WO2019122268A1 - Processes for the stereoselective preparation of bace inhibitors - Google Patents

Processes for the stereoselective preparation of bace inhibitors Download PDF

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Publication number
WO2019122268A1
WO2019122268A1 PCT/EP2018/086439 EP2018086439W WO2019122268A1 WO 2019122268 A1 WO2019122268 A1 WO 2019122268A1 EP 2018086439 W EP2018086439 W EP 2018086439W WO 2019122268 A1 WO2019122268 A1 WO 2019122268A1
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Prior art keywords
compound
formula
salt
alkoxy
hydrogen
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PCT/EP2018/086439
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French (fr)
Inventor
Phillip Anthony INGLESBY
Robert Leslie WOODWARD
James Alexander MORRISON
Stephen GOTTSCHLING
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Astrazeneca Ab
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Publication of WO2019122268A1 publication Critical patent/WO2019122268A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems

Definitions

  • Abs amyloid b peptide
  • BACE beta site APP Cleaving Enzyme
  • AD Alzheimer's disease
  • the disease progresses with increasing dementia and elevated deposition of Ab.
  • a hyperphosphorylated form of the microtubule-associated protein tau accumulates within neurons, leading to a plethora of deleterious effects on neuronal function.
  • the prevailing working hypothesis regarding the temporal relationship between Ab and tau pathologies states that Ab deposition precedes tau aggregation in humans and animal models of the disease.
  • the Ab peptide is an integral fragment of the Type I protein APP (Ab amyloid precursor protein), a protein ubiquitously expressed in human tissues. Since soluble Ab can be found in both plasma and cerebrospinal fluid (CSF), and in the medium from cultured cells, APP has to undergo proteolysis. There are three main cleavages of APP that are relevant to the pathobiology of AD, the so-called a-, b-, and g-cleavages. The a-cleavage, which occurs roughly in the middle of the Ab domain in APP, is executed by the metalloproteases
  • ADAMI10 or ADAMI17 (the latter also known as TACE).
  • TACE transmembrane aspartyl protease Beta site
  • BACE1 Cleaving Enzymel
  • the g-cleavage, generating the Ab C termini and subsequent release of the peptide, is carried out by a multi-subunit aspartyl protease named g-secretase.
  • ADAM 10/ 17 cleavage followed by g-secretase cleavage results in the release of the soluble p3 peptide, an N-terminally truncated Ab fragment that fails to form amyloid deposits in humans.
  • This proteolytic route is commonly referred to as the nonamyloidogenic pathway.
  • Consecutive cleavages by BACE1 and g-secretase generate the intact Ab peptides; hence this processing scheme has been termed the amyloidogenic pathway.
  • Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHW A-D), and other neurodegenerative disorders.
  • b-amyloid deposits are predominately an aggregate of Ab peptide, which in turn is a product of the proteolysis of amyloid precursor protein (APP).
  • APP amyloid precursor protein
  • Ab peptide results from the cleavage of APP at the C-terminus by one or more g-secretases, and at the N- terminus by b-secretase enzyme (BACE), also known as aspartyl protease or Asp2 or Beta site APP Cleaving Enzyme (BACE), as part of the b-amyloidogenic pathway.
  • BACE b-secretase enzyme
  • BACE Beta site APP Cleaving Enzyme
  • BACE activity is correlated directly to the generation of Ab peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540), and studies increasingly indicate that the inhibition of BACE inhibits the production of Ab peptide (Roberds, S. L., et al, Human Molecular Structure
  • BACE amyloid ⁇ -peptide
  • BACE is therefore an important candidate for the development of drugs as a treatment and/or prophylaxis of Ab-related pathologies such as Down's syndrome; b-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage; disorders associated with cognitive
  • MCI mimild cognitive impairment
  • Alzheimer's Disease a cognitive impairment
  • memory loss attention deficit symptoms associated with Alzheimer's disease
  • neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia, and dementia associated with Parkinson's disease; progressive supranuclear palsy or cortical basal degeneration. It would therefore be useful to inhibit the deposition of Ab and portions thereof by inhibiting BACE through inhibitors.
  • Described herein are processes for the stereos lective preparation of dihydroimidazole ring systems that are useful in the preparation of such compounds.
  • the present application provides processes for preparing the compounds disclosed herein, wherein the compounds are BACE inhibitors, or salts thereof, and/or intermediates useful in the preparation of BACE inhibitors.
  • the BACE inhibitors are useful in the treatment or prevention of Ab-related pathologies, such as a b- amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer's Disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • Ab-related pathologies such as a b- amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI (“mild
  • the present application provides a process for preparing a compound of formula (I”)
  • R 1 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR 5 ;
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)al
  • the present application further provides a process for preparing a compound of
  • R 1 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl
  • W is NHR 5
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl
  • Y is NHR 4 or SR 4
  • R 4 independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy,
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl;
  • W is NHR 5 ;
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl;
  • Y is NHR 4 or SR 4 ;
  • R 4 independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkeny
  • the present application further provides a process of preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl
  • W is NHR 5 ;
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl;
  • Y is NHR 4 or SR 4 ;
  • R 4 independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl
  • W is Nfb.
  • R 3 is optionally substituted alkyl, such as methyl.
  • r is 2.
  • o is 1.
  • s is 1.
  • (II), or a salt thereof is a compound of formula (Ila), , or a salt thereof.
  • Z is NH.
  • the compound of formula (II), or a salt thereof is reacted with the compound of formula (III), or a salt thereof, in the presence of a base, such as an amine base (e.g., a trialkyl amine base).
  • a base such as an amine base (e.g., a trialkyl amine base).
  • the base is N- methylmorpholine, triethylamine, or N,N-diisopropylethyl amine (e.g., N,N-diisopropylethyl amine).
  • the compound of formula (II), or a salt thereof is reacted with the compound of formula (III), or a salt thereof, in the presence of one or more dehydrating agents.
  • the dehydrating agent is a molecular sieve, such as a 3 A or 4 A molecular sieve.
  • the compound of formula (IV), or a salt thereof is a
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
  • the compound of formula (Ilia), or salt thereof is selected from:
  • the compound of formula (Ilia), or salt thereof is selected from salt thereof.
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • X is NH;
  • R 4 is hydrogen;
  • the compound of formula (IV), or a salt thereof is prepared according to any one of the foregoing processes.
  • the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
  • the compound of formula (IV), or a salt thereof is reacted with the oxidizing agent at room temperature.
  • the compound of formula (IV), or a salt thereof is reacted with the oxidizing agent for at least 8 hours.
  • the compound of formula (IV), or a salt thereof is reacted with the oxidizing agent in an organic solvent, such as a halogenated solvent (e.g., dichloromethane) .
  • an organic solvent such as a halogenated solvent (e.g., dichloromethane) .
  • the compound of formula (IV), or a salt thereof is a
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
  • the compound of formula (I), or a salt thereof is a compound
  • the compound formula (la) and the compound of formula (lb) are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
  • the present invention further provides a process for preparing a compound of formula
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • X is O;
  • R 4 is selected from hydrogen and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl,
  • the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
  • the compound of formula (IV), or a salt thereof is reacted with the oxidizing agent at room temperature.
  • the compound of formula (IV), or a salt thereof reacted with the oxidizing agent for at least 8 hours.
  • the compound of formula (IV), or a salt thereof is reacted with the oxidizing agent in an organic solvent.
  • the compound of formula (IV), or a salt thereof is a
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
  • the compound of formula (V), or a salt thereof is a
  • the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
  • the present application further provides a process for preparing a compound of
  • formula ( salt thereof comprising reacting a compound of formula ( salt thereof, with a source of sulfur
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • X is O
  • R 4 is hydrogen
  • o 1, 2, or 3
  • the source of sulfur is selected from P2S5, H2S, Ss, 2,4-Bis(4- methoxyphenyl)- 1,3, 2, 4-dithiadiphosphetane-2, 4-disulfide (Lawesson’s reagent), MSH, and M2S, where M is Na, K, Li, or NIL.
  • the compound of formula (VI), or a salt thereof is reacted with a source of sulfur for at least 30 minutes.
  • the compound of formula (VI), or a salt thereof is reacted with the source of sulfer in an organic solvent.
  • the compound of formula (V), or a salt thereof is a
  • the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
  • the compound of formula (VI), or a salt thereof is a
  • the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
  • the present application further provides a process of preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • X is O;
  • R 4 is hydrogen; o is 1, 2, or 3;
  • the activating agent is triflic anhydride.
  • Q is selected from the group consisting of halogen, - 0(C0)R 7 , -0(C0 2 R 7 ), -OR 7 , -0(S0)R 7 , -0(S0 2 )R 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , -OPCl 2 , and - 0P(0)(0R 7 ) 2 , wherein R 7 is optionally substituted alkyl.
  • the compound of formula (V), or a salt thereof is a
  • the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
  • the compound of formula (VII), or a salt thereof is a
  • the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
  • the present application further provides a process of preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • X is S;
  • R 4 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl,
  • the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
  • the compound of formula (IV), or a salt thereof is reacted with the oxidizing agent at room temperature.
  • the compound of formula (IV), or a salt thereof is reacted with the oxidizing agent for at least 8 hours.
  • the compound of formula (IV), or a salt thereof is reacted with the oxidizing agent in an organic solvent.
  • the compound of formula (IV), or a salt thereof is a
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
  • the compound of formula (VI), or a salt thereof is a
  • the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl;
  • W is NHR 5 ;
  • X is NH;
  • Y is SR 4 ;
  • R 4 independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
  • R 5 is selected from hydrogen, and optionally substituted alky
  • the compound of formula (II), or a salt thereof is reacted with the compound of formula (III), or a salt thereof, in the presence of a base, such as an amine base (e.g., a trialkyl amine base).
  • a base such as an amine base (e.g., a trialkyl amine base).
  • the base is N- methylmorpholine, triethylamine, or N,N-diisopropylethyl amine (e.g., N,N-diisopropylethyl amine).
  • the compound of formula (II), or a salt thereof is reacted with the compound of formula (III), or a salt thereof, in the presence of one or more dehydrating agents.
  • the dehydrating agent is a molecular sieve, such as a 3 A or 4 A molecular sieve.
  • the compound of formula (IX), or a salt thereof is a
  • the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
  • NBS l-bromo-2,5-pyrrolidinedione
  • NBS tert-butyl hypochlorite
  • the compound of formula (IX), or a salt thereof is reacted with the oxidizing agent at room temperature.
  • the compound of formula (IX), or a salt thereof is reacted with the oxidizing agent for at least 8 hours.
  • the compound of formula (IX), or a salt thereof is reacted with the oxidizing agent in an organic solvent.
  • the compound of formula (IX), or a salt thereof is a
  • the compound of formula or a salt thereof, or a mixture of any of the foregoing.
  • the compound of formula or a salt thereof, or a mixture of any of the foregoing.
  • the compound of formula (VIII), or a salt thereof is a
  • the compound of formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • Q is a leaving group
  • the compound of formula (VIII), or a salt thereof is prepared according to any one of the foregoing processes. In certain embodiments, the compound of formula (VI), or a salt thereof, is prepared according to any one of the foregoing processes. In certain embodiments, the compound of formula (VII), or a salt thereof, is prepared according to any one of the foregoing processes.
  • the source of ammonia is selected from liquid ammonia, ammonia solution, or an ammonium salt.
  • the ammonium salt is ammonium chloride, ammonium acetate, or ammonium carbonate.
  • the compound of formula (VIII), or a salt thereof is a
  • the compound formula (Villa), or a salt thereof, and the compound of formula (Vlllb), or a salt thereof are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
  • the compound of formula (VI), or a salt thereof is a
  • the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
  • the compound of formula (VII), or a salt thereof is a
  • the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
  • the compound of formula (I), or a salt thereof is a compound
  • the compound formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
  • the present application provides a process for preparing a compound of formula (I”)
  • R 1 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR 5 ;
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alky
  • R 1 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR 5 ;
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alky
  • the present application further provides a process for preparing a compound of
  • R 1 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl;
  • W is NHR 5 ;
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl;
  • Y is OR 4 , NHR 4 or SR 4 , such as NHR 4 or SR 4 ;
  • R 4 independently for each occurrence, is
  • the present application further provides a process for preparing a compound of
  • R 1 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl
  • W is NHR 5
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl
  • Y is OR 4 , NHR 4 or SR 4 , such as NHR 4 or SR 4 ;
  • R 4 independently for each occurrence, is selected from hydrogen and
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl
  • W is NHR 5
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl
  • Y is OR 4 , NHR 4 or SR 4 , such as NHR 4 or SR 4 ;
  • R 4 independently for each occurrence, is selected from hydrogen
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl;
  • W is NHR 5 ;
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl;
  • Y is OR 4 , NHR 4 or SR 4 , such as NHR 4 or SR 4 ;
  • R 4 independently for each occurrence, is
  • the compound of formula (I), or salt thereof, the compound of formula (G), or salt thereof, or the compound of formula (I”), or salt thereof is prepared comprising a reaction with a compound of formula (Ilia), the compound of formula (I), or salt thereof, the compound of formula (G), or salt thereof, or the compound of formula (I”), or salt thereof, is a compound of formula (la),
  • the compound of formula (I), or salt thereof, the compound of formula (G), or salt thereof, or the compound of formula (I”), or salt thereof is prepared comprising a reaction with a compound of formula (Illb), the compound of formula (I), or salt thereof, the compound of formula (G), or salt thereof, or the compound of formula (I”), or salt thereof, is a compound of formula (lb),
  • the present application further provides a process of preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl;
  • W is NHR 5 ;
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl;
  • Y is OR 4 , NHR 4 or SR 4 , such as NHR 4 or SR 4 ;
  • R 4 independently for each occurrence, is
  • the present application further provides a process of preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl
  • W is NHR 5 ;
  • X is O, S, or NR 10 , where R 10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl;
  • Y is OR 4 , NHR 4 or SR 4 , such as NHR 4 or SR 4 ;
  • R 4 independently for each occurrence, is selected
  • W is Nfh.
  • R 3 is optionally substituted alkyl, such as methyl.
  • r is 2.
  • o is 1. In certain embodiments, s is 1.
  • W is NH2; R 3 is optionally substituted alkyl, such as methyl; r is 2; 0 is 1; and s is 1
  • (II), or a salt thereof is a compound of formula (Ila), , or a salt thereof.
  • Z is NH.
  • the compound of formula (II), or a salt thereof, such as a compound of formula (Ila), or a salt thereof is reacted with the compound of formula (III), or a salt thereof, such as compound of formula (Ilia), or a salt thereof, or a compound of formula (Illb), or a salt thereof, in the presence of a suitable base.
  • suitable bases include organic bases, inorganic bases and resinous bases.
  • Organic bases include amine bases such as ammonia, alkyl amines, for example methyl amine, dimethyl amine, diethyl amine, trimethyl amine, tri ethyl amine, butyl amine, tetra-methy lethy 1 d i amin e, isopropyl amine and diisopropyl amine, aniline, indole, pyridine, pyrimidine, pyrrolidine, N-methylpyrrolidone, pyrrole, pyrazole, imidazole, morpholine, N-methylmorpholine, piperidine, piperazine, N,N- dimethylpiperizine, and the like.
  • amine bases such as ammonia, alkyl amines, for example methyl amine, dimethyl amine, diethyl amine, trimethyl amine, tri ethyl amine, butyl amine, tetra-methy lethy 1 d i amin e,
  • Inorganic bases include bicarbonate, carbonate and hydroxide bases, for example, ammonium hydroxide, ammonium carbonate, barium hydroxide, barium carbonate, calcium carbonate, calcium hydroxid, cesium carbonate, cesium hydroxide, lithium amide, lithium carbonate, lithium hydroxide, magnesium hydroxide, magnesium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium amide and soda lime.
  • the base is an amine base (e.g., a trialkyl amine base).
  • the base is N-methylmorpholine, triethylamine, or N,N- diisopropylethyl amine (e.g., N,N-diisopropy lethy 1 amine).
  • the compound of formula (II), or a salt thereof, such as a compound of formula (Ila), or a salt thereof is reacted with the compound of formula (III), or a salt thereof, such as compound of formula (Ilia), or a salt thereof, or a compound of formula (Illb), or a salt thereof, in the presence of one or more dehydrating agents.
  • the dehydrating agent is a molecular sieve, such as a 3 A or 4 A molecular sieve.
  • the compound of formula (IV), or a salt thereof is a
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99: 1, or about 100: 1.
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (IV’), or a salt thereof is a
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1 : 1, at least 2:1, at least 3: 1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (Ilia), or salt thereof is selected from:
  • the compound of formula (Ilia), or salt thereof is selected from salt thereof.
  • the compound of formula (Illb), or salt thereof is selected from:
  • the compound of formula (Illb), or salt thereof is selected from salt thereof.
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • X is NH; NHR 4 or SR 4
  • the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent at about room temperature, between about 1 °C below room temperature to about 1 °C above room temperature, between about 2 °C below room temperature to about 2 °C above room temperature, between about 5 °C below room temperature to about 5 °C above room temperature, between about 10 °C below room temperature to about 10 °C above room temperature, between about 15 °C below room temperature to about 15 °C above room temperature, or between about 20 °C below room temperature to about 120 °C above room temperature.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent at about room temperature.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 hours. In certain embodiments, the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent in a suitable solvent.
  • the solvent is a halogenated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane, tetrachloroethylene, trichloroethane, or trichloroethylene), an aliphatic hydrocarbon (e.g., cyclohexene, cyclohexane, n-hexane, n- heptane, pentane, or petroleum ether), an aromatic hydrocarbon (e.g., benzene, naphthalene, toluene, or xylenes), an alcohol (e.g., methanol, ethanol, propanol, or butanol), a glycol (e.g., ethylene glycol), an ether (e.g., ethylene glycol), an
  • the compound of formula (I), or a salt thereof is prepared from a compound of formula (IV), or a salt thereof, the compound of formula (IV), or a salt thereof, is a compound of formula (IV a), or a sat t ereo, or a mxture o any o t e foregoing.
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (I), or a salt thereof is prepared from a compound of formula (IV), or a salt thereof, the compound of formula (IV’), or a salt thereof, is a compound of formula (IV’a),
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (I), or a salt thereof is prepared from a compound of formula (IV), or a salt thereof, the compound formula (la) , or a salt thereof, and the compound of formula (lb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20: 1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100: 1.
  • the compound of formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (I), or a salt thereof is prepared from a compound of formula (IV’), or a salt thereof, the compound formula (lb) , or a salt thereof, and the compound of formula (la), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (lb), or a salt thereof, and the compound of formula (la), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100:1.
  • the compound of formula (lb), or a salt thereof, and the compound of formula (la), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the present invention further provides a process for preparing a compound of formula
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • X is O;
  • R 4 is selected from hydrogen and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl,
  • the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent at room temperature, between about 1 °C below room temperature to about 1 °C above room temperature, between about 2 °C below room temperature to about 2 °C above room temperature, between about 5 °C below room temperature to about 5 °C above room temperature, between about 10 °C below room temperature to about 10 °C above room temperature, between about 15 °C below room temperature to about 15 °C above room temperature, or between about 20 °C below room temperature to about 120 °C above room temperature.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent at about room temperature.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof reacted with the oxidizing agent for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 hours.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent for at least 8 hours.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent in a suitable solvent, such as an organic solvent.
  • the solvent is a halogenated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane, tetrachloroethylene, trichloroethane, or trichloroethylene), an aliphatic hydrocarbon (e.g., cyclohexene, cyclohexane, n-hexane, n-heptane, pentane, or petroleum ether), an aromatic hydrocarbon (e.g., benzene, naphthalene, toluene, or xylenes), an alcohol (e.g., methanol, ethanol, propanol, or butanol), a glycol (e.g., ethylene glycol), an halogenated hydrocarbon (e.
  • the compound of formula (V), or a salt thereof is prepared from a compound of formula (IV), or a salt thereof, the compound of formula (IV), or a salt thereof, is a compound of formula (IVa),
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.1 n certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of about
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (V), or a salt thereof is prepared from a compound of formula (IV’), or a salt thereof, the compound of formula (IV’), or a salt thereof, is a compound of formula (IV’a),
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (IV’ a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (V), or a salt thereof is a
  • the compound of formula (V), or a salt thereof is prepared from a compound of formula (IV), or a salt thereof, the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99: 1, or at least 100:1.
  • the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of from at least 1 : 1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (V), or a salt thereof is prepared from a compound of formula (IV’), or a salt thereof
  • the compound formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • X is O;
  • the compound of formula (V), or a salt thereof is prepared according to any one of the foregoing processes.
