422.1475.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-(N-methylsulfamoyl)phenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ESI) m/z 458.1; HRMS: calcd for C23H18F3N3O2S+H+, 458.11446. found (ESI, [M+H]+ Obs'd), 458.1142.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-(pyrrolidine-1-carbonyl)phenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ESI) m/z 462.2; HRMS: calcd for C27H22F3N3O+H+, 462.17877. found (ESI, [M+H]+ Obs'd), 462.1789.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-(4-boronophenyl)propanoic acid in place of 3-methylsulfonylphenylboronic acid; HRMS: calcd for C25H19F3N2O2+H+, 437.14714. found (ESI, [M+H]+ Obs'd), 437.1469.
The title compound was prepared using a procedure analogous to that described in Example 36 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(ethylsulfonyl)benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; HRMS: calcd for C24H18ClF3N2O3S+H+, 507.07515. found (ESI, [M+H]+ Obs'd), 507.0748.
The title compound was prepared using a procedure analogous to that described in Example 36 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(isopropylsulfonyl)benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 521.1; HRMS: calcd for C25H20ClF3N2O3S+H+, 521.09080. found (ESI, [M+H]+ Obs'd), 521.0905.
The title compound was prepared using a procedure analogous to that described in Example 36 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 3-(3-fluorophenylsulfonyl)propan-1-ol in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 537.1.
The title compound was prepared using a procedure analogous to that described in Example 36 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1,3-difluoro-5-(methylsulfonyl)benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 511.1.
The title compound was prepared using a procedure analogous to that described in Example 36 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1-chloro-3-fluoro-5-(methylsulfonyl)-benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)-benzene; MS (ESI) m/z 527.0.
The title compound was prepared using a procedure analogous to that described in Example 36 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(ethylsulfonyl)benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; HRMS: calcd for C24H18ClF3N2O3S+H+, 507.07515. found (ESI, [M+H]+ Obs'd), 507.0747.
The title compound was prepared using a procedure analogous to that described in Example 36 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(isopropylsulfonyl)benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 521.1; HRMS: calcd for C25H20ClF3N2O3S+Na+, 543.07274. found (ESI, [M+Na]+ Obs'd), 543.0723.
The title compound was prepared using a procedure analogous to that described in Example 36 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 3-(3-fluorophenylsulfonyl)propan-1-ol in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 537.1; HRMS: calcd for C25H20ClF3N2O4S+Na+, 559.06766. found (ESI, [M+Na]+ Obs'd), 559.0669.
The title compound was prepared using a procedure analogous to that described in Example 36 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1,3-difluoro-5-(methylsulfonyl)benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 511.1; HRMS: calcd for C23H15ClF4N2O3S+Na+, 533.03202. found (ESI, [M+Na]+ Obs'd), 533.0323.
The title compound was prepared using a procedure analogous to that described in Example 36 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and 1-chloro-3-fluoro-5-(methylsulfonyl)benzene in place of 1-(3-methoxyphenyl)propane-1,2-dione and 1-fluoro-3-(methylsulfonyl)benzene; MS (ESI) m/z 527.0.