  • the source of sulfur is selected from P2S5, H2S, Ss, 2,4-Bis(4- methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson’s reagent), MSH, and M2S, where M is Na, K, Li, or NH 4 .
  • the compound of formula (VI), or a salt thereof is reacted with a source of sulfur for at least 5, at least 10, at least 15, at least 20, at least 25, at least 30 minutes, or at least an hour. In certain embodiments, the compound of formula (VI), or a salt thereof, is reacted with a source of sulfur for at least 30 minutes.
  • the compound of formula (VI), or a salt thereof is reacted with the source of sulfur in a suitable solvent, such as an organic solvent.
  • the solvent is a halogenated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane, tetrachloroethylene, trichloroethane, or trichloroethylene), an aliphatic hydrocarbon (e.g., cyclohexene, cyclohexane, n-hexane, n-heptane, pentane, or petroleum ether), an aromatic hydrocarbon (e.g., benzene, naphthalene, toluene, or xylenes), an alcohol (e.g., methanol, ethanol, propanol, or butanol), a glycol (e.g., ethylene glycol), an ether (e.g., diethyl ether), an halogenated hydrocarbon (e.
  • the compound of formula (V), or a salt thereof is a
  • the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1 : 1, at least 2: 1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, at least 9: 1, at least 10: 1, at least 20: 1, at least 30: 1, at least 40: 1, at least 50: 1, at least 60: 1, at least 70: 1, at least 80: 1, at least 90: 1, at least 95: 1, at least 96:1, at least 97: 1, at least 98: 1, at least 99: 1, or at least 100: 1.
  • the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, or at least 9:1, such as at least 9:1.
  • the compound of formula (V), or a salt thereof is prepared from a compound of formula (IV), or a salt thereof
  • the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (V), or a salt thereof is prepared from a compound of formula (IV’), or a salt thereof.
  • the compound of formula (VI), or a salt thereof is a
  • the compound formula (Via), or a salt thereof, and the compound of formula (Vlb), or a salt thereof are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1 : 1, at least 2: 1, at least 3: 1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Via), or a salt thereof, and the compound of formula (Vlb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96: 1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (Via), or a salt thereof, and the compound of formula (Vlb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound formula (Vlb), or a salt thereof, and the compound of formula (Via), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Vlb), or a salt thereof, and the compound of formula (Via), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (Vlb), or a salt thereof, and the compound of formula (Via), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the present application further provides a process of preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • X is O;
  • the activating agent is triflic anhydride.
  • Q is selected from the group consisting of halogen, - 0(CO)R 7 , -0(C0 2 R 7 ), -OR 7 , -0(SO)R 7 , -0(S0 2 )R 7 , -SR 7 , -SOR 7 , -S0 2 R 7 , -OPCl 2 , and - 0P(0)(0R 7 ) 2 , wherein R 7 is optionally substituted alkyl.
  • the compound of formula (VII), or a salt thereof is prepared from a compound of formula (V), or a salt thereof, the compound of formula (V), or a salt thereof, is a compound of formula (Va),
  • the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6: 1, at least 7: 1, at least 8: 1, or at least 9:1, such as at least.
  • the compound of formula (VII), or a salt thereof is prepared from a compound of formula (V), or a salt thereof, the compound formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1 : 1, at least 2: 1, at least 3: 1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96: 1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (Vb), or a salt thereof, and the compound of formula (V a), or a salt thereof are present in a ratio of from at least 1 : 1 , at least 2 : 1 , at least 3 : 1 , at least 4:1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8:1, or at least 9:1, such as at least.
  • the compound of formula (VII), or a salt thereof is a
  • the compound formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof are present in ratio of from at least 1 : 1 to 100: 1, such as at least 1 : 1, at least 2: 1, at least 3: 1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96: 1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof are present in ratio of from at least 1 : 1 to 100: 1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8: 1, about 9: 1, about 10: 1, about 20: 1, about 30: 1, about 40: 1, about 50: 1, about 60: 1, about 70: 1, about 80: 1, about 90: 1, about 95: 1, about 96: 1, about 97: 1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof are present in a ratio of from at least 1: 1, at least 2: 1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, or at least 9: 1, such as at least 9: 1.
  • the present application further provides a process of preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • X is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl
  • the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent at room temperature, between about 1 °C below room temperature to about 1 °C above room temperature, between about 2 °C below room temperature to about 2 °C above room temperature, between about 5 °C below room temperature to about 5 °C above room temperature, between about 10 °C below room temperature to about 10 °C above room temperature, between about 15 °C below room temperature to about 15 °C above room temperature, or between about 20 °C below room temperature to about 120 °C above room temperature.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent at about room temperature.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof reacted with the oxidizing agent for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 hours.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent for at least 8 hours.
  • the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof is reacted with the oxidizing agent in a suitable solvent, such as an organic solvent.
  • the solvent is a halogenated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane, tetrachloroethylene, trichloroethane, or trichloroethylene), an aliphatic hydrocarbon (e.g., cyclohexene, cyclohexane, n-hexane, n-heptane, pentane, or petroleum ether), an aromatic hydrocarbon (e.g., benzene, naphthalene, toluene, or xylenes), an alcohol (e.g., methanol, ethanol, propanol, or butanol), a glycol (e.g., ethylene glycol), an halogenated hydrocarbon (e.
  • the compound of formula (VI), or a salt thereof is prepared from a compound of formula (IV), or a salt thereof, the compound of formula (IV), or a salt thereof, is a compound of formula (IVa), or a sat t ereo, or a mxture o any o t e foregoing.
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (VI), or a salt thereof is prepared from a compound of formula (IV), or a salt thereof, the compound of formula (IV’), or a salt thereof, is a compound of formula (IV’a),
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about
  • the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (VI), or a salt thereof is a
  • the compound of formula (VI), or a salt thereof is preparared from a compound of formula (IV), or a salt thereof
  • the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of from at least 1 : 1 to 100: 1 , such as at least 1 : 1 , at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of from at least 1 : 1 , at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (VI), or a salt thereof is preparared from a compound of formula (IV’), or a salt thereof
  • the compound formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99: 1, or about 100: 1.
  • the compound of formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • Z is O, S, or NR 9 , where R 9 is selected from H, hydroxyl,
  • the compound of formula (II), or a salt thereof is reacted with the compound of formula (III), or a salt thereof (e.g., a compound of formula (Ilia), or a salt thereof, or a compound of formula (Illb), or a salt thereof), in the presence of a base, such as an amine base (e.g., a trialkyl amine base).
  • a base such as an amine base (e.g., a trialkyl amine base).
  • the base is N- methylmorpholine, triethylamine, or N,N-diisopropylethyl amine (e.g., N,N-diisopropylethyl amine).
  • the compound of formula (II), or a salt thereof is reacted with the compound of formula (III), or a salt thereof (e.g., a compound of formula (Ilia), or a salt thereof, or a compound of formula (Illb), or a salt thereof), in the presence of one or more dehydrating agents.
  • the dehydrating agent is a molecular sieve, such as a 3 A or 4 A molecular sieve.
  • the compound of formula (IX), or a salt thereof is a
  • the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1: 1, at least 2:1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, at least 9: 1, at least 10: 1, at least 20: 1, at least 30: 1, at least 40: 1, at least 50: 1, at least 60: 1, at least 70: 1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99: 1, or about 100: 1.
  • the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (IX’), or a salt thereof is a
  • the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1 : 1, at least 2:1, at least 3: 1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or
  • the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
  • the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof is reacted with the oxidizing agent at room temperature, between about 1 °C below room temperature to about 1 °C above room temperature, between about 2 °C below room temperature to about 2 °C above room temperature, between about 5 °C below room temperature to about 5 °C above room temperature, between about 10 °C below room temperature to about 10 °C above room temperature, between about 15 °C below room temperature to about 15 °C above room temperature, or between about 20 °C below room temperature to about 120 °C above room temperature.
  • the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof is reacted with the oxidizing agent at about room temperature.
  • the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof is reacted with the oxidizing agent for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 hours.
  • the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof is reacted with the oxidizing agent for at least 8 hours.
  • the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof is reacted with the oxidizing agent in a suitable solvent, such as an organic solvent.
  • the solvent is a halogenated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane, tetrachloroethylene, trichloroethane, or trichloroethylene), an aliphatic hydrocarbon (e.g., cyclohexene, cyclohexane, n-hexane, n-heptane, pentane, or petroleum ether), an aromatic hydrocarbon (e.g., benzene, naphthalene, toluene, or xylenes), an alcohol (e.g., methanol, ethanol, propanol, or butanol), a glycol (e.g., ethylene glycol),
  • the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof is reacted with the oxidizing agent in a halogenated solvent (e.g., dichloromethane).
  • a halogenated solvent e.g., dichloromethane
  • the compound of formula (VIII), or a salt thereof is prepared from a compound of formula (IX), or a salt thereof, the compound of formula (IX), or a salt thereof, is a compound of formula (IXa),
  • the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6: 1, at least 7: 1, at least 8: 1, or at least 9:1, such as at least.
  • the compound of formula (VIII), or a salt thereof is prepared from a compound of formula (IX’), or a salt thereof, the compound of formula (IX’), or a salt thereof, is a compound of formula (IX’a),
  • the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100:1.
  • the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (VIII), or a salt thereof is a
  • the compound formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof are present in a ratio of from at least 1 : 1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof are present in a ratio of from at least 1: 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100:1.
  • the compound of formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the present application further provides a process for preparing a compound of
  • R 6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R 1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
  • R 2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • R 3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
  • Q is a leaving group;
  • R 4 is lower alkyl;
  • the compound of formula (VIII), or a salt thereof is prepared according to any one of the foregoing processes. In certain embodiments, the compound of formula (VI), or a salt thereof, is prepared according to any one of the foregoing processes. In certain embodiments, the compound of formula (VII), or a salt thereof, is prepared according to any one of the foregoing processes.
  • the source of ammonia is selected from liquid ammonia, ammonia solution, or an ammonium salt.
  • the ammonium salt is ammonium chloride, ammonium acetate, or ammonium carbonate.
  • the compound of formula (I), or a salt thereof is prepared from a compound of formula (VIII), or a salt thereof, the compound of formula (VIII), or a salt thereof, is a compound of formula (Villa),
  • the compound formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (I), or a salt thereof is prepared from a compound of formula (VIII), such as a compound of formula (VUIb), or a salt thereof, or a compound of formula (VUIb), or a salt thereof, or a mixture of nay one ofhte foreiong, the compound formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99: 1, or at least 100
  • the compound of formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
  • the compound of formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof are present in a ratio of from at least 1: 1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100:1.
  • the compound of formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (I), or a salt thereof is prepared from a compound of formula (VII), the compound of formula (VII), or a
  • the compound formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound of formula (I), or a salt thereof is a compound
  • the compound formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1.
  • the compound of formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof are present in a ratio of from at least 1 : 1, at least 2: 1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • the compound formula (lb), or a salt thereof, and the compound of formula (la), or a salt thereof are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.
  • the compound of formula (lb), or a salt thereof, and the compound of formula (la), or a salt thereof are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20: 1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100: 1.
  • the compound of formula (lb), or a salt thereof, and the compound of formula (la), or a salt thereof are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
  • alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or oxime are substituted, they are substituted, valency permitting, with one or more substituents selected from substituted or unsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g., trifluoromethoxy), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy, aminoalkoxy, acylamino, acylaminoalkyl
  • optically active or racemic forms Compounds of the present application containing one or multiple asymmetrically substituted atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or by synthesis using optically active reagents.
  • compounds of the application may be racemic. In certain embodiments, compounds of the application may be enriched in one enantiomer. For example, a compound of the application may have greater than 30% ee, 40% ee, 50% ee,
  • the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula (I), (la), such as (la’), or (lb), such as (lb’)).
  • An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
  • compounds of the application may have more than one stereocenter. In certain such embodiments, compounds of the application may be enriched in one or more diastereomer. For example, a compound of the application may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
  • the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of formula (I), (la), such as (la’), or (lb), such as (lb’)).
  • a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product; the type of transformation is limited only by the inherent incompatibility of other functional groups contained in the molecule to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood by one skilled in the art of organic synthesis.
  • any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or tautomeric forms, or a mixture thereof.
  • any formula given herein is intended to refer also to a solvate, such as a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • Any formula given herein is intended to refer to amorphous and/or crystalline physical forms of the compound.
  • the compounds described herein may be analytically pure, or a mixture in which the compound comprises at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% by weight of the mixture.
  • “subject” refers to both mammals and non-mammals.
  • Mammals include, e.g., humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. mice, rats, rabbits, dogs, cats, cattle, horses, sheep, and goats.
  • Non-mammals include, e.g., worms, fish and birds.
  • the subject is a human.
  • substantially refers to being completely or almost completely; e.g., a composition that is "substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is
  • substantially pure is there are only negligible traces of impurities present.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino refers to an amino group substituted with an acyl group and may be represented, e.g., by the formula hydrocarbylC(0)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and “substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds.
  • substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. E.g., substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing one or more hydrogens on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds.
  • substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. E.g., substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • An“alkyl” group or“alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated.
  • a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, such as from 1 to 12 carbon atoms, preferably from 1 to about 10, more preferably from 1 to 4, unless otherwise defined.
  • straight chained and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec -butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, pentyl and octyl.
  • a Ci-Ce straight chained or branched alkyl group is also referred to as a "lower alkyl" group.
  • alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen or more hydrogens on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, e.g., a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF 3 , -CN, and the like.
  • the term“(ATOM)i j” with j > i when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from i to j (including i and j) atoms.
  • the term“C x-y alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc.
  • Co alkyl refers to a hydrogen atom where the group is in a terminal position, a bond if internal.
  • C 3-6 cycloalkyl refers to a cycloalkyl as defined herein that has 3 to 6 carbon ring atoms.
  • the terms“C2- y alkenyl” and “C2- y alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
  • the terms“amine” and“amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein each R 30 independently represents a hydrogen or a hydrocarbyl group, or two R 30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • amide refers to a group: wherein each R 30 independently represent a hydrogen or hydrocarbyl group, or two R 30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • R 29 and R 30 independently represent hydrogen or a hydrocarbyl group, such as an alkyl
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • halo represents fluoro, chloro, bromo, or iodo.
  • haloalkyl refers to an alkyl group with one or more halo substituents, or one, two, or three halo substituents.
  • haloalkyl groups include -
  • heteroatom refers to an atom of any element other than carbon or hydrogen.
  • exemplary heteroatoms include but are not limited to nitrogen, oxygen, and sulfur.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
  • aryl includes substituted or unsubstituted monocyclic aromatic rings in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • An“aroyl” group refers to an aryl group bonded via an exocyclic carbonyl group, such as a benzoyl group.
  • heteroaryl includes substituted or unsubstituted monocyclic aromatic ring system, preferably 5- to 7-membered aromatic rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one to two heteroatoms.
  • a 5- membered heteroaryl is furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole.
  • a 6- membered heteroaryl is pyridine, pyrazine, pyrimidine, pyridazine, or triazine.
  • heteroaryl also include substituted or unsubstituted“polycyclic” ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • heteroaryl groups include but are not limited to the following entities, in the form of properly bonded moieties:
  • heteroarylkyl refers to an alkyl group substituted with a heteroaryl group.
  • A“heteroaroyl” group refers to a heteroaryl group bonded via an exocyclic carbonyl group, analogous to a benzoyl group but wherein the phenyl ring of the benzoyl group is replaced by a heteroaryl group.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to lO-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and“heterocyclic” also include substituted or unsubstituted polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or
  • heterocyclyls include, e.g., piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group which is optionally substituted.
  • carbocycle refers to a saturated or unsaturated ring in which each atom of the ring is carbon.
  • carbocycle includes both aromatic carbocycles and non-aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term“fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings ln an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • Exemplary“carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2. l]heptane, l,5-cyclooctadiene, l,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, l,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- lH-indene and bicyclo[4. l.0]hept-3-ene.“Carbocycles” may be susbstituted at any one or more positions capable of bearing a hydrogen atom.
  • A“cycloalkyl” group refers to a substituted or unsubstituted cyclic hydrocarbon which is completely saturated.“Cycloalkyl” includes substituted or
  • a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. Such a monocyclic cycloalkyl group may be substituted or unsubstituted.
  • the second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings that are substituted or unsubstituted.
  • Cycloalkyl includes substituted or unsubstituted bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • fused cycloalkyl refers to a substituted or unsubstituted bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • A“cycloalkenyl” group refers to a cyclic hydrocarbon containing one or more double bonds.
  • A“cycloalkynyl” group is a cyclic hydrocarbon containing one or more triple bonds.
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are“fused rings”.
  • rings e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • carbonate is art-recognized and refers to a group -OCO2-R 30 , wherein R 30 represents a hydrocarbyl group.
  • ester refers to a group -C(0)OR 3 ° wherein R 30 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.
  • ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle.
  • Ethers include“alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • sulfate is art-recognized and refers to the group -OSO3H, or a
  • R 29 and R 30 independently represents hydrogen or hydrocarbyl, such as alkyl, or R 29 and R 30 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • sulfoxide is art-recognized and refers to the group -S(0)-R 3 °, wherein R 30 represents a hydrocarbyl.
  • sulfonate is art-recognized and refers to the group SO3H, or a
  • sulfone is art-recognized and refers to the group -S(0)2-R 3 °, wherein R 30 represents a hydrocarbyl.
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(0)SR 3 ° or -SC(0)R 3 ° wherein R 30 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with asulfur.
  • urea is art-recognized and may be represented by the general formula "N'V r3 °
  • R 29 and R 30 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R 29 taken together with R 30 and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • substitution refers to moieties having substituents replacing one or more hydrogens on one or more carbons of the backbone. It will be understood that“substitution” or“substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term“substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • “substituted” means that the specified group or moiety bears one, two, or three substituents.
  • “substituted” means that the specified group or moiety bears one or two substituents.
  • “substituted” refers to the specified group or moiety bears one substituent.
  • Substituents can include any substituents described herein, e.g., a lower alkyl (such as Ci-6 alkyl, e.g., -methyl, -ethyl, and -propyl), a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a
  • references to chemical moieties herein are understood to include substituted variants.
  • reference to an“aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • the term“unsubstituted” refers to that the specified group bears no substituents.
  • any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al, Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY.
  • nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2 -trimethyls ilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro- veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxy lprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or T1PS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • A“pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al, “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, e.g., treatment of the free base with an inorganic acid, such as hydrochloric acid,
  • hydrobromic acid sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a s
  • base addition salts can be prepared by any suitable method available in the art, e.g., treatment of such compound with a sufficient amount of the desired the desired base, either neat or in a suitable inert solvent.
  • suitable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, ammonium, zinc, or magnesium salt, or other metal salts; organic amino salts, such as, alkyl, dialkyl, trialkyl, or tetra-alkyl ammonium salts.
  • salts include, but are not limited to, camsylate, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen- phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fiimarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsul
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present application.
  • A“hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • A“solvate” is a similar composition except that a solvent other that water, such as with methanol, ethanol, dimethylformamide, diethyl ether and the like replaces the water.
  • methanol or ethanol can form an “alcoholate,”” which can again be stoichiometic or non-stoichiometric.
  • Mixtures of such solvates or hydrates can also be prepared.
  • the source of such solvate or hydrate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • the compounds of the application can exist as various polymorphs, pseudo-polymorphs, or in amorphous state.
  • polymorph refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo-polymorphs, such as hydrates, solvates, or salts of the same compound.
  • pseudo-polymorphs such as hydrates, solvates, or salts of the same compound.
  • Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as x-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents.
  • crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry.
  • isolated compound refers to a preparation of a compound, or a mixture of compounds, wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds.“Isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically.
  • an“isolated compound” refers to a preparation of a compound of any of the formulae disclosed herein, or a mixture of compounds according to any of the formulae disclosed herein, which contains the named compound or mixture of compounds according to any of the formulae disclosed herein in an amount of at least 10 percent by weight of the total weight.
  • the preparation contains the named compound or mixture of compounds in an amount of at least 50% by weight of the total weight; more preferably at least 80% by weight of the total weight; and most preferably at least 90%, at least 95% or at least 98% by weight of the total weight of the preparation.
  • the compounds of the application and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
  • a compound described herein or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the application encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings.
  • Such tautomerism can also occur with substituted pyrazoles such as 3 -methyl, 5- methyl, or 3,5-dimethylpyrazoles, and the like.
  • Another example of tautomerism is amido- imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom. E.g., the equilibrium: example of tautomerism.
  • a structure of any compound depicted herein as one tautomer is intended to also include the other tautomer.
  • the isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called“enantiomers.”
  • Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light.
  • Single enantiomers are designated according to the Cahn-Ingold-Prelog system.
  • the priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer.