The title compound was prepared using a procedure analogous to that described in Example 2 but using 1-(2-chloro-5-methoxyphenyl)propane-1,2-dione and benzene-1,2-diamine in place of 1-(3-methoxyphenyl)propane-1,2-dione and 3-(trifluoromethyl)benzene-1,2-diamine; MS (ESI) m/z 425.1; HRMS: calcd for C22H17ClN2O3S+H+, 425.07212. found (ESI, [M+H]+ Obs'd), 425.0727.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-chlorobenzene-1,2-diamine in place of 3-(trifluoromethyl)benzene-1,2-diamine; MS (ESI) m/z 409.1; HRMS: calcd for C22H17ClN2O2S+H+, 409.07720. found (ESI, [M+H]+ Obs'd), 409.0774.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-chlorobenzene-1,2-diamine in place of 3-(trifluoromethyl)benzene-1,2-diamine; MS (ESI) m/z 409.1; HRMS: calcd for C22H17ClN2O2S+H+, 409.07720. found (ESI, [M+H]+ Obs'd), 409.0775.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-methoxybenzene-1,2-diamine in place of 3-(trifluoromethyl)benzene-1,2-diamine; MS (ESI) m/z 405.1; HRMS: calcd for C23H20N2O3S+H+, 405.12674. found (ESI, [M+H]+ Obs'd), 405.1259.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 3-methoxybenzene-1,2-diamine in place of 3-(trifluoromethyl)benzene-1,2-diamine; MS (ESI) m/z 405.2; HRMS: calcd for C23H20N2O3S+H+, 405.12674. found (ESI, [M+H]+ Obs'd), 405.1262.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 2,3-diaminobenzonitrile in place of 3-(trifluoromethyl)benzene-1,2-diamine; HRMS: calcd for C23H17N3O2S+H+, 400.11142. found (ESI, [M+H]+ Obs'd), 400.1115.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 2,3-diaminobenzonitrile in place of 3-(trifluoromethyl)benzene-1,2-diamine; HRMS: calcd for C23H17N3O2S+H+, 400.11142. found (ESI, [M+H]+ Obs'd), 400.1114.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 5-(methylsulfonyl)pyridin-3-ylboronic acid in place of 3-(methylsulfonyl)phenylboronic acid; MS (ESI) m/z 444.1; HRMS: calcd for C22H16F3N3O2S+H+, 444.09881. found (ESI, [M+H]+ Obs'd), 444.0997.
The title compound was prepared using a procedure analogous to that described in Example 1 but using 5-(methylsulfonyl)pyridin-3-ylboronic acid in place of 3-(methylsulfonyl)phenylboronic acid; MS (ESI) m/z 444.1; HRMS: calcd for C22H16F3N3O2S+H+, 444.09881. found (ESI, [M+H]+ Obs'd), 444.0991.
Step 1: In a flash at 0° C. under a nitrogen atmosphere was placed 3-(3-(4-chloro-3-(3-methyl-5-(trifluoromethyl)quinoxalin-2-yl)phenoxy)phenylsulfonyl)propan-1-ol (660 mg, 1.229 mmol) in CH2Cl2 (20 ml) followed by in order methanesulfonyl chloride (155 mg, 1.352 mmol), triethylamine (148 mg, 1.478 mmol). The resulting yellow solution was stirred at 0° C. for 30 min. Complete conversion was confirmed by LCMS upon which the reaction was quenched with H2O (10 ml). Extraction, separation, drying with MgSO4, and concentration in vacuo of the organic phase to a yellow syrup. Purification of this same syrup by chromatography SiO2 (elution with Hexane: EtOAc) afforded 3-[(3-{4-chloro-3-[3-methyl-5-(trifluoromethyl)quinoxalin-2-yl]phenoxy}phenyl)sulfonyl]propyl methanesulfonate as a yellow powder (592 mg, 78% yield); MS (ESI) m/z 615.1. HRMS: calcd for C26H22ClF3N2O6S2+H+, 615.06326. found (ESI, [M+H]+ Obs'd), 615.0639.
Step 2: In an open reaction vial at room temperature was placed 3-[(3-{4-chloro-3-[3-methyl-5-(trifluoromethyl)quinoxalin-2-yl]phenoxy}phenyl)sulfonyl]propyl methanesulfonate (40 mg, 0.065 mmol) and potassium fluoride (4 mg, 0.071 mmol) in DMF (1 ml). The reaction vial was capped and heated at 70° C. for 3 h. Complete conversion was confirmed by LCMS upon which the reaction was quenched with H2O (5 ml). Partition with EtOAc (5 ml) extraction, separation, extraction of the aqueous layer with EtOAc (3 ml). All organics were combined, dried with MgSO4, and concentration in vacuo of the organic phase to a yellow powder. This same yellow powder was purified by reversed phase chromatography (CH3CN:H2O) affording the title compound as a white powder (9 mg, 26% yield). MS (ESI) m/z 539.1.
The title compound was prepared using a procedure analogous to that described in Example 75 but using sodium chloride in place of potassium fluoride; MS (ESI) m/z 555.1. HRMS: calcd for C25H19Cl2F3N2O3S+H+, 555.05183. found (ESI, [M+H]+ Obs'd), 555.0526.
The title compound was prepared using a procedure analogous to that described in Example 75 but using potassium cyanide in place of potassium fluoride; MS (ESI) m/z 546.1. HRMS: calcd for C26H19ClF3N3O3S+H+, 546.08605. found (ESI, [M+H]+ Obs'd), 546.0866.
Step 1: 3-chloro-2-nitroaniline (5.0 g, 29 mmol), zinc dust (18.9 g, 290 mmol) and ammonium chloride (31.0 g, 579 mmol) were stirred in 100 mL of a 1:1 solution of ethanol and water, at room temperature for 18 hours. The reaction was filtered and the filtrate concentrated to give a brown solid, which was transferred to a separatory funnel and partitioned between methylene chloride and water. The organic extracts were separated, combined, dried (MgSO4), filtered and the solvent removed, in vacuo, to give 3-chlorobenzene-1,2-diamine as a brown solid (4.00 g, 97% Yield).
Step 2: 3-chlorobenzene-1,2-diamine (3.60 g, 25.3 mmol) and ethyl glyoxylate solution (50% in toluene; 6.0 mL, 30.3 mmol) were heated in ethanol (87 mL) to 75° C. for 18 hours. The reaction was placed in a refrigerator to cool and the product filtered to give a rust colored solid (3.42 g). This material was purified by supercritical fluid chromatography to give 5-chloroquinoxalin-2(1H)-one; MS (ESI) m/z 180.0.
Step 3: 5-chloroquinoxalin-2(1H)-one (0.60 g, 3.32 mmol) was heated to 90° C. in phosphorus oxychloride (10 mL, 109 mmol) for 3 hours. The reaction was poured onto ice and extracted with ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered and the solvent removed to give a dark brown solid. This material was adsorbed onto silica and purified by column chromatography, eluting with a gradient of 0-30% ethyl acetate in hexane to afford 2,5-dichloroquinoxaline as a white solid (210 mg, 32% Yield).
Step 4: 2,5-dichloroquinoxaline (90 mg, 0.452 mmol), 3-bromophenol (86 mg, 0.497 mmol) and potassium carbonate (82 mg, 0.542 mmol) were heated to 90° C. in anhydrous acetonitrile (3 mL) for 18 hours. The reaction was allowed to cool to room temperature and transferred to a separatory funnel with ethyl acetate and washed with water, 1N aqueous sodium hydroxide solution, brine, dried (MgSO4), filtered, and the solvent removed in vacuo, to give an off white solid. This material was adsorbed onto silica and purified by column chromatography, eluting with a gradient of 0-25% ethyl acetate in hexane to afford 2-(3-bromophenoxy)-5-chloroquinoxaline as a white solid (130 mg, 86% Yield); MS (ESI) m/z 333.95087; HRMS: calcd for C14H8BrClN2O+H+, 334.9581. found (ESI, [M+H]+ Obs'd), 334.9583.
Step 5: 2-(3-bromophenoxy)-5-chloroquinoxaline (50 mg, 0.149 mmol), 3-methylsulfonylphenyl-boronic acid (45 mg, 0.223 mmol), tetrakis(triphenylphosphine) palladium (0) (17 mg, 0.0149 mmol), and 2M aqueous sodium carbonate solution (149 μL, 0.298 mmol) were heated to 80° C. in a 1.5 mL of a 2:1 solution of toluene:ethanol for 18 hours. The reaction was filtered through celite and the filtrate adsorbed onto silica and purified by column chromatography eluting with a gradient of 0-75% ethyl acetate in hexane to give impure product which was purified by supercritical fluid chromatography to give the title compound as a white solid (26 mg, 43% Yield); MS (ESI) m/z 411.1; HRMS: calcd for C21H15ClN2O3S+H+, 411.05647. found (ESI, [M+H]+ Obs'd), 411.0567.