  • the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula (I), (I-A) or (I-B)).
  • An enantiomerically enriched mixture may comprise, e.g., at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • a compound of the application may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee.
  • the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
  • compounds of the application may have more than one stereocenter. In certain such embodiments, compounds of the application may be enriched in one or more diastereomer. E.g., a compound of the application may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
  • Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques, such as but not limited to, normal and reverse phase chromatography, and crystallization. According to one such method, a racemic mixture of a compound of the application, or a chiral intermediate thereof, is separated using a chiral salt or carried out on a Chiralcell OD column. The column is operated according to the manufacturer’s instructions.
  • Isolated optical isomers can also be prepared by the use of chiral intermediates or catalysts in synthesis.
  • the optical center chiral center
  • Chiral catalyst can be used to impart at least some degree of enantiomeric purity to products of reactions catalyzed by the chiral catalyst.
  • compounds having at least some degree of enantiomeric enrichment can be obtained by physical processes such as selective
  • a variety of compounds in the present application may exist in particular geometric or stereoisomeric forms.
  • the present application takes into account all such compounds, including tautomers, cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this application. All tautomeric forms are encompassed in the present application. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this application, unless the stereochemistry or isomeric form is specifically indicated.
  • the preferred compounds of the present application have a particular spatial arrangement of substituents on the aromatic rings, which are related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature“para” for 1 ,4-substitution,“meta” for
  • the present application further includes all pharmaceutically acceptable isotopically labeled compound [e.g., of formula (I), (I-A) or (I-B)].
  • An “isotopically” or “radio-labeled” compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
  • hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a Ci-6 alkyl or a Ci-6 alkoxy are replaced with deuterium, such as ⁇ /3-methoxy or 1 , 1 ,2,2-c/4-3-mcthylbutyl).
  • deuterium or tritium e.g., hydrogen atoms on a Ci-6 alkyl or a Ci-6 alkoxy are replaced with deuterium, such as ⁇ /3-methoxy or 1 , 1 ,2,2-c/4-3-mcthylbutyl.
  • isotopically labeled compounds e.g., compounds of formula(I), (I-A) or (I- B)
  • compounds of formula(I), (I-A) or (I- B) e.g., those incorporating a radioactive isotope
  • the radioactive isotopes tritium, i.e., 3 H, and carbon 14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Such isotopically labeled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds e.g., of formula (I), (I-A) or (I-B)] or their corresponding prodrugs can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Suitable isotopes that may be incorporated in compounds of the present application include but are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H (also written as D for deuterium), 3 H (also written as T for tritium), U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl , 82 B r, 75 Br, 76 B r, 77 Br, 123 I, 124 I, 125 I, 131 1, 31 P, and 32 P.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine such as 2 H (also written as D for deuterium), 3 H (also written as T for tritium), U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 Cl , 82 B r, 75 Br, 76 B
  • Isotopically labeled compounds of this application and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Provisos may apply to any of the disclosed categories or embodiments such that specific embodiments or species may be excluded from such categories or embodiments.
  • the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • the solvents used in preparing the example compounds were commercial anhydrous grades and were used without further drying or purification.
  • MgS0 4 anhydrous magnesium sulfate (drying agent); MPLC: medium pressure liquid chromatography; MTBE: methyl /er/-butyl ether; NaHCCh: sodium bicarbonate; NH 4 Cl: ammonium chloride; q: quartet; quin: quintet; rt: room temperature; sat: saturated; t: triplet; TEA: triethylamine; tBuOH: /er/-butanol; td: triplet of doublet; TFA: trifluoroacetic acid; and THF: tetrahydrofuran.
  • MPLC medium pressure liquid chromatography
  • MTBE methyl /er/-butyl ether
  • NaHCCh sodium bicarbonate
  • NH 4 Cl ammonium chloride
  • q quartet
  • quin quintet
  • rt room temperature
  • sat saturated
  • t triplet
  • TEA triethylamine
  • tBuOH /
  • the X H NMR spectra were recorded on a Bruker Ultrashield AV3 500 MHz spectrometer fitted with a QCI cryoprobe and operating with Topspin3.5pl5 software or on a Bruker Ultrashield AV3 400 MHz spectrometer fitted with a BBFO probe and operating with Topspin3.5pl5 software.
  • NMR data were processed using either ACD Spectrus Processor 2015 Pack 2 or Mestrenova version 11.0.2. The chemical shifts (d) are reported in parts-per- million from the deuterated solvent used.
  • the 13 C NMR spectra were recorded on a Bruker Ultrashield AV3 500 MHz spectrometer fitted with a QCI cryoprobe and operating with Topspin3.5pl5 software or on a Bruker Ultrashield AV3 400 MHz spectrometer fitted with a BBFO probe and operating with Topspin3.5pl5 software.
  • NMR data were processed using either ACD Spectrus Processor 2015 Pack 2 or Mestrenova version 11.0.2. The chemical shifts (d) are reported in parts-per- million from the deuterated solvent used.
  • Waters UHPLC-MS consisting of an Acquity UHPLC (mobile phase: 5-90% B with 5% 250 mM ammonium acetate; A: Water, B: MeCN; 4.1 mins) on an Acquity BEH C18 column (50 mm x 2.1 mm with a 1.7 pm particle size) and a Waters QDa single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative ion mode.
  • the mass spectrometer was operated with a source temperature of 120 °C, capillary voltage of 0.8 kV, probe temperature of 600 °C.
  • the mass spectrometer scanning range was m/z 100-1200.
  • Waters UHPLC-MS consisting of an Acquity UHPLC (mobile phase: 5-90% B with 5% 250 mM ammonium acetate; A: Water, B: MeCN; 4.1 mins) on an Acquity BEH Phenyl column (50 mm x 2.1 mm with a 1.7 pm particle size) and a Waters QDa single quadrupole mass spectrometer.
  • the mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative ion mode.
  • the mass spectrometer was operated with a source temperature of 120 °C, capillary voltage of 0.8 kV, probe temperature of 600 °C.
  • the mass spectrometer scanning range was m/z 100-1200.
  • Agilent HPLC-MS consisting of an Agilent 1100 HPLC and an Agilent 6150 single quadmpole mass spectrometer.
  • the mass spectrometer was equipped with a multimode ion source (both electrospray (ESI) and atmospheric pressure chemical ionisation(APCI)) operated in positive or negative ion mode.
  • the mass spectrometer was operated with a drying gas flow rate of 6 litres/minute, nebuliser pressure of 60 psi, drying gas temperature of 300 °C, vaporiser temperature of 200 °C, capillary voltage of 2000 V, charging voltage of 2000 V, corona current of 1 mA and fragmentor voltages of 130 and 275 V.
  • the mass spectrometer scanning range was m/z 85-1200.
  • UPLC-MS Method 1, TAC Diode Array Detector.
  • the crude reaction mixture was purified by chromatography (silica gel, 3 cm x 9cm, eluting with 60% hexane / 35% ethyl acetate / 5% methanol) to afford 2/3 as a colourless oil (263 mg, 96%).
  • HPLC-MS Method 3, TAC Diode Array Detector.
  • UPLC-MS Method 1, TAC Diode Array Detector.
  • Enantiopurity (area% by chiral HPLC): Enantiomer 13 - 80.3%, Enantiomer 14 - 19.7%.
  • a 4 1 mixture of 13/14 (303.6 mg, 0.81 mmol) and /V, /V- Dii s 0 p ro pyl e t h yl a mi n e (1 mL, 6.44 mmol) were dissolved in anhydrous toluene (6 mL). Phosphorus oxychloride (0.65 mL, 6.9 mmol) was added dropwise and the mixture was heated to 90 °C for 46 hours. The mixture was cooled to room temperature to afford 15/16 as a solution in toluene.
  • UPLC-MS method Method 1, TAC Diode Array Detector.
  • HPLC-MS Method 3, TAC Diode Array Detector.
  • a 1 : 1 mixture of 13/14 (107.1 mg, 0.213 mmol), phosphorus pentasulfide (49.75 mg, 0.22 mmol) and sodium bicarbonate (29.93 mg, 0.36 mmol) were suspended in anhydrous tetrahydrofuran (3.2 mL). The mixture was heated to 50 °C for 90 mins and cooled to room temperature to afford a solution of 17/18 in tetrahydrofuran.
  • HPLC-MS Method 1, TAC Diode Array Detector.
  • UPLC-MS Method 3, TAC Diode Array Detector.
  • the b-secretase enzyme used in the TR-FRET is prepared as follows:
  • Human BACE1 the cDNA for the soluble part of the human b-Secretasel (AA1-AA460) is cloned using the BACE 1 (1 -460)-(AVT)-Fc-pGEN-IRES-neo mammalian expression vector.
  • the gene is fused to the Fc domain of IgGl (affinity tag) and stably cloned into HEK 293 cells.
  • Purified sBACE-Fc is stored in -80°C in Tris buffer, pH 9.2 and has a purity of ⁇ 40%.
  • Human BACE2 the cDNA for the soluble part of the human b-8eoG6 ⁇ h8e2 (AA1-AA473) is cloned using B ACE2( 1 -473 )-(AVT)-Fc-pDEST 12.2 mammalian expression vector.
  • the gene is fused to the Fc domain of IgGl (affinity tag) and stably cloned into HEK 293 cells.
  • Purified sBACE-Fc is stored in -80°C in 50 mM Glycine, 10 mM Tris-HCl, pH 7-8, and has a purity of -70%.
  • the enzyme (truncated form) is diluted to 6 pg/mL (stock hBacel: l.3mg/mL, hBace2: l.6mg/ml) and the TruPoint BACE1 Substrate to 200 nM (stock 120 uM) in reaction buffer (NaAcetate, chaps, triton c-100, EDTA pH4.5). A multidrop Combi is used for the liquid handling. Enzyme (7 pL) is added to the compound plate (containing 0.8 pL of compound in dimethylsulphoxide). The plate is incubated for 10 minutes. Substrate (8 pL) is then added, and the reaction proceeds for 17 minutes at r.t.
  • the reaction is stopped with the addition of Stop solution (5.5 pL, NaOAc, pH 9). Fluorescence is measured on a Pherastar plate reader using HTRF module.
  • the assay is performed in a 384 well polystyrene, black, round bottom, small volume plate (Greiner 784076).
  • the final concentration of the enzyme is 2.7 pg/mL; the final concentration of substrate is 100 nM (Km hBACEl: 250 nM, hBACE2: 350 nM).
  • the dimethylsulphoxide control instead of test compound, defines the 100% activity level and 0% activity is defined by a control inhibitor compound (2-amino-6-(3 '-methoxybiphenyl- 3-yl)-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-one, at a final concentration of 50 pM). 5 reference inhibitors with different affinities are used at all screen occasions in dose response. Diluted TR-FRET Assay
  • SH-SY5Y cells are cultured in DMEM/F-12 with Glutamax, 10% FCS and 1% non- essential amino acids and cryopreserved and stored at -140 °C at a concentration of 7.5- 9.5xl0 6 cells per vial.
  • DMEM/F- 12 with Glutamax, 10% FCS and 1 % non-essential amino acids to a 384-well tissue culture treated plate, 30 pL cell susp/well. The cell plates are then incubated for 7-24 h at 37 °C, 5% C0 2 .
  • the cell medium is removed, followed by addition of 50 pL compound diluted in DMEM/F- 12 with Glutamax, 10% FCS, 1 % non-essential amino acids to a final cone of 0.5% DMSO.
  • the compounds are incubated with the cells for 16-17 h (overnight) at 37 °C, 5%
  • MSD Meso Scale Discovery
  • the plates are used to analyse cytotoxicity using the
  • YiaLightTM Plus cell proliferation/cytotoxicity kit from Cambrex Bioscience that measures total cellular ATP.
  • the assay is performed according to the manufacture's protocol. Briefly, 10 uL cell lysis reagent is added per well. The plates are incubated at r.t. for 10 min. Two min after addition of 25 pL reconstituted ViaLightTM Plus ATP reagent, the luminescence is measured in an Envision reader. Tox threshold is a signal below 70% of the control.

Abstract

The present application relates to processes for the stereoselective preparation of dihydroimidazole ring systems. Compounds prepared according to the disclosed processes are useful in treating at least one condition associated with inhibitition of the deposition of amyloid ß peptide (Aß) and portions thereof by inhibiting or the beta site APP Cleaving Enzyme (BACE).

Description

PROCESSES FOR THE STEREOSELECTIVE PREPARATION OF BACE INHIBITORS
Related Application
This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/609,006, filed December 21, 2017, which application is hereby incorporated by reference in its entirety.
Background
Presented herein are processes for the stereoselective preparation of dihydroimidazole ring systems that are useful in treating at least one condition associated with inhibitition of the deposition of amyloid b peptide (Ab) and portions thereof by inhibiting or the beta site APP Cleaving Enzyme (BACE).
The prime neuropathological event distinguishing Alzheimer's disease (AD) is deposition of the 40-42 residue Ab in brain parenchyma and cerebral vessels. A large body of genetic, biochemical and in vivo data supports a pivotal role for Ab in the pathological cascade that eventually leads to AD. Patients usually present early symptoms (commonly memory loss) in their sixth or seventh decades of life. The disease progresses with increasing dementia and elevated deposition of Ab. In parallel, a hyperphosphorylated form of the microtubule-associated protein tau accumulates within neurons, leading to a plethora of deleterious effects on neuronal function. The prevailing working hypothesis regarding the temporal relationship between Ab and tau pathologies states that Ab deposition precedes tau aggregation in humans and animal models of the disease. Within this context, it is worth noting that the exact molecular nature of Ab mediating this pathological function is presently an issue under intense study. Most likely, there is a continuum of toxic species ranging from lower order Ab oligomers to supramolecular assemblies such as Ab fibrils.
The Ab peptide is an integral fragment of the Type I protein APP (Ab amyloid precursor protein), a protein ubiquitously expressed in human tissues. Since soluble Ab can be found in both plasma and cerebrospinal fluid (CSF), and in the medium from cultured cells, APP has to undergo proteolysis. There are three main cleavages of APP that are relevant to the pathobiology of AD, the so-called a-, b-, and g-cleavages. The a-cleavage, which occurs roughly in the middle of the Ab domain in APP, is executed by the metalloproteases
ADAMI10 or ADAMI17 (the latter also known as TACE). The b-cleavage, occurring at the N terminus of Ab, is generated by the transmembrane aspartyl protease Beta site APP
Cleaving Enzymel (BACE1). The g-cleavage, generating the Ab C termini and subsequent release of the peptide, is carried out by a multi-subunit aspartyl protease named g-secretase. ADAM 10/ 17 cleavage followed by g-secretase cleavage results in the release of the soluble p3 peptide, an N-terminally truncated Ab fragment that fails to form amyloid deposits in humans. This proteolytic route is commonly referred to as the nonamyloidogenic pathway. Consecutive cleavages by BACE1 and g-secretase generate the intact Ab peptides; hence this processing scheme has been termed the amyloidogenic pathway. With this knowledge at hand, it is possible to envision two possible avenues of lowering Ab production: stimulating non-amyloidogenic processing, or inhibiting or modulating amyloidogenic processing. This application focuses on the latter strategy, inhibition or modulation of amyloidogenic processing.
Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHW A-D), and other neurodegenerative disorders.
Neurofibrillary tangles also occur in other neurodegenerative disorders including dementia- inducing disorders (Varghese, J., et al, Journal of Medicinal Chemistry, 2003, 46, 4625-4630). b-amyloid deposits are predominately an aggregate of Ab peptide, which in turn is a product of the proteolysis of amyloid precursor protein (APP). More specifically, Ab peptide results from the cleavage of APP at the C-terminus by one or more g-secretases, and at the N- terminus by b-secretase enzyme (BACE), also known as aspartyl protease or Asp2 or Beta site APP Cleaving Enzyme (BACE), as part of the b-amyloidogenic pathway.
BACE activity is correlated directly to the generation of Ab peptide from APP (Sinha, et al, Nature, 1999, 402, 537-540), and studies increasingly indicate that the inhibition of BACE inhibits the production of Ab peptide (Roberds, S. L., et al, Human Molecular
Genetics, 2001, 10, 1317-1324). BACE is a membrane-bound type 1 protein that is synthesized as a partially active proenzyme and is abundantly expressed in brain tissue. It is thought to represent the major b-secretase activity, and is considered to be the rate-limiting step in the production of amyloid^-peptide (Ab).
Drugs that reduce or block BACE activity should therefore reduce Ab levels and levels of fragments of Ab in the brain, or elsewhere where Ab or fragments thereof deposit, and thus slow the formation of amyloid plaques and the progression of AD or other maladies involving deposition of Ab or fragments thereof. BACE is therefore an important candidate for the development of drugs as a treatment and/or prophylaxis of Ab-related pathologies such as Down's syndrome; b-amyloid angiopathy, such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage; disorders associated with cognitive
impairment such as but not limited to MCI ("mild cognitive impairment"); Alzheimer's Disease; memory loss; attention deficit symptoms associated with Alzheimer's disease;
neurodegeneration associated with diseases, such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia, and dementia associated with Parkinson's disease; progressive supranuclear palsy or cortical basal degeneration. It would therefore be useful to inhibit the deposition of Ab and portions thereof by inhibiting BACE through inhibitors.
International PCT publications WO 2012/087237 and WO 2016/055858 describe the synthesis of a number of compounds with dihydroimidazole ring systems shown to be BACE inhibitors. Improved processes of making these compounds would be advantageous.
Described herein are processes for the stereos lective preparation of dihydroimidazole ring systems that are useful in the preparation of such compounds.
Summary of the Application
The present application provides processes for preparing the compounds disclosed herein, wherein the compounds are BACE inhibitors, or salts thereof, and/or intermediates useful in the preparation of BACE inhibitors. In certain such embodiments, the BACE inhibitors are useful in the treatment or prevention of Ab-related pathologies, such as a b- amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, a disorder associated with cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer's Disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
The present application provides a process for preparing a compound of formula (I”)
( I")
Figure imgf000004_0001
, or a salt thereof, comprising reacting a compound of formula (II”) , or a salt thereof, with a compound of formula (Ilia),
Figure imgf000005_0001
w , or a salt thereof, wherein R1, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl; Y is NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; R7 is selected from halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R8 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or R7 and R8 taken together with with the carbon(s) to which they are attached, form an optionally substituted fused cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl ring; q is 0, 1, 2, 3, 4, or 5; and o is 1, 2, or 3.
The present application further provides a process for preparing a compound of
formula (
Figure imgf000005_0002
salt thereof, comprising reacting a
compound of formula (
Figure imgf000005_0003
salt thereof, with a compound (Ilia)
Figure imgf000006_0001
of formula (Ilia) , or a salt thereof, wherein R1, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; Y is NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and o is 1, 2, or 3.
The present application further provides a process for preparing a compound of
formula
Figure imgf000006_0003
, or a salt thereof, comprising reacting a
compound of formula (
Figure imgf000006_0004
, or a salt thereof, with a
X
(Ilia)
Figure imgf000006_0002
compound of formula (Ilia), W , or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or
heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl; Y is NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6.
In certain embodiments of the foregoing, the compound of formula (I), or salt thereof, the compound of formula (G), or salt thereof, or the compound of formula (I”), or salt thereof,
is a compound of formula (
Figure imgf000007_0003
, or salt thereof.
The present application further provides a process of preparing a compound of
formula
Figure imgf000007_0004
, or a salt thereof, comprising reacting a
compound of formula (
Figure imgf000007_0001
salt thereof, with a compound
X
(Ilia)
Figure imgf000007_0002
of formula (Ilia), W , or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl; Y is NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6.
In certain embodiments, W is Nfb.
In certain embodiments, R3 is optionally substituted alkyl, such as methyl.
In certain embodiments, r is 2.
In certain embodiments, o is 1.
In certain embodiments, s is 1.
In certain embodiments, wherein R1 is other than hydrogen, the compound of formula
("a)
(II), or a salt thereof, is a compound of formula (Ila),
Figure imgf000008_0001
, or a salt thereof. In certain such embodiments, Z is NH.
In certain embodiments, the compound of formula (II), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof, in the presence of a base, such as an amine base (e.g., a trialkyl amine base). In certain such embodiments, the base is N- methylmorpholine, triethylamine, or N,N-diisopropylethyl amine (e.g., N,N-diisopropylethyl amine).
In certain embodiments, the compound of formula (II), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof, in the presence of one or more dehydrating agents. In certain such embodiments, the dehydrating agent is a molecular sieve, such as a 3 A or 4 A molecular sieve.
In certain embodiments, the compound of formula (IV), or a salt thereof, is a
compound of formula
Figure imgf000008_0002
or a salt thereof, or a
compound of formula
Figure imgf000008_0003
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
In certain embodiments, the compound of formula (Ilia), or salt thereof, is selected
from the group consisting of:
Figure imgf000009_0001
Figure imgf000009_0002
salt thereof. In certain such embodiments, the compound of formula (Ilia), or salt thereof, is selected from
Figure imgf000009_0003
salt thereof.
The present application further provides a process for preparing a compound of
formula
Figure imgf000009_0004
salt thereof, comprising reacting a compound
of formula (
Figure imgf000009_0005
salt thereof, with an oxidizing agent for a period sufficient to form the compound of formula (I), or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is NH; R4 is hydrogen; R5 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (IV), or a salt thereof, is prepared according to any one of the foregoing processes. In certain embodiments, the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
In certain embodiments, the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent at room temperature.
In certain embodiments, the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
In certain embodiments, the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent in an organic solvent, such as a halogenated solvent (e.g., dichloromethane) .
In certain embodiments, the compound of formula (IV), or a salt thereof, is a
compound of formula
Figure imgf000010_0001
or a salt thereof, or a
compound of formula
Figure imgf000010_0002
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
In certain embodiments, the compound of formula (I), or a salt thereof, is a compound
of formula (
Figure imgf000010_0003
, or a salt thereof, or a compound of
formula (
Figure imgf000010_0004
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound formula (la) and the compound of formula (lb) are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
The present invention further provides a process for preparing a compound of formula
Figure imgf000011_0001
agent for a period sufficient to form the compound of formula (V), or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is O; R4 is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylakyl, or heteroarylalkyl; R5 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (IV), or a salt thereof, is prepared according to any one of the foregoing processes.
In certain embodiments, the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
In certain embodiments, the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent at room temperature.
In certain embodiments, the compound of formula (IV), or a salt thereof, reacted with the oxidizing agent for at least 8 hours.
In certain embodiments, the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent in an organic solvent. In certain embodiments, the compound of formula (IV), or a salt thereof, is a
compound of formula
Figure imgf000012_0002
, or a salt thereof, or a
compound of formula
Figure imgf000012_0003
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
In certain embodiments, the compound of formula (V), or a salt thereof, is a
compound of formula (
Figure imgf000012_0004
, or a salt thereof, or a
compound of formula (
Figure imgf000012_0005
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
The present application further provides a process for preparing a compound of
formula (
Figure imgf000012_0001
salt thereof, comprising reacting a compound of formula (
Figure imgf000013_0001
salt thereof, with a source of sulfur wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is O; R4 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (V), or a salt thereof, is prepared according to any one of the foregoing processes.
In certain embodiments, the source of sulfur is selected from P2S5, H2S, Ss, 2,4-Bis(4- methoxyphenyl)- 1,3, 2, 4-dithiadiphosphetane-2, 4-disulfide (Lawesson’s reagent), MSH, and M2S, where M is Na, K, Li, or NIL.
In certain embodiments, the compound of formula (VI), or a salt thereof, is reacted with a source of sulfur for at least 30 minutes.
In certain embodiments, the compound of formula (VI), or a salt thereof, is reacted with the source of sulfer in an organic solvent.
In certain embodiments, the compound of formula (V), or a salt thereof, is a
compound of formula (
Figure imgf000013_0002
, or a salt thereof, or a
compound of formula (
Figure imgf000013_0003
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
In certain embodiments, the compound of formula (VI), or a salt thereof, is a
compound of formula (
Figure imgf000014_0003
or a salt thereof, or
a compound of formula (
Figure imgf000014_0004
, or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
The present application further provides a process of preparing a compound of
formula (
Figure imgf000014_0001
, or a salt thereof, comprising reacting
a compound of formula (
Figure imgf000014_0002
, or a salt thereof, with an activating agent wherein Q is a leaving group; R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is O; R4 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (V), or a salt thereof, is prepared according to the foregoing processes.
In certain embodiments, the activating agent is triflic anhydride.
In certain embodiments, Q is selected from the group consisting of halogen, - 0(C0)R7, -0(C02R7), -OR7, -0(S0)R7, -0(S02)R7, -SR7, -SOR7, -S02R7, -OPCl2, and - 0P(0)(0R7)2, wherein R7 is optionally substituted alkyl.
In certain embodiments, the compound of formula (V), or a salt thereof, is a
compound of formula (
Figure imgf000015_0001
, or a compound of
formula (
Figure imgf000015_0002
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
In certain embodiments, the compound of formula (VII), or a salt thereof, is a
compound of formula (Vila),
Figure imgf000015_0003
or a salt thereof,
or a compound of formula (Vllb),
Figure imgf000015_0004
, or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
The present application further provides a process of preparing a compound of
formula (
Figure imgf000016_0001
salt thereof, comprising reacting a
compound of formula
Figure imgf000016_0002
, or a salt thereof, with an oxidizing agent for a period sufficient to form the compound of formula (VI), or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is S; R4 is hydrogen; R5 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (IV), or a salt thereof, is prepared according to any one of the foregoing processes.
In certain embodiments, the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
In certain embodiments, the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent at room temperature.
In certain embodiments, the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
In certain embodiments, the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent in an organic solvent. In certain embodiments, the compound of formula (IV), or a salt thereof, is a
compound of formula
Figure imgf000017_0001
, or a salt thereof, or a
compound of formula
Figure imgf000017_0002
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
In certain embodiments, the compound of formula (VI), or a salt thereof, is a
compound of formula
Figure imgf000017_0003
or a salt thereof, or
a compound of formula (
Figure imgf000017_0004
, or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
The present application further provides a process for preparing a compound of
formula
Figure imgf000017_0005
or a salt thereof, comprising reacting a compound of formula
Figure imgf000018_0001
salt thereof, with a (Ilia)
Figure imgf000018_0002
compound of formula (Ilia) W , or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or
heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR5; X is NH; Y is SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6.
In certain embodiments, the compound of formula (II), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof, in the presence of a base, such as an amine base (e.g., a trialkyl amine base). In certain such embodiments, the base is N- methylmorpholine, triethylamine, or N,N-diisopropylethyl amine (e.g., N,N-diisopropylethyl amine).
In certain embodiments, the compound of formula (II), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof, in the presence of one or more dehydrating agents. In certain such embodiments, the dehydrating agent is a molecular sieve, such as a 3 A or 4 A molecular sieve.
In certain embodiments, the compound of formula (IX), or a salt thereof, is a
compound of formula
Figure imgf000018_0003
, or a salt thereof, or a compound of formula
Figure imgf000019_0001
salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof, are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
The present application further provides a process for preparing a compound of
formula (
re
Figure imgf000019_0002
acting a compound of of formula , or a salt thereof, with an oxidizing agent for a period sufficient to form the compound of formula (VIII), or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is NH; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (IX), or a salt thereof, is prepared according to any one of the foregoing processes.
In certain embodiments, the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS). In certain embodiments, the compound of formula (IX), or a salt thereof, is reacted with the oxidizing agent at room temperature.
In certain embodiments, the compound of formula (IX), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
In certain embodiments, the compound of formula (IX), or a salt thereof, is reacted with the oxidizing agent in an organic solvent.
In certain embodiments, the compound of formula (IX), or a salt thereof, is a
compound of formula or a salt thereof, or a
compound of formula
Figure imgf000020_0001
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula
(IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof, are present in a ratio of at least 1 :1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
In certain embodiments, the compound of formula (VIII), or a salt thereof, is a
compound of formula (Villa),
Figure imgf000020_0002
or a salt thereof, or a
compound of formula (
Figure imgf000020_0003
, or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1. The present application further provides a process for preparing a compound of
formula
a)
Figure imgf000021_0001
a compound of formula ( , or a salt thereof:
b) a compound of formula (
Figure imgf000021_0002
or a salt thereof: or
c) a compound of formula (
Figure imgf000021_0003
or a salt thereof, with a source of ammonia to form the compound of formula (I), or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Q is a leaving group; R4 is lower alkyl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (VIII), or a salt thereof, is prepared according to any one of the foregoing processes. In certain embodiments, the compound of formula (VI), or a salt thereof, is prepared according to any one of the foregoing processes. In certain embodiments, the compound of formula (VII), or a salt thereof, is prepared according to any one of the foregoing processes.
In certain embodiments, the source of ammonia is selected from liquid ammonia, ammonia solution, or an ammonium salt.
In certain embodiments, the ammonium salt is ammonium chloride, ammonium acetate, or ammonium carbonate.
In certain embodiments, the compound of formula (VIII), or a salt thereof, is a
compound of formula (Villa),
Figure imgf000022_0001
or a salt thereof, or a
compound of formula (Vlllb),
Figure imgf000022_0002
, or a salt thereof, or a mixture of any one of the foregoing. In certain suchembodiments, the compound formula (Villa), or a salt thereof, and the compound of formula (Vlllb), or a salt thereof, are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
In certain embodiments, the compound of formula (VI), or a salt thereof, is a
compound of formula (
Figure imgf000022_0003
or a salt thereof, or
a compound of formula (
Figure imgf000022_0004
, or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1. In certain embodiments, the compound of formula (VII), or a salt thereof, is a
compound of formula (Vila),
Figure imgf000023_0001
or a salt thereof,
or a compound of formula (Vllb),
Figure imgf000023_0002
, or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
In certain embodiments, the compound of formula (I), or a salt thereof, is a compound
of formula (
Figure imgf000023_0003
, or a salt thereof, or a compound of
formula (
Figure imgf000023_0004
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof, are present in a ratio of at least 1: 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1, such as a ratio of at least 9: 1.
Additional embodiments, features, and advantages of the application will be apparent from the following detailed description and through practice of the embodiments described in this application. Detailed Description
The present application provides a process for preparing a compound of formula (I”)
( I")
, or a salt thereof, comprising reacting a compound of formula (II”)
(II")
Figure imgf000024_0001
, or a salt thereof, with a compound of formula (Ilia), (Ilia)
Figure imgf000024_0002
W , or a salt thereof, wherein R1, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl; Y is OR4, NHR4 or SR4, such as NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; R7 is selected from halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R8 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or R7 and R8 taken together with with the carbon(s) to which they are attached, form an optionally substituted fused cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl ring; q is 0, 1, 2, 3, 4, or 5; and o is 1, 2, or 3. The present application provides a process for preparing a compound of formula (I”)
Figure imgf000025_0002
W , or a salt thereof, wherein R1, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl; Y is OR4, NHR4 or SR4, such as NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; R7 is selected from halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R8 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or R7 and R8 taken together with with the carbon(s) to which they are attached, form an optionally substituted fused cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl ring; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, 4, or 5; and o is 1, 2, or 3.
The present application further provides a process for preparing a compound of
formula (
Figure imgf000025_0001
salt thereof, comprising reacting a compound of formula (
Figure imgf000026_0001
salt thereof, with a compound
X
R3 Jl
Y (Ilia)
of formula (Ilia) W , or a salt thereof, wherein R1, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl; Y is OR4, NHR4 or SR4, such as NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and o is 1, 2, or 3.
The present application further provides a process for preparing a compound of
formula (
Figure imgf000026_0002
salt thereof, comprising reacting a
compound of formula (
Figure imgf000026_0003
salt thereof, with a compound
X
(I llb)
Figure imgf000026_0004
of formula (Illb) W , or a salt thereof, wherein R1, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl; Y is OR4, NHR4 or SR4, such as NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; and o is 1, 2, or 3.
The present application further provides a process for preparing a compound of
formula
Figure imgf000027_0001
, or a salt thereof, comprising reacting a
compound of formula (
Figure imgf000027_0002
, or a salt thereof, with a
Figure imgf000027_0003
compound of formula (Ilia), W , or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or
heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl; Y is OR4, NHR4 or SR4, such as NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6.
The present application further provides a process for preparing a compound of
formula
Figure imgf000028_0003
, or a salt thereof, comprising reacting a
compound of formula (
Figure imgf000028_0001
salt thereof, with a
X
(Illb)
Figure imgf000028_0002
compound of formula (Illb), w , or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or
heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl; Y is OR4, NHR4 or SR4, such as NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6.
In certain embodiments of the foregoing wherein the compound of formula (I), or salt thereof, the compound of formula (G), or salt thereof, or the compound of formula (I”), or salt thereof, is prepared comprising a reaction with a compound of formula (Ilia), the compound of formula (I), or salt thereof, the compound of formula (G), or salt thereof, or the compound of formula (I”), or salt thereof, is a compound of formula (la),
( la)
Figure imgf000029_0001
, or salt thereof.
In certain embodiments of the foregoing wherein the compound of formula (I), or salt thereof, the compound of formula (G), or salt thereof, or the compound of formula (I”), or salt thereof, is prepared comprising a reaction with a compound of formula (Illb), the compound of formula (I), or salt thereof, the compound of formula (G), or salt thereof, or the compound of formula (I”), or salt thereof, is a compound of formula (lb),
( lb)
Figure imgf000029_0002
, or salt thereof.
The present application further provides a process of preparing a compound of
formula
Figure imgf000029_0005
, or a salt thereof, comprising reacting a
compound of formula (
Figure imgf000029_0003
salt thereof, with a compound
Figure imgf000029_0004
of formula (Ilia), W , or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; Y is OR4, NHR4 or SR4, such as NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6.
The present application further provides a process of preparing a compound of
formula
Figure imgf000030_0002
, or a salt thereof, comprising reacting a
compound of formula (
Figure imgf000030_0001
salt thereof, with a compound
R '" Y (Nib)
of formula (Illb), W , or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl; W is NHR5; X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CChalkyl; Y is OR4, NHR4 or SR4, such as NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6.
In certain embodiments, W is Nfh.
In certain embodiments, R3 is optionally substituted alkyl, such as methyl.
In certain embodiments, r is 2.
In certain embodiments, o is 1. In certain embodiments, s is 1.
In certain embodiments, W is NH2; R3 is optionally substituted alkyl, such as methyl; r is 2; 0 is 1; and s is 1
In certain embodiments, wherein R1 is other than hydrogen, the compound of formula
(II), or a salt thereof, is a compound of formula (Ila),
Figure imgf000031_0001
, or a salt thereof. In certain such embodiments, Z is NH.
In certain embodiments, the compound of formula (II), or a salt thereof, such as a compound of formula (Ila), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof, such as compound of formula (Ilia), or a salt thereof, or a compound of formula (Illb), or a salt thereof, in the presence of a suitable base. Suitable bases include organic bases, inorganic bases and resinous bases. Organic bases include amine bases such as ammonia, alkyl amines, for example methyl amine, dimethyl amine, diethyl amine, trimethyl amine, tri ethyl amine, butyl amine, tetra-methy lethy 1 d i amin e, isopropyl amine and diisopropyl amine, aniline, indole, pyridine, pyrimidine, pyrrolidine, N-methylpyrrolidone, pyrrole, pyrazole, imidazole, morpholine, N-methylmorpholine, piperidine, piperazine, N,N- dimethylpiperizine, and the like. Inorganic bases include bicarbonate, carbonate and hydroxide bases, for example, ammonium hydroxide, ammonium carbonate, barium hydroxide, barium carbonate, calcium carbonate, calcium hydroxid, cesium carbonate, cesium hydroxide, lithium amide, lithium carbonate, lithium hydroxide, magnesium hydroxide, magnesium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium amide and soda lime. In certain embodiments, the base is an amine base (e.g., a trialkyl amine base). In certain such embodiments, the base is N-methylmorpholine, triethylamine, or N,N- diisopropylethyl amine (e.g., N,N-diisopropy lethy 1 amine).
In certain embodiments, the compound of formula (II), or a salt thereof, such as a compound of formula (Ila), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof, such as compound of formula (Ilia), or a salt thereof, or a compound of formula (Illb), or a salt thereof, in the presence of one or more dehydrating agents. In certain such embodiments, the dehydrating agent is a molecular sieve, such as a 3 A or 4 A molecular sieve. In certain embodiments, the compound of formula (IV), or a salt thereof, is a
compound of formula
Figure imgf000032_0001
, or a salt thereof, or a
compound of formula
Figure imgf000032_0002
salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound of formula (IV’), or a salt thereof, is a
compound of formula
Figure imgf000032_0003
, or a salt thereof, or a
compound of formula
Figure imgf000032_0004
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1 : 1, at least 2:1, at least 3: 1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound of formula (Ilia), or salt thereof, is selected
from the group consisting of:
Figure imgf000033_0001
Figure imgf000033_0002
salt thereof. In certain such embodiments, the compound of formula (Ilia), or salt thereof, is selected from
Figure imgf000033_0003
salt thereof.
In certain embodiments, the compound of formula (Illb), or salt thereof, is selected
from the group consisting of:
Figure imgf000033_0005
salt thereof. In certain such embodiments, the compound of formula (Illb), or salt thereof, is selected from
Figure imgf000034_0001
salt thereof.
The present application further provides a process for preparing a compound of
formula
Figure imgf000034_0002
salt thereof, comprising reacting a compound
of formula (
Figure imgf000034_0003
salt thereof, or a compound of
formula
Figure imgf000034_0004
salt thereof, with an oxidizing agent for a period sufficient to form the compound of formula (I), or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is NH; NHR4 or SR4, such as NHR4 or SR4; R4 is hydrogen; R5 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (IV), or a salt thereof, is prepared according to any one of the foregoing processes.
In certain embodiments, the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent at about room temperature, between about 1 °C below room temperature to about 1 °C above room temperature, between about 2 °C below room temperature to about 2 °C above room temperature, between about 5 °C below room temperature to about 5 °C above room temperature, between about 10 °C below room temperature to about 10 °C above room temperature, between about 15 °C below room temperature to about 15 °C above room temperature, or between about 20 °C below room temperature to about 120 °C above room temperature. In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent at about room temperature.
In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 hours. In certain embodiments, the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent in a suitable solvent. In certain embodiments, the solvent is a halogenated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane, tetrachloroethylene, trichloroethane, or trichloroethylene), an aliphatic hydrocarbon (e.g., cyclohexene, cyclohexane, n-hexane, n- heptane, pentane, or petroleum ether), an aromatic hydrocarbon (e.g., benzene, naphthalene, toluene, or xylenes), an alcohol (e.g., methanol, ethanol, propanol, or butanol), a glycol (e.g., ethylene glycol), an ether (e.g., diethyl ether), an ester (e.g., ethyl acetate), a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, or methyl n-butyl ketone), an aldehydes (e.g., formaldehyde or glutaraldehyde), carbon disulfide, pyridine, an amide, or an amine. In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent in a halogenated solvent (e.g., dichloromethane).
In certain embodiments of the foregoing wherein the compound of formula (I), or a salt thereof, is prepared from a compound of formula (IV), or a salt thereof, the compound of formula (IV), or a salt thereof, is a compound of formula (IV a),
Figure imgf000036_0002
or a sat t ereo, or a mxture o any o t e foregoing. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments of the foregoing wherein the compound of formula (I), or a salt thereof, is prepared from a compound of formula (IV), or a salt thereof, the compound of formula (IV’), or a salt thereof, is a compound of formula (IV’a),
Figure imgf000036_0001
, or a salt thereof, or a compound of formula (IV’b),
Figure imgf000037_0001
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments of the foregoing, the compound of formula (I), or a salt
thereof, is a compound of formula (
Figure imgf000037_0002
or a salt
thereof, or a compound of formula (
Figure imgf000037_0003
or a salt thereof, or a mixture of any of the foregoing. In certain embodiments of the foregoing wherein the compound of formula (I), or a salt thereof, is prepared from a compound of formula (IV), or a salt thereof, the compound formula (la) , or a salt thereof, and the compound of formula (lb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20: 1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100: 1. In certain such embodiments, the compound of formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments of wherein the compound of formula (I), or a salt thereof, is prepared from a compound of formula (IV’), or a salt thereof, the compound formula (lb) , or a salt thereof, and the compound of formula (la), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (lb), or a salt thereof, and the compound of formula (la), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100:1. In certain such embodiments, the compound of formula (lb), or a salt thereof, and the compound of formula (la), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
The present invention further provides a process for preparing a compound of formula
Figure imgf000038_0001
, or a salt thereof, comprising reacting a compound of formula
Figure imgf000039_0001
salt thereof, or a compound of
formula
Figure imgf000039_0002
salt thereof, with an oxidizing agent for a period sufficient to form the compound of formula (V), or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is O; R4 is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylakyl, or heteroarylalkyl; R5 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is prepared according to any one of the foregoing processes.
In certain embodiments, the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent at room temperature, between about 1 °C below room temperature to about 1 °C above room temperature, between about 2 °C below room temperature to about 2 °C above room temperature, between about 5 °C below room temperature to about 5 °C above room temperature, between about 10 °C below room temperature to about 10 °C above room temperature, between about 15 °C below room temperature to about 15 °C above room temperature, or between about 20 °C below room temperature to about 120 °C above room temperature. In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent at about room temperature.