Step 1: 2-(4-bromophenoxy)-5-chloroquinoxaline was prepared using 4-bromophenol and utilizing essentially the same conditions as Example 78 Step 4; MS (ESI) m/z [M+H]+334.9; HRMS: calcd for C14H8BrClN2O+H+, 334.9581. found (ESI, [M+H]+ Obs'd), 334.9582.
Step 2: The title compound was prepared utilizing essentially the same conditions as Example 78 Step 5; MS (ESI) m/z 411.1; HRMS: calcd for C21H15ClN2O3S+H+, 411.05647. found (ESI, [M+H]+ Obs'd), 411.0564.
Step 1: 5-chloro-3-methylquinoxalin-2(1H)-one was prepared using ethyl pyruvate and utilizing essentially the same conditions as Example 78 Step 2; MS (ESI) m/z 195.0; HRMS: calcd for C9H7ClN2O+H+, 195.0320. found (ESI, [M+H]+ Obs'd), 195.0321.
Step 2: 2,5-dichloro-3-methylquinoxaline was prepared using 5-chloro-3-methylquinoxalin-2(1H)-one and utilizing essentially the same conditions as Example 78 Step 3; MS (ESI) m/z [M+H]+213.0.
Step 3: 2-(3-bromophenoxy)-5-chloro-3-methylquinoxaline was prepared using 2,5-dichloro-3-methylquinoxaline and utilizing essentially the same conditions as Example 78 Step 4; MS (ESI) m/z [M+H]+ 349.0; HRMS: calcd for C15H10BrClN2O+H+, 348.9738. found (ESI, [M+H]+ Obs'd), 348.9737.
Step 4: The title compound was prepared utilizing essentially the same conditions as Example 78 Step 5; MS (ESI) m/z 425.1; HRMS: calcd for C22H17ClN2O3S+H+, 425.07212. found (ESI, [M+H]+ Obs'd), 425.0718.
The title compound was prepared using 3-ethylsulfonylphenylboronic acid and utilizing essentially the same conditions as Example 80; MS (ESI) m/z 439.1; HRMS: calcd for C23H19ClN2O3S+H+, 439.08777. found (ESI, [M+H]+ Obs'd), 439.0881.
Step 1: 2-(4-bromophenoxy)-5-chloro-3-methylquinoxaline was prepared utilizing essentially the same conditions as Example 78 Step 4; MS (ESI) m/z [M+H]+ 349.0; HRMS: calcd for C15H10BrClN2O+H+, 348.9738. found (ESI, [M+H]+ Obs'd), 348.9735.
Step 2: The title compound was prepared utilizing essentially the same conditions as Example 78 Step 5; MS (ESI) m/z 425.1; HRMS: calcd for C22H17ClN2O3S+H+, 425.07212. found (ESI, [M+H]+ Obs'd), 425.0720.
The title compound was prepared utilizing essentially the same conditions as Example 80 but using 3-ethylsulfonylphenylboronic acid in place of 3-methylsulfonylphenylboronic acid; MS (ESI) m/z 439.1; HRMS: calcd for C23H19ClN2O3S+H+, 439.08777. found (ESI, [M+H]+ Obs'd), 439.0876.
Step 1: 3-Chloro-2-nitroaniline (5.0 g, 29 mmol), zinc (18.9 g, 290 mmol) and ammonium chloride (31.0 g, 579 mmol) were stirred in 100 mL of a 1:1 solution of ethanol and water, at room temperature for 18 hours. The reaction was filtered and the filtrate concentrated to give a brown solid which was transferred to a separatory funnel and partitioned between methylene chloride and water. The organic extracts were separated, combined, dried (MgSO4), filtered and the solvent removed, in vacuo, to give 3-chlorobenzene-1,2-diamine as a brown solid (4.00 g, 97% yield).