In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, reacted with the oxidizing agent for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 hours. In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent in a suitable solvent, such as an organic solvent. In certain embodiments, the solvent is a halogenated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane, tetrachloroethylene, trichloroethane, or trichloroethylene), an aliphatic hydrocarbon (e.g., cyclohexene, cyclohexane, n-hexane, n-heptane, pentane, or petroleum ether), an aromatic hydrocarbon (e.g., benzene, naphthalene, toluene, or xylenes), an alcohol (e.g., methanol, ethanol, propanol, or butanol), a glycol (e.g., ethylene glycol), an ether (e.g., diethyl ether), an ester (e.g., ethyl acetate), a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, or methyl n-butyl ketone), an aldehydes (e.g., formaldehyde or glutaraldehyde), carbon disulfide, pyridine, an amide, or an amine. In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent in a halogenated solvent (e.g., dichloromethane).
In certain embodiments of the foregoing wherein the compound of formula (V), or a salt thereof, is prepared from a compound of formula (IV), or a salt thereof, the compound of formula (IV), or a salt thereof, is a compound of formula (IVa),
Figure imgf000040_0001
, or a sa t t ereo , or a m xture o any o t e foregoing. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1.1 n certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments of the foregoing wherein the compound of formula (V), or a salt thereof, is prepared from a compound of formula (IV’), or a salt thereof, the compound of formula (IV’), or a salt thereof, is a compound of formula (IV’a),
Figure imgf000041_0001
, or a sat t ereo, or a mxture o any o t e foregoing. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (IV’ a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound of formula (V), or a salt thereof, is a
compound of formula (
Figure imgf000042_0001
or a salt thereof, or a
compound of formula (
Figure imgf000042_0002
or a salt thereof, or a mixture of any of the foregoing. In certain embodiments of the foregoing wherein the compound of formula (V), or a salt thereof, is prepared from a compound of formula (IV), or a salt thereof, the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99: 1, or at least 100:1. In certain such embodiments, the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of from at least 1 : 1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments wherein the compound of formula (V), or a salt thereof, is prepared from a compound of formula (IV’), or a salt thereof, the compound formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
The present application further provides a process for preparing a compound of
formula (
Figure imgf000043_0001
salt thereof, comprising reacting a
compound of formula (
Figure imgf000043_0002
, or a salt thereof, with a source of sulfur wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is O; R4 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (V), or a salt thereof, is prepared according to any one of the foregoing processes. In certain embodiments, the source of sulfur is selected from P2S5, H2S, Ss, 2,4-Bis(4- methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson’s reagent), MSH, and M2S, where M is Na, K, Li, or NH4.
In certain embodiments, the compound of formula (VI), or a salt thereof, is reacted with a source of sulfur for at least 5, at least 10, at least 15, at least 20, at least 25, at least 30 minutes, or at least an hour. In certain embodiments, the compound of formula (VI), or a salt thereof, is reacted with a source of sulfur for at least 30 minutes.
In certain embodiments, the compound of formula (VI), or a salt thereof, is reacted with the source of sulfur in a suitable solvent, such as an organic solvent. In certain such embodiments, the solvent is a halogenated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane, tetrachloroethylene, trichloroethane, or trichloroethylene), an aliphatic hydrocarbon (e.g., cyclohexene, cyclohexane, n-hexane, n-heptane, pentane, or petroleum ether), an aromatic hydrocarbon (e.g., benzene, naphthalene, toluene, or xylenes), an alcohol (e.g., methanol, ethanol, propanol, or butanol), a glycol (e.g., ethylene glycol), an ether (e.g., diethyl ether), an ester (e.g., ethyl acetate), a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, or methyl n-butyl ketone), an aldehydes (e.g., formaldehyde or glutaraldehyde), carbon disulfide, pyridine, an amide, or an amine.
In certain embodiments, the compound of formula (V), or a salt thereof, is a
compound of formula (
Figure imgf000044_0001
, or a salt thereof, or a
compound of formula (
Figure imgf000044_0002
or a salt thereof, or a mixture of any of the foregoing. In certain embodiments, the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1 : 1, at least 2: 1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, at least 9: 1, at least 10: 1, at least 20: 1, at least 30: 1, at least 40: 1, at least 50: 1, at least 60: 1, at least 70: 1, at least 80: 1, at least 90: 1, at least 95: 1, at least 96:1, at least 97: 1, at least 98: 1, at least 99: 1, or at least 100: 1. In certain such embodiments, the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, or at least 9:1, such as at least 9:1. In certain such embodiments, the compound of formula (V), or a salt thereof, is prepared from a compound of formula (IV), or a salt thereof
In certain embodiments, the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1. In certain such embodiments the compound of formula (V), or a salt thereof, is prepared from a compound of formula (IV’), or a salt thereof.
In certain embodiments, the compound of formula (VI), or a salt thereof, is a
compound of formula (
Figure imgf000045_0001
or a salt thereof, or a compound of formula (
Figure imgf000046_0001
, or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Via), or a salt thereof, and the compound of formula (Vlb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1 : 1, at least 2: 1, at least 3: 1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Via), or a salt thereof, and the compound of formula (Vlb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96: 1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (Via), or a salt thereof, and the compound of formula (Vlb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound formula (Vlb), or a salt thereof, and the compound of formula (Via), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Vlb), or a salt thereof, and the compound of formula (Via), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (Vlb), or a salt thereof, and the compound of formula (Via), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1. The present application further provides a process of preparing a compound of
formula (
Figure imgf000047_0002
, or a salt thereof, comprising reacting
a compound of formula (
Figure imgf000047_0001
salt thereof, with an activating agent wherein Q is a leaving group; R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is O; R4 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (V), or a salt thereof, is prepared according to the foregoing processes.
In certain embodiments, the activating agent is triflic anhydride.
In certain embodiments, Q is selected from the group consisting of halogen, - 0(CO)R7, -0(C02R7), -OR7, -0(SO)R7, -0(S02)R7, -SR7, -SOR7, -S02R7, -OPCl2, and - 0P(0)(0R7)2, wherein R7 is optionally substituted alkyl.
In certain embodiments of the foregoing wherein the compound of formula (VII), or a salt thereof, is prepared from a compound of formula (V), or a salt thereof, the compound of formula (V), or a salt thereof, is a compound of formula (Va),
Figure imgf000047_0003
, or a compound of formula (Vb),
Figure imgf000048_0001
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6: 1, at least 7: 1, at least 8: 1, or at least 9:1, such as at least.
In certain embodiments of the foregoing wherein the compound of formula (VII), or a salt thereof, is prepared from a compound of formula (V), or a salt thereof, the compound formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1 : 1, at least 2: 1, at least 3: 1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Vb), or a salt thereof, and the compound of formula (Va), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96: 1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (Vb), or a salt thereof, and the compound of formula (V a), or a salt thereof, are present in a ratio of from at least 1 : 1 , at least 2 : 1 , at least 3 : 1 , at least 4:1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8:1, or at least 9:1, such as at least. In certain embodiments, the compound of formula (VII), or a salt thereof, is a
compound of formula (Vila),
Figure imgf000049_0001
or a salt thereof,
or a compound of formula (Vllb),
Figure imgf000049_0002
or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof, are present in ratio of from at least 1 : 1 to 100: 1, such as at least 1 : 1, at least 2: 1, at least 3: 1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96: 1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain such embodiments, the compound formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof, are present in ratio of from at least 1 : 1 to 100: 1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8: 1, about 9: 1, about 10: 1, about 20: 1, about 30: 1, about 40: 1, about 50: 1, about 60: 1, about 70: 1, about 80: 1, about 90: 1, about 95: 1, about 96: 1, about 97: 1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof, are present in a ratio of from at least 1: 1, at least 2: 1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, or at least 9: 1, such as at least 9: 1.
The present application further provides a process of preparing a compound of
formula (
Figure imgf000050_0001
salt thereof, comprising reacting a
compound of formula
Figure imgf000050_0002
, or a salt thereof, or a
compound off fformula
Figure imgf000050_0003
, or a salt thereof, with an oxidizing agent for a period sufficient to form the compound of formula (VI), or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is S; R4 is hydrogen; R5 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (IV), or a salt thereof, is prepared according to any one of the foregoing processes.
In certain embodiments, the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS). In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent at room temperature, between about 1 °C below room temperature to about 1 °C above room temperature, between about 2 °C below room temperature to about 2 °C above room temperature, between about 5 °C below room temperature to about 5 °C above room temperature, between about 10 °C below room temperature to about 10 °C above room temperature, between about 15 °C below room temperature to about 15 °C above room temperature, or between about 20 °C below room temperature to about 120 °C above room temperature. In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent at about room temperature.
In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, reacted with the oxidizing agent for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 hours. In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent in a suitable solvent, such as an organic solvent. In certain embodiments, the solvent is a halogenated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane, tetrachloroethylene, trichloroethane, or trichloroethylene), an aliphatic hydrocarbon (e.g., cyclohexene, cyclohexane, n-hexane, n-heptane, pentane, or petroleum ether), an aromatic hydrocarbon (e.g., benzene, naphthalene, toluene, or xylenes), an alcohol (e.g., methanol, ethanol, propanol, or butanol), a glycol (e.g., ethylene glycol), an ether (e.g., diethyl ether), an ester (e.g., ethyl acetate), a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, or methyl n-butyl ketone), an aldehydes (e.g., formaldehyde or glutaraldehyde), carbon disulfide, pyridine, an amide, or an amine. In certain embodiments, the compound of formula (IV), or a salt thereof, or the compound of formula (IV’), or a salt thereof, is reacted with the oxidizing agent in a halogenated solvent (e.g., dichloromethane).
In certain embodiments of the foregoing wherein the compound of formula (VI), or a salt thereof, is prepared from a compound of formula (IV), or a salt thereof, the compound of formula (IV), or a salt thereof, is a compound of formula (IVa),
Figure imgf000052_0002
or a sat t ereo, or a mxture o any o t e foregoing. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments of the foregoing wherein the compound of formula (VI), or a salt thereof, is prepared from a compound of formula (IV), or a salt thereof, the compound of formula (IV’), or a salt thereof, is a compound of formula (IV’a),
Figure imgf000052_0001
, or a salt thereof, or a compound of formula (IV’b),
Figure imgf000053_0001
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about
50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100:1. In certain such embodiments, the compound of formula (IV’a), or a salt thereof, and the compound of formula (IV’b), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound of formula (VI), or a salt thereof, is a
compound of formula
Figure imgf000053_0002
, or a salt thereof, or
a compound of formula (
Figure imgf000053_0003
, or a salt thereof, or a mixture of any one of the foregoing. In certain embodiments wherein the compound of formula (VI), or a salt thereof, is preparared from a compound of formula (IV), or a salt thereof, the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100: 1 , such as at least 1 : 1 , at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of from at least 1 : 1 , at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments wherein the compound of formula (VI), or a salt thereof, is preparared from a compound of formula (IV’), or a salt thereof, the compound formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
The present application further provides a process for preparing a compound of
formula (
Figure imgf000054_0001
, or a salt thereof, comprising reacting a compound of formula
Figure imgf000055_0001
salt thereof, (Il ia)
Figure imgf000055_0002
with a compound of formula (Ilia) W , or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CC alkyl; W is NHR5; X is NH; Y is SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6.
The present application further provides a process for preparing a compound of
formula
Figure imgf000055_0003
, or a salt thereof, comprising
reacting a compound of formula
Figure imgf000055_0004
salt thereof,
X
(Illb)
Figure imgf000055_0005
with a compound of formula (Illb) W , or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, CCkalkyl; W is NHR5; X is NH; Y is SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6.
In certain embodiments, the compound of formula (II), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof (e.g., a compound of formula (Ilia), or a salt thereof, or a compound of formula (Illb), or a salt thereof), in the presence of a base, such as an amine base (e.g., a trialkyl amine base). In certain such embodiments, the base is N- methylmorpholine, triethylamine, or N,N-diisopropylethyl amine (e.g., N,N-diisopropylethyl amine).
In certain embodiments, the compound of formula (II), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof (e.g., a compound of formula (Ilia), or a salt thereof, or a compound of formula (Illb), or a salt thereof),, in the presence of one or more dehydrating agents. In certain such embodiments, the dehydrating agent is a molecular sieve, such as a 3 A or 4 A molecular sieve.
In certain embodiments, the compound of formula (IX), or a salt thereof, is a
compound of formula or a salt thereof, or a
compound of formula
Figure imgf000056_0001
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100: 1, such as at least 1: 1, at least 2:1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, at least 9: 1, at least 10: 1, at least 20: 1, at least 30: 1, at least 40: 1, at least 50: 1, at least 60: 1, at least 70: 1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound of formula (IX’), or a salt thereof, is a
compound of formula or a salt thereof, or a
compound of formula
Figure imgf000057_0001
or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1 : 1, at least 2:1, at least 3: 1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1. The present application further provides a process for preparing a compound of
formula ( rising
reacting a compound of of formula or a salt
thereof, o
Figure imgf000058_0001
r a compound of formula ( , or a salt thereof, with an oxidizing agent for a period sufficient to form the compound of formula (VIII), or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; X is NH; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl; R5 is hydrogen; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (VII), or a salt thereof, is prepared according to any one of the foregoing processes.
In certain embodiments, the oxidizing agent is l-bromo-2,5-pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
In certain embodiments, the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof, is reacted with the oxidizing agent at room temperature, between about 1 °C below room temperature to about 1 °C above room temperature, between about 2 °C below room temperature to about 2 °C above room temperature, between about 5 °C below room temperature to about 5 °C above room temperature, between about 10 °C below room temperature to about 10 °C above room temperature, between about 15 °C below room temperature to about 15 °C above room temperature, or between about 20 °C below room temperature to about 120 °C above room temperature. In certain embodiments, the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof, is reacted with the oxidizing agent at about room temperature.
In certain embodiments, the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof, is reacted with the oxidizing agent for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 hours. In certain embodiments, the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
In certain embodiments, the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof, is reacted with the oxidizing agent in a suitable solvent, such as an organic solvent. In certain embodiments, the solvent is a halogenated hydrocarbon (e.g., carbon tetrachloride, chloroform, dichloromethane, tetrachloroethylene, trichloroethane, or trichloroethylene), an aliphatic hydrocarbon (e.g., cyclohexene, cyclohexane, n-hexane, n-heptane, pentane, or petroleum ether), an aromatic hydrocarbon (e.g., benzene, naphthalene, toluene, or xylenes), an alcohol (e.g., methanol, ethanol, propanol, or butanol), a glycol (e.g., ethylene glycol), an ether (e.g., diethyl ether), an ester (e.g., ethyl acetate), a ketone (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, or methyl n-butyl ketone), an aldehydes (e.g., formaldehyde or glutaraldehyde), carbon disulfide, pyridine, an amide, or an amine. In certain embodiments, the compound of formula (IX), or a salt thereof, or the compound of formula (IX’), or a salt thereof, is reacted with the oxidizing agent in a halogenated solvent (e.g., dichloromethane).
In certain embodiments of the foregoing wherein the compound of formula (VIII), or a salt thereof, is prepared from a compound of formula (IX), or a salt thereof, the compound of formula (IX), or a salt thereof, is a compound of formula (IXa),
Figure imgf000059_0001
, or a salt thereof, or a compound of formula (IXb),
Figure imgf000060_0001
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6: 1, at least 7: 1, at least 8: 1, or at least 9:1, such as at least.
In certain embodiments of the foregoing wherein the compound of formula (VIII), or a salt thereof, is prepared from a compound of formula (IX’), or a salt thereof, the compound of formula (IX’), or a salt thereof, is a compound of formula (IX’a),
Figure imgf000060_0002
, or a sat t ereo , or a mxture o any o t e foregoing. In certain such embodiments, the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100:1. In certain such embodiments, the compound of formula (IX’a), or a salt thereof, and the compound of formula (IX’b), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound of formula (VIII), or a salt thereof, is a
compound of formula (Villa),
Figure imgf000061_0001
or a salt thereof, or a
compound of formula (
Figure imgf000061_0002
, or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1. In certain such embodiments, the compound of formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof, are present in a ratio of from at least 1 : 1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof, are present in a ratio of from at least 1: 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100:1. In certain such embodiments, the compound of formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
The present application further provides a process for preparing a compound of
formula
d
Figure imgf000062_0001
) a compound of formula ( , or a salt thereof;
e) a compound of formula (
Figure imgf000062_0002
, or a salt thereof; or f) a compound of formula (
Figure imgf000063_0001
a salt thereof, with a source of ammonia to form the compound of formula (I), or a salt thereof, wherein R6, independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring; R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; Q is a leaving group; R4 is lower alkyl; o is 1, 2, or 3; p is 0, 1, 2, 3, or 4; r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6. In certain such embodiments, the compound of formula (VIII), or a salt thereof, is prepared according to any one of the foregoing processes. In certain embodiments, the compound of formula (VI), or a salt thereof, is prepared according to any one of the foregoing processes. In certain embodiments, the compound of formula (VII), or a salt thereof, is prepared according to any one of the foregoing processes.
In certain embodiments, the source of ammonia is selected from liquid ammonia, ammonia solution, or an ammonium salt.
In certain embodiments, the ammonium salt is ammonium chloride, ammonium acetate, or ammonium carbonate.
In certain embodiments of the foregoing wherein the compound of formula (I), or a salt thereof, is prepared from a compound of formula (VIII), or a salt thereof, the compound of formula (VIII), or a salt thereof, is a compound of formula (Villa),
Figure imgf000063_0002
, or a salt thereof, or a compound of formula (Vlllb),
Figure imgf000064_0001
, or a salt thereof, or a mixture of any one of the foregoing. In certain suchembodiments, the compound formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments of the foregoing wherein the compound of formula (I), or a salt thereof, is prepared from a compound of formula (VIII), such as a compound of formula (VUIb), or a salt thereof, or a compound of formula (VUIb), or a salt thereof, or a mixture of nay one ofhte foreiong, the compound formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99: 1, or at least 100: 1. In certain such embodiments, the compound of formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 20:1, about 30:1, about 40:1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100:1.
In certain such embodiments, the compound of formula (VUIb), or a salt thereof, and the compound of formula (Villa), or a salt thereof, are present in a ratio of from at least 1: 1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments of the foregoing wherein the compound of formula (I), or a salt thereof, is prepared from a compound of formula (VI), the compound of formula (VI), or
a salt thereof, is a compound of formula (
Figure imgf000065_0001
or a salt thereof, or a compound of formula (VIb),
Figure imgf000065_0002
, or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100:1. In certain such embodiments, the compound of formula (VIb), or a salt thereof, and the compound of formula (Via), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments of the foregoing wherin the compound of formula (I), or a salt thereof, is prepared from a compound of formula (VII), the compound of formula (VII), or a
salt thereof, is a compound of formula (Vila),
Figure imgf000066_0001
or a salt thereof, or a compound of formula (Vllb),
Figure imgf000066_0002
, or a salt thereof, or a mixture of any one of the foregoing. In certain such embodiments, the compound formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (Vila), or a salt thereof, and the compound of formula (Vllb), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (Vllb), or a salt thereof, and the compound of formula (Vila), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments, the compound of formula (I), or a salt thereof, is a compound
of formula (
Figure imgf000067_0001
, or a salt thereof, or a compound of
formula (
Figure imgf000067_0002
, or a salt thereof, or a mixture of any of the foregoing. In certain such embodiments, the compound formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof, are present in a ratio of from at least 1 : 1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20:1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98: 1, about 99: 1, or about 100: 1. In certain such embodiments, the compound of formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof, are present in a ratio of from at least 1 : 1, at least 2: 1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain such embodiments, the compound formula (lb), or a salt thereof, and the compound of formula (la), or a salt thereof, are present in a ratio of from at least 1:1 to 100:1, such as at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 20:1, at least 30:1, at least 40:1, at least 50:1, at least 60:1, at least 70:1, at least 80:1, at least 90:1, at least 95:1, at least 96:1, at least 97:1, at least 98:1, at least 99:1, or at least 100:1. In certain such embodiments, the compound of formula (lb), or a salt thereof, and the compound of formula (la), or a salt thereof, are present in a ratio of about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10: 1, about 20: 1, about 30: 1, about 40: 1, about 50:1, about 60:1, about 70:1, about 80:1, about 90:1, about 95:1, about 96:1, about 97:1, about 98:1, about 99:1, or about 100: 1. In certain such embodiments, the compound of formula (lb), or a salt thereof, and the compound of formula (la), or a salt thereof, are present in a ratio of from at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, or at least 9:1, such as at least 9:1.