Step 2: 3-Chlorobenzene-1,2-diamine (3.60 g, 25.3 mmol) and ethyl glyoxylate solution (50% in toluene; 6.0 mL, 30.3 mmol) were heated in ethanol (87 mL) to 75° C. for 18 hours. The reaction was placed in a refrigerator to cool and the product filtered to give 5-chloroquinoxalin-2(1H)-one as a rust colored solid (3.42 g). This material was purified by supercritical fluid chromatography to give 5-chloroquinoxalin-2(1H)-one and 8-chloroquinoxalin-2(1H)-one.
Step 3: 5-Chloroquinoxalin-2(1H)-one (0.60 g, 3.32 mmol) was heated to 90° C. in phosphorus oxychloride (10 mL, 109 mmol) for 3 hours. The reaction was poured onto ice and extracted with ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered and the solvent removed to give a dark brown solid. This material was adsorbed onto silica and purified by column chromatography, eluting with a gradient of 0-30% ethyl acetate in hexane to afford 2,5-dichloroquinoxaline as a white solid (210 mg, 32% yield).
Step 4: 2,5-Dichloroquinoxaline (90 mg, 0.452 mmol), 3-bromophenol (86 mg, 0.497 mmol) and potassium carbonate (82 mg, 0.542 mmol) were heated to 90° C. in anhydrous acetonitrile (3 mL) for 18 hours. The reaction was allowed to cool to room temperature and transferred to a separatory funnel with ethyl acetate and washed with water, 1N aqueous sodium hydroxide solution, brine, dried (MgSO4), filtered, and the solvent removed in vacuo, to give an off white solid. This material was adsorbed onto silica and purified by column chromatography, eluting with a gradient of 0-25% ethyl acetate in hexane to afford 2-(3-bromophenoxy)-5-chloroquinoxaline as a white solid (130 mg, 86% yield); MS (ESI) m/z 334.0; HRMS: calcd for C14H8BrClN2O+H+, 334.9581. found (ESI, [M+H]+ Obs'd), 334.9583.
Step 5: 2-(3-Bromophenoxy)-5-chloroquinoxaline (25 mg, 0.0745 mmol), methyl-3-boronobenzenesulfamide (24 mg, 0.0112 mmol), tetrakis(triphenylphosphine) palladium (0) (9 mg, 0.0745 mmol), and 2M aqueous sodium carbonate solution (74 μL, 0.149 mmol) were heated to 80° C. in a 1.5 mL of a 2:1 solution of toluene:ethanol for 18 hours. The reaction was filtered through celite and the filtrate adsorbed onto silica and purified by column chromatography eluting with a gradient of 0-50% ethyl acetate in hexane to afford the title compound as a white solid (11 mg, 34% yield). MS (ESI) m/z 425.0; HRMS: calcd for C21H16ClN3O3S+H+, 426.0674. found (ESI, [M+H]+ Obs'd), 426.0673.
The title compound was prepared followed the same procedure as described in Example 84 Step 5 using 3-(methylsulfonamido)phenylboronic acid instead of methyl-3-boronobenzenesulfamide as a white solid (13 mg, 41% yield). MS (ESI) m/z 425.0; HRMS: calcd for C21H16ClN3O3S+H+, 426.0674. found (ESI, [M+H]+ Obs'd), 426.0672.
Step 1: 2-(4-Bromophenoxy)-5-chloroquinoxaline was prepared using 4-bromophenol and utilizing the same conditions as Example 78 Step 4 as a white solid (27 mg, 40% yield). MS (ESI) m/z 334.0; HRMS: calcd for C14H8BrClN2O+H+, 334.9581. found (ESI, [M+H]+ Obs'd), 334.9582.
Step 2: The title compound was prepared followed the same procedure as described in Example 84 using 2-(4-bromophenoxy)-5-chloroquinoxaline instead of 2-(3-bromophenoxy)-5-chloro-quinoxaline as a white solid (21 mg, 55% Yield). MS (ESI) m/z 425.0; HRMS: calcd for C21H16ClN3O3S+H+, 426.0674. found (ESI, [M+H]+ Obs'd), 426.0675.
The title compound was prepared followed the same procedure as described in Example 85 using 2-(4-bromophenoxy)-5-chloroquinoxaline instead of 2-(3-bromophenoxy)-5-chloroquinoxaline as a white solid (20 mg, 53% Yield). MS (ESI) m/z 425.0; HRMS: calcd for C21H16ClN3O3S+H+, 426.0674. found (ESI, [M+H]+ Obs'd), 426.0675.
Step 1: 5-Chloro-3-methylquinoxalin-2(1H)-one was prepared using ethyl pyruvate and utilizing the same conditions as in the preparation of Example 84 Step 2. MS (ESI) m/z 195.0; HRMS: calcd for C9H7ClN2O+H+, 195.0320. found (ESI, [M+H]+ Obs'd), 195.0321.
Step 2: 2,5-Dichloro-3-methylquinoxaline was prepared using 5-chloro-3-methylquinoxalin-2(1H)-one and utilizing the same conditions as in the preparation of Example 84 Step 3. MS (ESI) m/z [M+H]+213.0.
Step 3: 2-(3-Bromophenoxy)-5-chloro-3-methylquinoxaline was prepared using 2,5-dichloro-3-methylquinoxaline and utilizing the same conditions as in the preparation of Example 84 Step 4. MS (ESI) m/z [M+H]+ 349.0; HRMS: calcd for C15H10BrClN2O+H+, 348.9738. found (ESI, [M+H]+ Obs'd), 348.9737.
Step 4: The title compound was prepared using the same procedure as described in Example 84 Step 5 using 2-(3-bromophenoxy)-5-chloro-3-methylquinoxaline instead of 2-(3-bromophenoxy)-5-chloroquinoxaline as a pink colored solid (33 mg, 52% Yield). MS (ESI) m/z 439.1; HRMS: calcd for C22H18ClN3O3S+H+, 440.0830. found (ESI, [M+H]+ Obs'd), 440.0827.
The title compound was prepared followed the same procedure as described in Example 88 using 3-sulfamoylphenylboronic acid instead of methyl-3-boronobenzenesulfamide as a pink colored solid (31 mg, 51% Yield). MS (ESI) m/z 425.1; HRMS: calcd for C21H16ClN3O3S+H+, 426.0674; found (ESI, [M+H]+ Obs'd), 426.0675.
The title compound was prepared followed the same procedure as described in Example 88 using 3-methylsulfonylaminophenylboronic acid instead of methyl-3-boronobenzenesulfamide as a pink colored solid (38 mg, 60% Yield). MS (ESI) m/z 439.0; HRMS: calcd for C22H18ClN3O3S+H+, 440.0830. found (ESI, [M+H]+ Obs'd), 440.0830.
The title compound was prepared followed the same procedure as described in Example 84 Step 5 using 5-chloro-3-methylquinoxalin-2(1H)-one instead of 5-chloroquinoxalin-2(1H)-one as a pink colored solid (38 mg, 60% Yield). MS (ESI) m/z 439.0; HRMS: calcd for C22H18ClN3O3S+H+, 440.0830. found (ESI, [M+H]+ Obs'd), 440.0831.
The title compound was prepared followed the same procedure as described in Example 91 using 3-sulfamoylphenylboronic acid instead of methyl-3-boronobenzenesulfamide as a white solid (24 mg, 39% Yield). MS (ESI) m/z 425.1; HRMS: calcd for C21H16ClN3O3S+H+, 426.0674. found (ESI, [M+H]+ Obs'd), 426.0675.
The title compound was prepared followed the same procedure as described in Example 91 using 3-methylsulfonylaminophenylboronic acid instead of methyl-3-boronobenzenesulfamide as a white solid (38 mg, 60% Yield). MS (ESI) m/z 439.1;
HRMS: calcd for C22H18ClN3O3S+H+, 440.0830. found (ESI, [M+H]+ Obs'd), 440.0827.
The structures of the title compounds of Examples 1-42 and 44-83 are set forth below.