In certain embodiments wherein alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or oxime are substituted, they are substituted, valency permitting, with one or more substituents selected from substituted or unsubstituted alkyl, such as perfluoroalkyl (e.g., trifluoromethyl), alkenyl, alkoxy, alkoxyalkyl, aryl, aralkyl, arylalkoxy, aryloxy, aryloxyalkyl, hydroxyl, halo, alkoxy, such as perfluoroalkoxy (e.g., trifluoromethoxy), alkoxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy, amino, aminoalkyl, alkylamino, aminoalkylalkoxy, aminoalkoxy, acylamino, acylaminoalkyl, such as perfluoro acylaminoalkyl (e.g., trifluoromethylacylaminoalkyl), acyloxy, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy,
heteroaryloxyalkyl, heterocyclylaminoalkyl, heterocyclylaminoalkoxy, amido, amidoalkyl, amidine, imine, oxo, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl, including perfluoroacyl (e.g., C(0)CF3)), carbonylalkyl (such as carboxyalkyl, alkoxycarbonylalkyl, formylalkyl, or acylalkyl, including perfluoroacylalkyl (e.g., -alkylC(0)CF3)), carbamate, carbamatealkyl, urea, ureaalkyl, sulfate, sulfonate, sulfamoyl, sulfone, sulfonamide, sulfonamidealkyl, cyano, nitro, azido, sulfhydryl, alkylthio, thiocarbonyl (such as thioester, thioacetate, or thioformate), phosphoryl, phosphate, phosphonate or phosphinate.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents, positions of substituents and/or variables are permissible only if such combinations result in stable compounds.
Compounds of the present application containing one or multiple asymmetrically substituted atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or by synthesis using optically active reagents.
In certain embodiments, compounds of the application may be racemic. In certain embodiments, compounds of the application may be enriched in one enantiomer. For example, a compound of the application may have greater than 30% ee, 40% ee, 50% ee,
60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee.
In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula (I), (la), such as (la’), or (lb), such as (lb’)). An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
In certain embodiments, compounds of the application may have more than one stereocenter. In certain such embodiments, compounds of the application may be enriched in one or more diastereomer. For example, a compound of the application may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of formula (I), (la), such as (la’), or (lb), such as (lb’)). A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
Throughout this disclosure it is to be understood that, where appropriate, suitable protecting groups may be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in“Protective Groups in Organic Synthesis,” T. W. Green, P. G. M. Wuts, Wiley-Interscience, New York, (1999).
A transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product; the type of transformation is limited only by the inherent incompatibility of other functional groups contained in the molecule to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood by one skilled in the art of organic synthesis.
Examples of transformations are given throughout this disclosure, and it is understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in“Comprehensive Organic Transformations— A Guide to Functional Group Preparations” R. C. Larock, Wiley VCH, 2nd Edition (1999).
Examplary reaction conditions are given throughout this disclosure, and it is understood that the described reaction conditions are not limited only to the described reaction conditions. References and descriptions of other suitable reaction conditions are described in textbooks of organic chemistry, such as, for example,“Advanced Organic Chemistry”, March 6th Edition, Wiley Interscience (2007), and“Organic Synthesis”, Smith, 2nd Edition, McGraw Hill, (2001).
Definitions
The definitions set forth in this application are intended to clarify terms used throughout this application.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this application belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties to disclose and describe the methods and/or materials in connection with which the publications are cited. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.
Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the embodiments in present application, the preferred methods and materials are now described.
To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term“about.” It is understood that, whether the term“about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.
Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001. The nomenclature used herein to name the subject compounds is illustrated in the Examples herein. This nomenclature has generally been derived using the commercially - available ChemBioDraw Ultra software (Cambridgesoft/Perkin Elmer), Version 12.0.
It is to be understood that the present description is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present application will be limited only by the appended claims.
It is appreciated that certain features of the application, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the application, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present application and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present application and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.
Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. E.g., a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or tautomeric forms, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a solvate, such as a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. Any formula given herein is intended to refer to amorphous and/or crystalline physical forms of the compound. The compounds described herein may be analytically pure, or a mixture in which the compound comprises at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% by weight of the mixture.
In addition, where features or aspects of the embodiments of this application are described in terms of Markush groups, those skilled in the art will recognize that
embodiments described herein is also thereby described in terms of any individual member or subgroup of members of the Markush group. E.g., if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described.
The term "herein" refers to the entire application.
As used herein, the singular forms“a,”“an,” and“the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as“solely,”“only” and the like in connection with the recitation of claim elements, or use of a“negative” limitation.
As used herein, the terms“including,”“containing,” and“comprising” are used in their open, non-limiting sense.
As used herein,“subject” (as in the subject of the treatment) refers to both mammals and non-mammals. Mammals include, e.g., humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. mice, rats, rabbits, dogs, cats, cattle, horses, sheep, and goats. Non-mammals include, e.g., worms, fish and birds. In some embodiments, the subject is a human.
"Substantially" as the term is used herein refers to being completely or almost completely; e.g., a composition that is "substantially free" of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is
"substantially pure" is there are only negligible traces of impurities present.
The term“acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
The term“acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, e.g., by the formula hydrocarbylC(0)NH-.
The term“acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
The term“alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
The term“alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term“alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. E.g., substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
The term“alkynyl”, as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing one or more hydrogens on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds.
Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. E.g., substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
An“alkyl” group or“alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, such as from 1 to 12 carbon atoms, preferably from 1 to about 10, more preferably from 1 to 4, unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec -butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, pentyl and octyl. A Ci-Ce straight chained or branched alkyl group is also referred to as a "lower alkyl" group.
Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen or more hydrogens on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, e.g., a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
The term“(ATOM)i j” with j > i, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from i to j (including i and j) atoms. E.g., the term“Cx-yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. Co alkyl refers to a hydrogen atom where the group is in a terminal position, a bond if internal. Similarly, e.g., C3-6cycloalkyl refers to a cycloalkyl as defined herein that has 3 to 6 carbon ring atoms. The terms“C2-yalkenyl” and “C2-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
The term“alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.
The term“alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
The term“hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbon- hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof. The terms“amine” and“amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by
Figure imgf000076_0001
wherein each R30 independently represents a hydrogen or a hydrocarbyl group, or two R30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term“aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.
o
The term“amide”, as used herein, refers to a group:
Figure imgf000076_0002
wherein each R30 independently represent a hydrogen or hydrocarbyl group, or two R30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term“carbamate” is art-recognized and refers to a group
Figure imgf000076_0003
wherein R29 and R30 independently represent hydrogen or a hydrocarbyl group, such as an alkyl
group, or R29 and R30 taken together with the intervening atom(s) complete a heterocycle having
from 4 to 8 atoms in the ring structure.
The term“halogen,” or“halide” represents chlorine, fluorine, bromine, or iodine. The term“halo” represents fluoro, chloro, bromo, or iodo.
The term“haloalkyl”, as used herein, refers to an alkyl group with one or more halo substituents, or one, two, or three halo substituents. Examples of haloalkyl groups include -
CF3, -CH2F, -CHF2, -CFkBr, -CH2CF3, and -CH2CH2F.
The term“heteroatom”, as used herein, refers to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include but are not limited to nitrogen, oxygen, and sulfur.
The term“heteroalkyl”, as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent. The term“aryl”, as used herein, includes substituted or unsubstituted monocyclic aromatic rings in which each atom of the ring is carbon. Preferably the ring is a 5- to 7- membered ring, more preferably a 6-membered ring. The term“aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
The term“aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.
An“aroyl” group, as the term is used herein, refers to an aryl group bonded via an exocyclic carbonyl group, such as a benzoyl group.
The term“heteroaryl” , as used herein, includes substituted or unsubstituted monocyclic aromatic ring system, preferably 5- to 7-membered aromatic rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one to two heteroatoms. E.g., a 5- membered heteroaryl is furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. In another example, a 6- membered heteroaryl is pyridine, pyrazine, pyrimidine, pyridazine, or triazine. The term “heteroaryl” also include substituted or unsubstituted“polycyclic” ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
Illustrative examples of heteroaryl groups include but are not limited to the following entities, in the form of properly bonded moieties:
Figure imgf000077_0001
The term“heteroaralkyl” or“hetaralkyl”, as used herein, refers to an alkyl group substituted with a heteroaryl group.
A“heteroaroyl” group, as the term is used herein, refers to a heteroaryl group bonded via an exocyclic carbonyl group, analogous to a benzoyl group but wherein the phenyl ring of the benzoyl group is replaced by a heteroaryl group.
The terms“heterocyclyl”,“heterocycle”, and“heterocyclic”, as used herein, refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to lO-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms“heterocyclyl” and“heterocyclic” also include substituted or unsubstituted polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or
heterocyclyls. Heterocyclyl groups include, e.g., piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
The term“heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group which is optionally substituted.
The terms“carbocycle”, and“carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.“Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term“fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings ln an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary“carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2. l]heptane, l,5-cyclooctadiene, l,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, l,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- lH-indene and bicyclo[4. l.0]hept-3-ene.“Carbocycles” may be susbstituted at any one or more positions capable of bearing a hydrogen atom.
A“cycloalkyl” group, as used herein, refers to a substituted or unsubstituted cyclic hydrocarbon which is completely saturated.“Cycloalkyl” includes substituted or
unsubstituted monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. Such a monocyclic cycloalkyl group may be substituted or unsubstituted. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings that are substituted or unsubstituted. Cycloalkyl includes substituted or unsubstituted bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term“fused cycloalkyl” refers to a substituted or unsubstituted bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
The term“carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.
A“cycloalkenyl” group, as used herein, refers to a cyclic hydrocarbon containing one or more double bonds. A“cycloalkynyl” group is a cyclic hydrocarbon containing one or more triple bonds.
The terms“polycyclyl”,“polycycle”, and“polycyclic”, as used herein, refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are“fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
The term“carbonate” is art-recognized and refers to a group -OCO2-R30, wherein R30 represents a hydrocarbyl group.
The term“carboxy”, as used herein, refers to a group represented by the
formula -CO2H.
The term“ester”, as used herein, refers to a group -C(0)OR3° wherein R30 represents a hydrocarbyl group.
The term“ether,” as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.
Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include“alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
The term“sulfate” is art-recognized and refers to the group -OSO3H, or a
pharmaceutically acceptable salt thereof.
The term“sulfonamide” is art-recognized and refers to the group represented by the
general formulae
Figure imgf000080_0001
wherein R29 and R30 independently represents hydrogen or hydrocarbyl, such as alkyl, or R29 and R30 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term“sulfoxide” is art-recognized and refers to the group -S(0)-R3°, wherein R30 represents a hydrocarbyl.
The term“sulfonate” is art-recognized and refers to the group SO3H, or a
pharmaceutically acceptable salt thereof.
The term“sulfone” is art-recognized and refers to the group -S(0)2-R3°, wherein R30 represents a hydrocarbyl.
The term“thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.
The term“thioester”, as used herein, refers to a group -C(0)SR3° or -SC(0)R3° wherein R30 represents a hydrocarbyl.
The term“thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with asulfur.
The term“urea” is art-recognized and may be represented by the general formula "N'Vr3°
R29 R29
wherein R29 and R30 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R29 taken together with R30 and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term“substituted”, as used herein, refers to moieties having substituents replacing one or more hydrogens on one or more carbons of the backbone. It will be understood that“substitution” or“substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term“substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this application, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. In some embodiments,“substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments,“substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” refers to the specified group or moiety bears one substituent.
Substituents can include any substituents described herein, e.g., a lower alkyl (such as Ci-6 alkyl, e.g., -methyl, -ethyl, and -propyl), a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.
Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understood to include substituted variants. E.g., reference to an“aryl” group or moiety implicitly includes both substituted and unsubstituted variants. The term“unsubstituted” refers to that the specified group bears no substituents.
The term“optionally substituted”, as used herein, means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted.
Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. E.g., reference to disubstituent -A-B-, where A ¹ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
“Protecting group”, as used herein, refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al, Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2 -trimethyls ilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro- veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxy lprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or T1PS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
The term "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
A“pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al, “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
For a compound described herein that contains a basic group, such as an amine, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, e.g., treatment of the free base with an inorganic acid, such as hydrochloric acid,
hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
For a compound described herein that contains an acidic group, such as a carboxylic acid group, base addition salts can be prepared by any suitable method available in the art, e.g., treatment of such compound with a sufficient amount of the desired the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, ammonium, zinc, or magnesium salt, or other metal salts; organic amino salts, such as, alkyl, dialkyl, trialkyl, or tetra-alkyl ammonium salts.
Other examples of pharmaceutically acceptable salts include, but are not limited to, camsylate, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen- phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fiimarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene- 1- sulfonates, naphthalene-2 -sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, g-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17* Edition, Mack Publishing Company, Easton, Pa., 1985. The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present application.
Compounds of the present application can also exist as various“solvates” or “hydrates.” A“hydrate” is a compound that exists in a composition with water molecules.
The composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. A“solvate” is a similar composition except that a solvent other that water, such as with methanol, ethanol, dimethylformamide, diethyl ether and the like replaces the water. E.g., methanol or ethanol can form an “alcoholate,"” which can again be stoichiometic or non-stoichiometric. Mixtures of such solvates or hydrates can also be prepared. The source of such solvate or hydrate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
The compounds of the application, including their pharmaceutically acceptable salts and prodrugs, can exist as various polymorphs, pseudo-polymorphs, or in amorphous state. The term“polymorph”, as used herein, refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo-polymorphs, such as hydrates, solvates, or salts of the same compound. Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as x-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents. Thus crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry.
The present application further embraces isolated compounds, such as isolated compounds of any of the formulae disclosed herein. The term“isolated compound” refers to a preparation of a compound, or a mixture of compounds, wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds.“Isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically. Preferably an“isolated compound” refers to a preparation of a compound of any of the formulae disclosed herein, or a mixture of compounds according to any of the formulae disclosed herein, which contains the named compound or mixture of compounds according to any of the formulae disclosed herein in an amount of at least 10 percent by weight of the total weight. Preferably the preparation contains the named compound or mixture of compounds in an amount of at least 50% by weight of the total weight; more preferably at least 80% by weight of the total weight; and most preferably at least 90%, at least 95% or at least 98% by weight of the total weight of the preparation.
The compounds of the application and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
Isomerism and Tautomerism in Described Compounds
Tautomerism
Within the present application it is to be understood that a compound described herein or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the application encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been convenient to show graphically herein. E.g., tautomerism may be exhibited by a pyrazolyl group bonded as indicated by the wavy line. While both substituents would be termed a 4-pyrazolyl group, it is evident that a different nitrogen atom bears the hydrogen atom in each structure.
Figure imgf000085_0001
Such tautomerism can also occur with substituted pyrazoles such as 3 -methyl, 5- methyl, or 3,5-dimethylpyrazoles, and the like. Another example of tautomerism is amido- imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom. E.g., the equilibrium:
Figure imgf000086_0001
example of tautomerism.
Similarly, the following equilibrium is an example of tautomerism:
Figure imgf000086_0002
Accordingly, a structure of any compound depicted herein as one tautomer is intended to also include the other tautomer.
Optical Isomerism
It will be understood that when compounds of the present application contain one or more chiral centers, the compounds may exist in, and may be isolated as pure enantiomeric or diastereomeric forms or as racemic mixtures. The present application therefore includes any possible enantiomers, diastereomers, racemates in their pure forms or mixtures thereof, and salts thereof, of the compounds of the application.
The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called“enantiomers.” Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light. Single enantiomers are designated according to the Cahn-Ingold-Prelog system. The priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order of the other groups proceeds clockwise, the molecule is designated (R) and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated (S). In the example in Scheme 14, the Cahn-Ingold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the viewer.
Figure imgf000086_0003
(R) configuration (S) configuration In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula (I), (I-A) or (I-B)). An enantiomerically enriched mixture may comprise, e.g., at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent. In certain embodiments, a compound of the application may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. E.g., if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
In certain embodiments, compounds of the application may have more than one stereocenter. In certain such embodiments, compounds of the application may be enriched in one or more diastereomer. E.g., a compound of the application may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques, such as but not limited to, normal and reverse phase chromatography, and crystallization. According to one such method, a racemic mixture of a compound of the application, or a chiral intermediate thereof, is separated using a chiral salt or carried out on a Chiralcell OD column. The column is operated according to the manufacturer’s instructions.
Isolated optical isomers (enantiomerically pure compounds) can also be prepared by the use of chiral intermediates or catalysts in synthesis. When a chiral synthetic intermediate is used, the optical center (chiral center) can be preserved without racemization throughout the remainder of the preparative procedure, as is well known in the art. Chiral catalyst can be used to impart at least some degree of enantiomeric purity to products of reactions catalyzed by the chiral catalyst. And, in some cases, compounds having at least some degree of enantiomeric enrichment can be obtained by physical processes such as selective
crystallization of salts or complexes formed with chiral adjuvants.
A variety of compounds in the present application may exist in particular geometric or stereoisomeric forms. The present application takes into account all such compounds, including tautomers, cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this application. All tautomeric forms are encompassed in the present application. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this application, unless the stereochemistry or isomeric form is specifically indicated.
Rotational Isomerism
It is understood that due to chemical properties (i.e., resonance lending some double bond character to the C-N bond) of restricted rotation about the amide bond linkage (as illustrated below) it is possible to observe separate rotamer species and even, under some circumstances, to isolate such species (see below). It is further understood that certain structural elements, including steric bulk or substituents on the amide nitrogen, may enhance the stability of a rotamer to the extent that a compound may be isolated as, and exist indefinitely, as a single stable rotamer. The present application therefore includes any possible stable rotamers of formula (I) which are biologically active in the treatment of cancer or other proliferative disease states.
Figure imgf000088_0001
Regioisomerism
The preferred compounds of the present application have a particular spatial arrangement of substituents on the aromatic rings, which are related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature“para” for 1 ,4-substitution,“meta” for
1, 3-substitution and“ortho” for 1 ,2-substitution as shown below.
Figure imgf000088_0002
Isolonical Labeling in Described Compounds
The present application further includes all pharmaceutically acceptable isotopically labeled compound [e.g., of formula (I), (I-A) or (I-B)]. An "isotopically" or "radio-labeled" compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). E.g., in certain embodiments, in compounds [e.g., of formula(I), (I-A) or (I-B)], hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a Ci-6 alkyl or a Ci-6 alkoxy are replaced with deuterium, such as ί/3-methoxy or 1 , 1 ,2,2-c/4-3-mcthylbutyl).
Certain isotopically labeled compounds [e.g., compounds of formula(I), (I-A) or (I- B)], e.g., those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon 14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Such isotopically labeled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
Substitution with positron emitting isotopes, such as UC, 18F, 150, and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically labeled compounds [e.g., of formula (I), (I-A) or (I-B)] or their corresponding prodrugs can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed. Suitable isotopes that may be incorporated in compounds of the present application include but are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H (also written as D for deuterium), 3H (also written as T for tritium), UC, 13C,14C, 13N, 15N, 150, 170, 180, 18F, 35S, 36Cl , 82B r, 75Br, 76B r, 77Br, 123I, 124I, 125I, 1311, 31P, and 32P.
Isotopically labeled compounds of this application and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Provisos may apply to any of the disclosed categories or embodiments such that specific embodiments or species may be excluded from such categories or embodiments.
In various embodiments, the compound or set of compounds, such as are used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
Exemplification
The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the disclosure to various uses and conditions. As a result, the disclosure is not limited by the illustrative examples set forth hereinbelow.
All temperatures are in degrees Celsius (°C) and are uncorrected.
Unless otherwise noted, commercial reagents used in preparing the example compounds were used as received without additional purification.
Unless otherwise noted, the solvents used in preparing the example compounds were commercial anhydrous grades and were used without further drying or purification.
All starting materials are commercially available, unless stated otherwise.