Representative compounds of this invention were evaluated in conventional pharmacological test procedures which measured their affinity to bind to LXR and to upregulate the gene ABCA1, which causes cholesterol efflux from atherogenic cells, such as macrophages.
LXR activation can be critical for maintaining cholesterol homeostasis, but its coincident regulation of fatty acid metabolism may lead to increased serum and hepatic triglyceride levels. Selective LXR modulators that activate cholesterol efflux with minimal impact on SREBP-1c expression and triglyceride synthesis in liver would be expected to reduce atherosclerotic risk with an improved therapeutic index and minimize the potential for deleterious effects on metabolic balance.
The test procedures performed, and results obtained, are briefly described in the following sections:
I. Ligand-Binding Test Procedure for Human LXRβ
II. Ligand-Binding Test Procedure for Human LXRα
III. Quantitative Analysis of ABCA1 Gene Regulation in THP-1 Cells
IV. Results
Ligand-binding to the human LXRβ was demonstrated for representative compounds of this invention by the following procedure.
Buffer: 100 mM KCl, 100 mM TRIS (pH 7.4 at +4° C.), 8.6% glycerol, 0.1 mM PMSF*, 2 mM MTG*, 0.2% CHAPS (* not used in wash buffer)
Receptor source: E. coli extracted from cells expressing biotinylated hLXRβ. Extract was made in a similar buffer as above, but with 50 mM TRIS.
Washed streptavidin and coated flash plates with wash buffer.
Diluted receptor extract to give Bmax˜4000 cpm and add to the wells.
Wrapped the plates in aluminum foil and stored them at +4° C. overnight.
Made a dilution series in DMSO of the test ligands.
Made a 5 nM solution of the radioactive tracer in buffer.
Mixed 250 μl diluted tracer with 5 μl of the test ligand from each concentration of the dilution series.
Washed the receptor-coated flash plates.
Added 200 μl per well of the ligand/radiolabel mixture to the receptor-coated flash plates.
Wrapped the plates in aluminum foil and incubate at +4° C. over night.
Aspirated wells, and washed the flashed plates. Sealed the plate.
Measured the remaining radioactivity in the plate.
Ligand-binding to the human LXRα was demonstrated for representative compounds of this invention by the following procedure.
Buffer: 100 mM KCl, 100 mM TRIS (pH 7.4 at +4° C.), 8.6% glycerol, 0.1 mM PMSF*, 2 mM MTG*, 0.2% CHAPS (* not used in wash buffer)
Receptor source: E. coli extract from cells expressing biotinylated hLXRα. Extract was made in a similar buffer as above, but with 50 mM TRIS.
Washed streptavidin and coated flash plates with wash buffer.
Diluted receptor extract to give Bmax˜4000 cpm and add to the wells.
Wrapped the plates in aluminum foil and stored them at +4° C. over night.
Made a dilution series in DMSO of the test ligands.
Made a 5 nM solution of the radioactive tracer in buffer.
Mixed 250 μl diluted tracer with 5 μl of the test ligand from each concentration of the dilution series.
Washed the receptor-coated flash plates.
Added 200 μl per well of the ligand/radiolabel mixture to the receptor-coated flash plates.
Wrapped the plates in aluminum foil and incubate at +4° C. over night.
Aspirated wells, and wash the flashed plates. Sealed the plate.
Measured the remaining radioactivity in the plate.
The compounds of formula (I) effect on the regulation of the ABCA1 gene was evaluated using the following procedure.