The following abbreviations may be employed herein: 13C NMR: carbon nuclear magnetic resonance; d: doublet; DMF: A,A-dimethyl formamide; DMSO: dimethyl sulfoxide; EDCI x HC1: 1 -ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride; ES:
electrospray; g: gram; h: hour(s); XH NMR: proton nuclear magnetic resonance; HPLC: high pressure liquid chromatography; kg: kilogram; L: liter; m: multiplet; M: molar; mL: milliliter; MHz: megahertz; min: minute(s); mmol: millimole; mol: mole; MS: mass spectrometry; NMM: N-methyl-morpholine; ppm: parts per million; s: singlet; 2-MeTHF: 2-methyl- tetrahydrofuran; br.: broad; Bu: butyl; calcd: calculated; Celite® : brand of diatomaceous earth filtering agent, registered trader of Celite Corporation; d: doublet; dd: doublet of doublet; ddd: doublet of doublet of doublet; dddd: doublet of doublet of doublet of doublet; DABCO: l,4-diazabicyclo[2.2.2]octane; DCE: dichloroethane; DCM: dichloromethane; DIPEA: N-ethyl-N-diisopropylpropan-2-amine; DME: dimethyl ether; DMEA: dimethyl ethylamine; dq: doublet of quartet; dt: doublet of triplet; EDC: l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride; ESI: electrospray ion source; EtOAc: ethyl acetate; EtOH: ethanol; g: gram; h: hour(s); HBTU: 0-Benzotriazole-N,N,N’,N’- tetramethyl-uronium-hexafluoro-phosphate; HOBT: N-Hydroxybenzotriazole; HRMS: high resolution mass spectrometry; iPrOH: iso-propanol; MeOH: methanol; mg: milligram;
MgS04: anhydrous magnesium sulfate (drying agent); MPLC: medium pressure liquid chromatography; MTBE: methyl /er/-butyl ether; NaHCCh: sodium bicarbonate; NH4Cl: ammonium chloride; q: quartet; quin: quintet; rt: room temperature; sat: saturated; t: triplet; TEA: triethylamine; tBuOH: /er/-butanol; td: triplet of doublet; TFA: trifluoroacetic acid; and THF: tetrahydrofuran.
The XH NMR spectra were recorded on a Bruker Ultrashield AV3 500 MHz spectrometer fitted with a QCI cryoprobe and operating with Topspin3.5pl5 software or on a Bruker Ultrashield AV3 400 MHz spectrometer fitted with a BBFO probe and operating with Topspin3.5pl5 software. NMR data were processed using either ACD Spectrus Processor 2015 Pack 2 or Mestrenova version 11.0.2. The chemical shifts (d) are reported in parts-per- million from the deuterated solvent used.
The 13C NMR spectra were recorded on a Bruker Ultrashield AV3 500 MHz spectrometer fitted with a QCI cryoprobe and operating with Topspin3.5pl5 software or on a Bruker Ultrashield AV3 400 MHz spectrometer fitted with a BBFO probe and operating with Topspin3.5pl5 software. NMR data were processed using either ACD Spectrus Processor 2015 Pack 2 or Mestrenova version 11.0.2. The chemical shifts (d) are reported in parts-per- million from the deuterated solvent used.
Compound Synthesis
Compounds of the present invention have been synthesized according to the following general methods.
Chromatography Methods:
Method 1
Figure imgf000091_0001
Waters UHPLC-MS consisting of an Acquity UHPLC (mobile phase: 5-90% B with 5% 250 mM ammonium acetate; A: Water, B: MeCN; 4.1 mins) on an Acquity BEH C18 column (50 mm x 2.1 mm with a 1.7 pm particle size) and a Waters QDa single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative ion mode. The mass spectrometer was operated with a source temperature of 120 °C, capillary voltage of 0.8 kV, probe temperature of 600 °C. The mass spectrometer scanning range was m/z 100-1200.
Method 2
Figure imgf000092_0001
Waters UHPLC-MS consisting of an Acquity UHPLC (mobile phase: 5-90% B with 5% 250 mM ammonium acetate; A: Water, B: MeCN; 4.1 mins) on an Acquity BEH Phenyl column (50 mm x 2.1 mm with a 1.7 pm particle size) and a Waters QDa single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative ion mode. The mass spectrometer was operated with a source temperature of 120 °C, capillary voltage of 0.8 kV, probe temperature of 600 °C. The mass spectrometer scanning range was m/z 100-1200.
Method 3
Figure imgf000092_0002
Agilent HPLC-MS consisting of an Agilent 1100 HPLC and an Agilent 6150 single quadmpole mass spectrometer. The mass spectrometer was equipped with a multimode ion source (both electrospray (ESI) and atmospheric pressure chemical ionisation(APCI)) operated in positive or negative ion mode. The mass spectrometer was operated with a drying gas flow rate of 6 litres/minute, nebuliser pressure of 60 psi, drying gas temperature of 300 °C, vaporiser temperature of 200 °C, capillary voltage of 2000 V, charging voltage of 2000 V, corona current of 1 mA and fragmentor voltages of 130 and 275 V. The mass spectrometer scanning range was m/z 85-1200. Method 4
Figure imgf000093_0002
Agilent 1100 HPLC. Preparation of Compounds 2/3:
Figure imgf000093_0001
To a flask containing 1 (200 mg, 0.65 mmol), Ao-propanol (5 mL) and (R)-2- aminopropanamide hydrochloride (161 mg, 1.29 mmol) was added titanium(IV) isopropoxide (383 pL, 1.29 mmol). The mixture was heated to reflux for 24 hours and cooled to ambient to afford a solution of 2/3 in Ao-propanol.
UPLC-MS : Method 1 , UV - 220 nm.
Selectivity (2/3) unknown - isomers did not separate on this method.
Combined purity (area% by UPLC): 11.8%
MS [M+H]+: 379.102 (79Br) Preparation of Compounds 5/6
Figure imgf000094_0001
4 (1.21 g, 3.51 mmol) and 4Ά molecular sieves (2.35 g) were suspended in anhydrous iso propanol (15 mL). A' V-DiisopiOpylcthylaminc (1.5 mL, 8.6 mmol) and (S)-2- aminopropanamide hydrochloride (0.59 g, 4.74 mmol) were charged. The mixture was heated to reflux for 1 hour and cooled to ambient to afford a solution of 5/6 in /.sopropanol.
UPLC-MS: Method 1, TAC Diode Array Detector.
Selectivity (5/6) unknown - isomers did not separate on this method.
Combined purity (area% by UPLC): 82.3%
MS [M+H]+: 379.207 (79Br)
Preparation of Compounds 2/3:
Figure imgf000094_0002
To a flask containing 4 (250 mg, 0.73 mmol), /.so propanol (7.5 mL), NN- diisopropylethylamine (379 pL, 2.17 mmol) and (R)-2-aminopropanamide hydrochloride (181 mg, 1.45 mmol) was added 4Ά molecular sieves. The mixture was heated to 65 °C for 2.5 hours and cooled to ambient. The mixture was fdtered and the filtrate was concentrated to dryness to afford a solid. The solid was diluted with dichloromethane (20 mL) and washed with water (20 mL). The organic layer was dried (MgSCL) and concentrated to afford a pale yellow solid. The crude reaction mixture was purified by chromatography (silica gel, 3 cm x 9cm, eluting with 60% hexane / 35% ethyl acetate / 5% methanol) to afford 2/3 as a colourless oil (263 mg, 96%).
Selectivity (by CH- NMR): 9: 1 mixture of isomers 2 and 3.
¾-NMR of 2 (500 MHz, CDCb): d 1.4-1.2 (m, 3H) 1.5-1.4 (m, 4H) 1.6-1.5 (m, 2H) 1.8 (dt, J= 13.7, 3.2 Hz, 1H) 2.1-2.0 (m, 2H) 2.8-2.7 (m, 1H) 2.8-2.8 (m, 1H) 2.9-2.8 (m, 1H) 3.2-3.1 (m, 1H) 3.4-3.3 (m, 3H) 4.6 (q, J = 6.9 Hz, 1H) 6.4 (br s, 1H) 7.3-7.1 (m, 1H) 7.4 (br d, J = 3.7 Hz, 1H) 7.5- 7.4 (m, 1H) 7.8- 7.7 (m, 1H). 13C-NMR of 2 (125 MHz, CDCb): 5177.7, 174.8, 147.8, 135.0, 134.3, 129.6, 128.2, 120.7, 78.6, 58.4, 55.6, 48.8, 39.3, 34.4, 33.6, 28.4, 28.4, 19.0.
UPLC-MS: Method 1, UV - 220 nm.
Purity (area% by UPLC): Isomer 2 - 76.76%, Isomer 3 - 8.88%.
Selectivity (area% by UPLC): 9: 1 mixture of isomers 2 and 3.
MS [M+H]+: Isomer 2 - 379.094 (79Br), Isomer 3 - 379.151 (79Br)
Preparation of Compounds 7/8:
Figure imgf000095_0001
4 (250 mg, 0.73 mmol) and 4 A molecular sieves (500 mg) were suspended in anhydrous iso propanol (7.5 mL). ,V, ,V- Dii s 0 p ro pyl c t h yl a mi n c (379 pL, 2.17 mmol) and L-Scr-NH? (181 mg, 1.29 mmol) were charged. The mixture was heated to reflux for 3 hours and cooled to ambient to afford a solution of 7/8 in /.vopropanol.
UPLC-MS: Method 1, UV - 220 nm.
Purity (area% by UPLC): Isomer 7 - 43.69%, Isomer 8 - 9.04%.
Selectivity (area% by UPLC): 5: 1 mixture of isomers 7 and 8.
MS [M+H]+: Isomer 7 - 395.116 (79Br), Isomer 8 - 395.116 (79Br)
Preparation of Compounds 9/10:
Figure imgf000095_0002
4 (1.21 g, 3.51 mmol) and 4Ά molecular sieves (2.35 g) were suspended in anhydrous iso- propanol (15 mL). A' V-DiisopiOpylcthylaminc (1.5 mL, 8.6 mmol) and (S)-2- aminopropanthioamide hydrochloride (0.59 g, 4.74 mmol) were charged. The mixture was heated to reflux for 1 hour and cooled to ambient to afford a solution of 9/10 in /.vopropanol. UPLC-MS: Method 1, TAC Diode Array Detector.
Purity (area% by UPLC): Isomer 9 - 51.07 %, Isomer 10 - 34.71 %.
Selectivity (area% by UPLC): 3:2 mixture of isomers 9 and 10.
MS [M+H]+: Isomer 9 - 395.116 (79Br), Isomer 10 - 395.172 (79Br). Preparation of Compounds 11/12:
Figure imgf000096_0001
4 (104.6 mg, 0.3 mmol) and 4Ά molecular sieves (200 mg) were suspended in anhydrous iso propanol (2.1 mL). ,V, ,V- Dii s 0 p ro py l c t h y l am i n c (1.5 mL, 8.6 mmol) and (S)-2- aminopropanamide hydrochloride (0.59 g, 4.74 mmol) were charged. The mixture heated to 55 °C for 19 hours and cooled to ambient to afford a solution of 11/12 in /.vopropanol.
HPLC-MS: Method 3, TAC Diode Array Detector.
Purity (area% by HPLC): Isomer 11 - 14.56 %, Isomer 12 - 9.46 %.
MS [M+H]+: Isomer 11 - 378.200 (79Br), Isomer 12 - 378.200 (79Br)
Preparation of Compounds 13/14:
Figure imgf000096_0002
A 9: 1 mixture of 5/6 (148.9 mg, 0.3 mmol) was charged to a suspension of N- bromosuccinimide (80.04 mg, 0.45 mmol) and sodium bicarbonate (66.91 mg, 0.8 mmol) in anhydrous dichloromethane (4.5 mL). The mixture was stirred at ambient temperature for 2 hours. The reaction was halted to afford a solution of 13/14 in dichloromethane.
UPLC-MS: Method 1, TAC Diode Array Detector.
Purity (area% by UPLC): 13/14 - 81.07 %.
MS [M+H]+: 377.120 (79Br).
Chiral HPLC: Method 4, UV - 250 nm.
Enantiopurity (area% by chiral HPLC): Enantiomer 13 - 80.3%, Enantiomer 14 - 19.7%.
Preparation of Compounds 15/16:
Figure imgf000096_0003
A 4: 1 mixture of 13/14 (303.6 mg, 0.81 mmol) and /V, /V- Dii s 0 p ro pyl e t h yl a mi n e (1 mL, 6.44 mmol) were dissolved in anhydrous toluene (6 mL). Phosphorus oxychloride (0.65 mL, 6.9 mmol) was added dropwise and the mixture was heated to 90 °C for 46 hours. The mixture was cooled to room temperature to afford 15/16 as a solution in toluene.
UPLC-MS method: Method 1, TAC Diode Array Detector.
Purity (area% by UPLC): 93.0 %.
MS [M+H]+: 395.059 (35Cl: 79Br).
Preparation of Compounds 9/10:
Figure imgf000097_0001
5 (107.1 mg, 0.213 mmol), phosphorus pentasulfide (49.75 mg, 0.22 mmol) and sodium bicarbonate (29.93 mg, 0.36 mmol) were suspended in anhydrous tetrahydrofuran (3.2 mL). The mixture was heated to 50 °C for 90 mins and cooled to room temperature to afford a solution of 9/10 in tetrahydrofuran.
HPLC-MS: Method 3, TAC Diode Array Detector.
Purity (area% by HPLC): Isomer 9 - 62.60%, Isomer 10 - 36.56 %.
Selectivity (area% by UPLC): 2: 1 mixture of isomers 9 and 10.
MS [M+H]+: Isomer 9 - 395.059 (79Br), Isomer 10 - 395.059 (79Br).
Preparation of Compounds 17/18:
Figure imgf000097_0002
A 1 : 1 mixture of 13/14 (107.1 mg, 0.213 mmol), phosphorus pentasulfide (49.75 mg, 0.22 mmol) and sodium bicarbonate (29.93 mg, 0.36 mmol) were suspended in anhydrous tetrahydrofuran (3.2 mL). The mixture was heated to 50 °C for 90 mins and cooled to room temperature to afford a solution of 17/18 in tetrahydrofuran.
HPLC-MS: Method 1, TAC Diode Array Detector.
Purity (area% by HPLC): 100%.
MS [M+H]+: 393.085 (79Br). Preparation of Compounds 19/20:
Figure imgf000098_0001
4 (104.6 mg, 0.30 mmol) and -toluenesulfonic acid monohydrate (31.5 mg, 0.16 mmol) were suspended in anhydrous /.sopropanol (4 mL). /V,/V-Diisopropylcthylaminc (54 pL, 0.31 mmol) and (7?)-2-amino-/V-((7?)-l-phenylethyl)propanamide (94.9 mg, 0.49 mmol) were charged. The mixture heated to 100 °C for 30 minutes and cooled to ambient to afford a solution of 19/20 in /.sopropanol.
UPLC-MS: Method 1, UV - 220 nm.
Purity (area% by UPLC): Isomer 19 - 50.43 %, Isomer 20 - 4.08 %.
Selectivity (area% by UPLC): 12: 1 mixture of isomers 19 and 20.
MS [M+H]+: Isomer 19 - 483.179 (79Br), Isomer 20 - 483.179 (79Br).
Preparation of Compounds 21/22:
Figure imgf000098_0002
4 (104.6 mg, 0.30 mmol) and -toluenesulfonic acid monohydrate (31.5 mg, 0.16 mmol) were suspended in anhydrous /.sopropanol (4 mL). /V,/V-Diisopropylcthylaminc (54 pL, 0.31 mmol) and (7?)-2-amino-/V-((5)-l-phenylethyl)propanamide (132.0 mg, 0.69 mmol) were charged. The mixture heated to 100 °C for 30 minutes and cooled to ambient to afford a solution of 19/20 in /.sopropanol.
UPLC-MS: Method 2, UV - 220 nm.
Purity (area% by UPLC): Isomer 21 - 63.17 %, Isomer 22 - 6.69 %.
Selectivity (area% by UPLC): 9: 1 mixture of isomers 21 and 22.
MS [M+H]+: Isomer 21 - 483.179 (79Br), Isomer 21 - 483.235 (79Br). Preparation of Compounds 23/24/25/26:
Figure imgf000099_0001
23 24 25 26
4 (72.12 mg, 0.21 mmol, (5)-methyl 2-aminopropanimidothioate hydrochloride (48.2 mg, 0.31 mmol) and 4Ά molecular sieves (100 mg) were suspended in anhydrous Ao-propanol (1.5 mL). M/V-diisopropylethylamine (117 uL, 0.67 mmol) was added and the mixture heated to 75 °C for 16 hours. The reaction mixture was cooled to ambient to afford a solution of 23- 26 in Ao-propanol.
UPLC-MS: Method 3, TAC Diode Array Detector.
Purity (area % by UPLC): Isomer 23 - 2.27 %, Isomer 24 - 2.80 %, Isomer 25 - 1.71%, Isomer 26 - 0.62 %.
MS [M + H+] = Isomer 23 - 378.118 (79Br), Isomer 24 - 378.118 (79Br), Isomer 25 - 409.094 (79Br), Isomer 26 - 409.094 (79Br).
Example 2: Biological Activity
Assays
The level of activity of compounds prepared according to the processes disclosed here can be tested using the following methods:
TR-FRET Assay
The b-secretase enzyme used in the TR-FRET is prepared as follows:
Human BACE1: the cDNA for the soluble part of the human b-Secretasel (AA1-AA460) is cloned using the BACE 1 (1 -460)-(AVT)-Fc-pGEN-IRES-neo mammalian expression vector.
The gene is fused to the Fc domain of IgGl (affinity tag) and stably cloned into HEK 293 cells. Purified sBACE-Fc is stored in -80°C in Tris buffer, pH 9.2 and has a purity of ~40%. Human BACE2: the cDNA for the soluble part of the human b-8eoG6ίh8e2 (AA1-AA473) is cloned using B ACE2( 1 -473 )-(AVT)-Fc-pDEST 12.2 mammalian expression vector. The gene is fused to the Fc domain of IgGl (affinity tag) and stably cloned into HEK 293 cells.
Purified sBACE-Fc is stored in -80°C in 50 mM Glycine, 10 mM Tris-HCl, pH 7-8, and has a purity of -70%.
The enzyme (truncated form) is diluted to 6 pg/mL (stock hBacel: l.3mg/mL, hBace2: l.6mg/ml) and the TruPoint BACE1 Substrate to 200 nM (stock 120 uM) in reaction buffer (NaAcetate, chaps, triton c-100, EDTA pH4.5). A multidrop Combi is used for the liquid handling. Enzyme (7 pL) is added to the compound plate (containing 0.8 pL of compound in dimethylsulphoxide). The plate is incubated for 10 minutes. Substrate (8 pL) is then added, and the reaction proceeds for 17 minutes at r.t. The reaction is stopped with the addition of Stop solution (5.5 pL, NaOAc, pH 9). Fluorescence is measured on a Pherastar plate reader using HTRF module. The assay is performed in a 384 well polystyrene, black, round bottom, small volume plate (Greiner 784076). The final concentration of the enzyme is 2.7 pg/mL; the final concentration of substrate is 100 nM (Km hBACEl: 250 nM, hBACE2: 350 nM).
The dimethylsulphoxide control, instead of test compound, defines the 100% activity level and 0% activity is defined by a control inhibitor compound (2-amino-6-(3 '-methoxybiphenyl- 3-yl)-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-one, at a final concentration of 50 pM). 5 reference inhibitors with different affinities are used at all screen occasions in dose response. Diluted TR-FRET Assay
Compounds with a high affinity are further tested in a diluted TR-FRET assay, conditions as described above for the TR-FRET assay, but with 50 times less enzyme and a 6.5 h reaction time at r.t. in the dark.
sAPPB Release Assay
SH-SY5Y cells are cultured in DMEM/F-12 with Glutamax, 10% FCS and 1% non- essential amino acids and cryopreserved and stored at -140 °C at a concentration of 7.5- 9.5xl06 cells per vial.
Cells are thawed and seeded at a concentration of around 10000 cells/well in
DMEM/F- 12 with Glutamax, 10% FCS and 1 % non-essential amino acids to a 384-well tissue culture treated plate, 30 pL cell susp/well. The cell plates are then incubated for 7-24 h at 37 °C, 5% C02.
The cell medium is removed, followed by addition of 50 pL compound diluted in DMEM/F- 12 with Glutamax, 10% FCS, 1 % non-essential amino acids to a final cone of 0.5% DMSO. The compounds are incubated with the cells for 16-17 h (overnight) at 37 °C, 5%
CO2.
Meso Scale Discovery (MSD) plates are used for the detection of sAPP release. MSD sAPPp plates are blocked in 1% BSA in Tris wash buffer for 1 h on shake at r.t. and washed 1 time in Tris wash buffer. 20 pL of medium is transferred to the pre-blocked and washed MSD sAPP microplates, and the cell plates are further used in an ATP assay to measure cytotoxicity. The MSD plates are incubated with shaking at r.t. for 2 h and the media discarded. 10 pL detection antibody is added (1 nM) per well followed by incubation with shaking at r.t. for 2 h and then discarded. 35 pL Read Buffer is added per well and the plates are read in a Meso Scale Discovery SECTOR6000 Imager.
ATP assay
As indicated in the sAPPp release assay, after transferring 20 pL medium from the cell plates for sAPPp detection, the plates are used to analyse cytotoxicity using the
YiaLightTM Plus cell proliferation/cytotoxicity kit from Cambrex Bioscience that measures total cellular ATP. The assay is performed according to the manufacture's protocol. Briefly, 10 uL cell lysis reagent is added per well. The plates are incubated at r.t. for 10 min. Two min after addition of 25 pL reconstituted ViaLightTM Plus ATP reagent, the luminescence is measured in an Envision reader. Tox threshold is a signal below 70% of the control.
Equivalents
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the compounds and methods of use thereof described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims.
The contents of all references, patents and published patent applications cited throughout this Application, as well as their associated figures are hereby incorporated by reference in entirety.

Claims

Claims
1. A process for preparing a compound of formula (
Figure imgf000102_0001
(II") salt thereof, comprising reacting a compound of formula
Figure imgf000102_0002
, or
R3 A
Y (Ilia)
a salt thereof, with a compound of formula (Ilia), W , or a salt thereof, wherein:
R1 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, - and -CC alkyl;
W is NHR5;
X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, and -CChalkyl;
Y is NHR4 or SR4;
R4, independently for each occurrence, is selected from hydrogen and optionally
substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl;
R7 is selected from halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R8 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or R7 and R8 taken together with with the carbon(s) to which they are attached, form an optionally substituted fused cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl ring;
q is 0, 1, 2, 3, 4, or 5; and
o is 1, 2, or 3. aring a compound of formula (G)
( !' )
Figure imgf000103_0001
or a salt thereof, comprising reacting a compound of
formula (
Figure imgf000103_0002
salt thereof, with a compound of formula
X
(Ilia)
Figure imgf000103_0003
(Ilia) W , or a salt thereof,
wherein:
R1 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, - and -CCkalkyl;
W is NHR5;
X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, and -CCkalkyl;
Y is NHR4 or SR4; R4, independently for each occurrence, is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl;
p is 0, 1, 2, 3, or 4;
q is 0, 1, 2, 3, or 4; and
o is 1, 2, or 3.
3. A process for preparing a compound of formula (I),
Figure imgf000104_0003
, or a salt thereof, comprising reacting a compound of
formula (
Figure imgf000104_0001
salt thereof, with a compound of
Figure imgf000104_0002
formula (Ilia), W , or a salt thereof,
wherein:
R6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, - and -CC alkyl;
W is NHR5;
X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, and -CChalkyl; Y is NHR4 or SR4;
R4, independently for each occurrence, is selected from hydrogen and optionally
substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl;
o is 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
r is 1, 2, or 3; and
s is 0, 1, 2, 3, 4, 5, or 6.
4. The process of any one of claims 1-3, wherein the compound of formula (I), or salt thereof, the compound of formula (G), or salt thereof, or the compound of formula (I”), or
salt thereof, is a compound of formula (
Figure imgf000105_0001
or salt thereof.
5. A process of preparing a compound of formula (IV),
Figure imgf000105_0002
(Ilia), W , or a salt thereof,
wherein:
R6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and
optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, and CCtealkyl;
W is NHR5;
X is O, S, or NR10, where R10 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, and -CChalkyl;
Y is NHR4 or SR4;
R4, independently for each occurrence, is selected from hydrogen and optionally
substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl;
o is 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
r is 1, 2, or 3; and
s is 0, 1, 2, 3, 4, 5, or 6.
6. The process of claim 5, wherein W is ML·.
7. The process of claim 5 or 6, wherein R3 is optionally substituted alkyl, such as methyl.
8. The process of any one of claims 5-7, wherein r is 2.
9. The process of any one of claims 5-8, wherein o is 1.
10. The process of any one of claims 5-9, wherein s is 1.
11. The process of any one of claims 5-10, wherein when R1 is other than hydrogen, the compound of formula (II), or a salt thereof, is a compound of formula (Ila),
(Ila)
Figure imgf000107_0001
, or a salt thereof. 12. The process of claim 11, wherein Z is NH.
13. The process of any one of claims 5-12, wherein the compound of formula (II), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof, in the presence of a base, such as an amine base (e.g., a trialkyl amine base).
14. The process of claim 13, wherein the base is N-methylmorpholine, triethylamine, or N,N-diisopropylethyl amine (e.g., N,N-diisopropylethyl amine).
15. The process of any one of claims 5-14, wherein the compound of formula (II), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof, in the presence of one or more dehydrating agents.
16. The process of claim 15, wherein the dehydrating agent is a molecular sieve. 17. The process of claim 16, wherein the dehydrating agent is a 3 A or 4 A molecular sieve.
18. The process of any one of claims 5-17, wherein the compound of formula (IV), or a
salt thereof, is a compound of formula (
Figure imgf000107_0002
salt thereof, or a compound of formula
Figure imgf000108_0005
or a salt thereof, or a mixture of any of the foregoing.
19. The process of claim 18, wherein the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
20. The process of any one of claims 5-19, wherein the compound of formula (Ilia), or
salt thereof, is selected from the group consisting of:
Figure imgf000108_0001
Figure imgf000108_0002
salt thereof.
21. The process of claim 20, wherein the compound of formula (Ilia), or salt thereof, is
O
Figure imgf000108_0003
selected from NH2 , or a salt thereof.
22. A process for preparing a compound of formula
Figure imgf000108_0004
a salt thereof, comprising reacting a compound of formula (IV),
Figure imgf000109_0001
, or a salt thereof, with an oxidizing agent for a period sufficient to form the compound of formula (I), or a salt thereof,
wherein:
R6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
X is NH;
R4 is hydrogen;
R5 is hydrogen;
o is 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
r is 1, 2, or 3; and
s is 0, 1, 2, 3, 4, 5, or 6.
23. The process of claim 22, wherein the compound of formula (IV), or a salt thereof, is prepared according to the process of any one of claims 5-19.
24. The process of claim 22 or 23, wherein the oxidizing agent is l-bromo-2,5- pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
25. The process of any one of claims 22-24, wherein the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent at room temperature.
26. The process of any one of claims 22-25, wherein the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
27. The process of any one of claims 22-26, wherein the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent in an organic solvent, such as a halogenated solvent (e.g., dichloromethane) .
28. The process of any one of claims 22-27, wherein the compound of formula (IV), or a
salt thereof, is a compound of formula (
Figure imgf000110_0001
or a
salt thereof, or a compound of formula
Figure imgf000110_0002
or a salt thereof, or a mixture of any of the foregoing.
29. The process of claim 28, wherein the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
30. The process of any one of claims 22-29, wherein the compound of formula (I), or a
salt thereof, is a compound of formula (
Figure imgf000110_0003
or a salt
thereof, or a compound of formula (
Figure imgf000110_0004
or a salt thereof, or a mixture of any of the foregoing.
31. The process of claim 30, wherein the compound formula (la) and the compound of formula (lb) are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
32. The process of claim 31, wherein the compound formula (la) and the compound of formula (lb) are present in a ratio of at least 9: 1.
33. A process for preparing a compound of formula (V),
Figure imgf000111_0001
or a salt thereof, comprising reacting a compound of
formula
Figure imgf000111_0002
, or a salt thereof, with an oxidizing agent for a period sufficient to form the compound of formula (V), or a salt thereof, wherein:
R6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
X is O;
R4 is selected from hydrogen and optionally substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylakyl, or heteroarylalkyl;
R5 is hydrogen;
o is 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
r is 1, 2, or 3; and
s is 0, 1, 2, 3, 4, 5, or 6.
34. The process of claim 33, wherein the compound of formula (IV), or a salt thereof, is prepared according to the process of any one of claims 5-19.
35. The process claim 33 or 34, wherein the oxidizing agent is l-bromo-2,5- pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
36. The process of any one of claims 33-35, wherein the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent at room temperature.
37. The process of any one of claims 33-36, wherein the compound of formula (IV), or a salt thereof, reacted with the oxidizing agent for at least 8 hours.
38. The process of any one of claims 33-37, wherein the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent in an organic solvent.
39. The process of any one of claims 33-38, wherein the compound of formula (IV), or a
salt thereof, is a compound of formula (
Figure imgf000112_0001
, or a
salt thereof, or a compound of formula (
Figure imgf000112_0002
or a salt thereof, or a mixture of any of the foregoing.
40. The process of claim 39, wherein the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
41. The process of any one of claims 33-40, wherein the compound of formula (V), or a
salt thereof, is a compound of formula (
Figure imgf000113_0002
or a
salt thereof, or a compound of formula (
Figure imgf000113_0001
salt thereof, or a mixture of any of the foregoing.
42. The process of claim 41, wherein the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1. 43. The process of claim 42, wherein the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of at least 9: 1.
44. A process for preparing a compound of formula (VI),
Figure imgf000113_0003
wherein:
R6 independently for each occurrence, is selected from hydrogen, halogen, CN, and
optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and
optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
X is O;
R4 is hydrogen;
o is 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
r is 1, 2, or 3; and
s is 0, 1, 2, 3, 4, 5, or 6.
45. The process of claim 44, wherein the compound of formula (V), or a salt thereof, is prepared according to the process of any one of claims 33-43.
46. The process of claim 44 or 45, wherein the source of sulfur is selected from P2S5, H2S, S8, 2,4-Bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson’s reagent), MSH, and M2S, where M is Na, K, Li, or NH4.
47. The process of any one of claims 44-46, wherein a compound of formula (VI), or a salt thereof, is reacted with a source of sulfur for at least 30 minutes.
48. The process of any one of claims 44-47, wherein a compound of formula (VI), or a salt thereof, is reacted with the source of sulfer in an organic solvent.
49. The process of any one of claims 44-48, wherein the compound of formula (V), or a
salt thereof, is a compound of formula (
Figure imgf000114_0001
salt thereof, or a compound of formula (
Figure imgf000115_0001
salt thereof, or a mixture of any of the foregoing.
50. The process of claim 49, wherein the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
51. The process of any one of claims 44-50, wherein a compound of formula (VI), or a
salt thereof, is a compound of formula (
Figure imgf000115_0003
, or
a salt thereof, or a compound of formula (
Figure imgf000115_0002
or a salt thereof, or a mixture of any one of the foregoing.
52. The process of claim 51, wherein the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3 : 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
53. The process of claim 52, wherein the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 9: 1.
54. A process of preparing a compound of formula (VII),
Figure imgf000116_0001
t wherein:
Q is a leaving group;
R6 independently for each occurrence, is selected from hydrogen, halogen, CN, and
optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and
optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
X is O;
R4 is hydrogen;
o is 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
r is 1, 2, or 3; and
s is 0, 1, 2, 3, 4, 5, or 6.
55. The process of claim 54, wherein the compound of formula (V), or a salt thereof, is prepared according to the process of any one of claims 33-43.
56. The process of claim 54 or 55, wherein the activating agent is triflic anhydride.
57. The process of claim 54 or 55, wherein Q is selected from the group consisting of halogen, -0(C0)R7, -0(C02R7), -OR7, -0(S0)R7, -0(S02)R7, -SR7, -SOR7, -S02R7, -OPCl2, and -0P(0)(0R7)2, wherein R7 is optionally substituted alkyl. 58. The process of any one of claims 54-57, wherein the compound of formula (V), or a
salt thereof, is a compound of formula (
Figure imgf000117_0001
or a
compound of formula (
Figure imgf000117_0002
, or a salt thereof, or a mixture of any of the foregoing. 59. The process of claim 58, wherein the compound formula (Va), or a salt thereof, and the compound of formula (Vb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
60. The process of any one of claims 54-59, wherein the compound of formula (VII), or a
salt thereof, is a compound of formula (Vila),
Figure imgf000117_0003
or a salt thereof, or a compound of formula (Vllb),
Figure imgf000117_0004
, or a salt thereof, or a mixture of any one of the foregoing.
61. The process of claim 60, wherein the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
62. The process of claim 61, wherein the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 9: 1.
63. A process of preparing a compound of formula (VI),
Figure imgf000118_0001
agent for a period sufficient to form the compound of formula (VI), or a salt thereof, wherein:
R6 independently for each occurrence, is selected from hydrogen, halogen, CN, and
optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and
optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
X is S;
R4 is hydrogen;
R5 is hydrogen;
o is 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
r is 1, 2, or 3; and s is 0, 1, 2, 3, 4, 5, or 6.
64. The process of claim 63, wherein the compound of formula (IV), or a salt thereof, is prepared according to the process of any one of claims 5-19.
65. The process of claim 63 or 64, wherein the oxidizing agent is l-bromo-2,5- pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
66. The process of any one of claims 63-65, wherein the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent at room temperature.
67. The process of any one of claims 63-66, wherein the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
68. The process of any one of claims 63-67, wherein the compound of formula (IV), or a salt thereof, is reacted with the oxidizing agent in an organic solvent.
69. The process of any one of claims 63-68, wherein the compound of formula (IV), or a
salt thereof, is a compound of formula (
Figure imgf000119_0002
or a
salt thereof, or a compound of formula (
Figure imgf000119_0001
salt thereof, or a mixture of any of the foregoing.
70. The process of claim 69, wherein the compound of formula (IVa), or a salt thereof, and the compound of formula (IVb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
71. The process of any one of claims 63-70, wherein the compound of formula (VI), or a
salt thereof, is a compound of formula (
Figure imgf000120_0003
or
a salt thereof, or a compound of formula (
Figure imgf000120_0004
or a salt thereof, or a mixture of any one of the foregoing
72. The process of claim 71, wherein the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3 : 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
73. The process of claim 72, wherein the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 9: 1.
74. A process for preparing a compound of formula (IX),
Figure imgf000120_0005
or a salt thereof, comprising
reacting a compound of formula
Figure imgf000120_0001
salt thereof, with a
Figure imgf000120_0002
compound of formula (Ilia) W , or a salt thereof,
wherein:
R6 independently for each occurrence, is selected from hydrogen, halogen, CN, and
optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and
optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
Z is O, S, or NR9, where R9 is selected from H, hydroxyl, alkyl, alkoxy, -S(0)alkyl, - and -CC alkyl;
W is NHR5;
X is NH;
Y is SR4;
R4, independently for each occurrence, is selected from hydrogen and optionally
substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R5 is selected from hydrogen, and optionally substituted alkyl, alkenyl, alkoxy, aryl, or heteroaryl;
o is 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
r is 1, 2, or 3; and
s is 0, 1, 2, 3, 4, 5, or 6.
75. The process of claim 74, wherein the compound of formula (II), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof, in the presence of a base, such as an amine base (e.g., a trialkyl amine base).
76. The process of claim 75, wherein the base is N-methylmorpholine, triethylamine, or N,N-diisopropylethyl amine (e.g., N,N-diisopropylethyl amine).
77. The process of any one of claims 74-76, wherein the compound of formula (II), or a salt thereof, is reacted with the compound of formula (III), or a salt thereof, in the presence of one or more dehydrating agents.
78. The process of claim 77, wherein the dehydrating agent is a molecular sieve.
79. The process of claim 78, wherein the dehydrating agent is a 3 A or 4 A molecular sieve.
80. The process of any one of claims 74-79, wherein the compound of formula (IX), or a
salt thereof, is a compound of formula ( , or a
salt thereof, or a compound of formula (
Figure imgf000122_0001
, or a salt thereof, or a mixture of any of the foregoing.
81. The process of claim 80, wherein the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
82. A process for preparing a compound of formula (VIII),
Figure imgf000122_0002
or a salt thereof, comprising
reacting a compound of of formula
Figure imgf000122_0003
, or a salt thereof, with an oxidizing agent for a period sufficient to form the compound of formula
(VIII), or a salt thereof,
wherein:
R6 independently for each occurrence, is selected from hydrogen, halogen, CN, and
optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
R4, independently for each occurrence, is selected from hydrogen and optionally
substituted alkyl, alkenyl, alkoxy, aryl, heteroaryl, arylalkyl, or heteroarylalkyl;
R5 is hydrogen;
o is 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
r is 1, 2, or 3; and
s is 0, 1, 2, 3, 4, 5, or 6.
83. The process of claim 82, wherein the compound of formula (IX), or a salt thereof, is prepared according to the process of any one of claims 74-81.
84. The process of claim 82 or 83, wherein the oxidizing agent is l-bromo-2,5- pyrrolidinedione (NBS) or tert-butyl hypochlorite, such as l-bromo-2,5-pyrrolidinedione (NBS).
85. The process of any one of claims 82-84, wherein the compound of formula (IX), or a salt thereof, is reacted with the oxidizing agent at room temperature.
86. The process of any one of claims 82-85, wherein the compound of formula (IX), or a salt thereof, is reacted with the oxidizing agent for at least 8 hours.
87. The process of any one of claims 82-86, wherein the compound of formula (IX), or a salt thereof, is reacted with the oxidizing agent in an organic solvent. X), or a
salt thereof, is a compound of formula ( , or a
s
Figure imgf000124_0001
alt thereof, or a compound of formula ( , or a salt thereof, or a mixture of any of the foregoing.
89. The process of claim 88, wherein the compound of formula (IXa), or a salt thereof, and the compound of formula (IXb), or a salt thereof, are present in a ratio of at least 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
90. The process of any one of claims 82-89, wherein the compound of formula (VIII), or
a salt thereof, is a compound of formula (Villa),
Figure imgf000124_0002
or a salt thereof, or a compound of formula (VUIb),
Figure imgf000124_0003
or a salt thereof, or a mixture of any one of the foregoing.
91. The process of claim 90, wherein the compound formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof, are present in a ratio of at least 1 : 1 , 2: 1 , 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, or 9: 1.
92. The process of claim 91, wherein the compound formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof, are present in a ratio of at least 9: 1.
A process for preparing a compound of formula
a salt thereof, comprising reacting
Figure imgf000125_0001
, or a salt thereof:
Figure imgf000125_0002
or a salt thereof: or
Figure imgf000125_0003
or a salt thereof,
with a source of ammonia to form the compound of formula (I), or a salt thereof, wherein:
R6 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; or two occurrences of R1 taken together with the carbon(s) to which they are attached form a fused or spiro carbocyclic or heterocyclic ring;
R2 independently for each occurrence, is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime; R3 is selected from hydrogen, halogen, CN, and optionally substituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, or oxime;
Q is a leaving group;
R4 is lower alkyl;
o is 1, 2, or 3;
p is 0, 1, 2, 3, or 4;
r is 1, 2, or 3; and
s is 0, 1, 2, 3, 4, 5, or 6.
94. The process of claim 93, wherein the compound of formula (VIII), or a salt thereof, is prepared according to the process of any one of claims 82-92.
95. The process of claim 93, wherein the compound of formula (VI), or a salt thereof, is prepared according to the process of any one of claims 63-73.
96. The process of claim 93, wherein the compound of formula (VII), or a salt thereof, is prepared according to the process of any one of claims 54-62.
97. The process of any one of claims 93-96, wherein the source of ammonia is selected from liquid ammonia, ammonia solution, or an ammonium salt.
98. The process of claim 97, wherein the ammonium salt is ammonium chloride, ammonium acetate, or ammonium carbonate.
99. The process of any one of claims 93-94 or 97-98, wherein the compound of formula (VIII), or a salt thereof, is a compound of formula (Villa),
Figure imgf000126_0001
, or a salt thereof, or a compound of formula (Vlllb),
Figure imgf000127_0001
, or a salt thereof, or a mixture of any one of the foregoing.
100. The process of claim 99, wherein the compound formula (Villa), or a salt thereof, and the compound of formula (VUIb), or a salt thereof, are present in a ratio of at least 1 : 1 , 2: 1 ,
3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1.
101. The process of any one of claims 93, 95, or 97-98, wherein a compound of formula (VI), or a salt thereof, is a compound of formula (Via),
Figure imgf000127_0002
one of the foregoing.
102. The process of claim 101, wherein the compound formula (Via), or a salt thereof, and the compound of formula (Vlb), or a salt thereof, are present in a ratio of at least 1:1, 2:1, 3:1,
4:1, 5:1, 6:1, 7:1, 8:1, or 9:1.
103. The process of any one of claims 93 or 96-98, wherein the compound of formula (VII), or a salt thereof, is a compound of formula (Vila),
Figure imgf000128_0001
one of the foregoing. 104. The process of claim 103, wherein the compound formula (Via), or a salt thereof, and the compound of formula (VIb), or a salt thereof, are present in a ratio of at least 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1.
105. The process of any one of claims 93-104, wherein the compound of formula (I), or a
salt thereof, is a compound of formula (
Figure imgf000128_0002
or a salt
thereof, or a compound of formula (
Figure imgf000128_0003
or a salt thereof, or a mixture of any of the foregoing.
106. The process of claim 105, wherein the compound formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof, are present in a ratio of at least 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1.
107. The process of claim 106, wherein the compound formula (la), or a salt thereof, and the compound of formula (lb), or a salt thereof, are present in a ratio of at least 9:1.
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