Cell culture: The THP-1 monocytic cell line (ATCC # TIB-202) was obtained from American Type Culture Collection (Manassas, Va.) and cultured in RPMI 1640 medium (Gibco, Carlsbad, Calif.) containing 10% FBS, 2 mM L-glutamine, and 55 uM beta-Mercaptoethanol (BME). Cells were plated in 96-well format at a density of 7.5×104 in complete medium containing 50-100 ng/ml phorbal 12,13-dibutyrate (Sigma, St. Louis, Mo.) for three days to induce differentiation into adherent macrophages. Differentiated THP-1 cells were treated with test compounds or ligands dissolved in DMSO (Sigma, D-8779) in culture medium lacking phorbal ester. Final concentrations of DMSO did not exceed 0.3% of the media volume. Dose response effects were measured in duplicate, in the range of 0.001 to 30 micromolar concentrations and treated cells were incubated for an additional 18 hrs prior to RNA isolation. Unstimulated cells treated with vehicle were included as negative controls on each plate. An LXR agonist reference, N-(2,2,2-Trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-benzenesulfonamide (Schultz, Joshua R., Genes & Development (2000), 14(22), 2831-2838), was dosed at 1.0 uM and served as a positive control. In antagonist mode, the compound under study is analyzed in the presence of 150 nM GW3965, trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy]-phenyl)-acetic acid (Collins, J. L., J. Med. Chem. (2000), 45:1963-1966.). Results of antagonist analysis are expressed as % antagonism and IC50 (in μM).
RNA isolation and quantitation: Total cellular RNA was isolated from treated cells cultured in 96-well plates using PrepStation 6100 (Applied Biosystems, Foster City, Calif.), according to the manufacturer's recommendations. RNA was resuspended in ribonuclease-free water and stored at −70° C. prior to analysis. RNA concentrations were quantitated with RiboGreen test procedure, #R-11490 (Molecular Probes, Eugene, Oreg.).
Gene expression analysis: Gene-specific mRNA quantitation was performed by real-time PCR with the Perkin Elmer Corp. chemistry on an ABI Prism 7700 Sequence detection system (Applied Biosystems, Foster City, Calif.) according to the manufacturer's instructions. Samples (50-100 ng) of total RNA were assayed in duplicate or triplicate in 50 μl reactions using one-step RT-PCR and the standard curve method to estimate specific mRNA concentrations. Sequences of gene-specific primer and probe sets were designed with Primer Express Software (Applied Biosystems, Foster City, Calif.). The human ABCA1 primer and probe sequences are: forward, CAACATGAATGCCATTTTCCAA, reverse, ATAATCCCCTGAACCCAAGGA, and probe, 6FAM-TAAAGCCATGCCCTCTGCAGGAACA-TAMRA. RT and PCR reactions were performed according to PE Applied Biosystem's protocol for Taqman Gold RT-PCR or Qiagen's protocol for Quantitect probe RT-PCR. Relative levels of ABCA1 mRNA are normalized using GAPDH mRNA or 18S rRNA probe/primer sets purchased commercially (Applied Biosystems, Foster City, Calif.).
Mean, standard deviation and statistical significance of duplicate evaluations of RNA samples were assessed using ANOVA, one-way analysis of variance using SAS analysis.
Qiagen Quantitect probe RT-PCR 204443.
Based on the results obtained in the standard pharmacological test procedures, the compounds of this invention can be useful in treating or inhibiting LXR mediated diseases. In particular, the compounds of this invention can be useful in the treatment or prevention of atherosclerosis and atherosclerotic lesions, lowering LDL cholesterol levels, increasing HDL cholesterol levels, increasing reverse cholesterol transport, inhibiting cholesterol absorption, treatment or inhibition of cardiovascular diseases (e.g., acute coronary syndrome, restenosis, coronary artery disease), atherosclerosis, atherosclerotic lesions, type I diabetes, type II diabetes, Syndrome X, obesity, lipid disorders (e.g., dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL), cognitive disorders (e.g., Alzheimer's disease, dementia), inflammatory diseases (e.g., multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, endometriosis, LPS-induced sepsis, acute contact dermatitis of the ear, chronic atherosclerotic inflammation of the artery wall), celiac, thyroiditis, skin aging (e.g., skin aging is derived from chronological aging, photoaging, steroid-induced skin thinning, or a combination thereof), or connective tissue disease (e.g., osteoarthritis or tendonitis).
A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are in the claims.
| Number | Date | Country | |
|---|---|---|---|
| 61112456 | Nov 2008 | US |
