WO2017070081A1 - Pyrazolone derivatives as nitroxyl donors - Google Patents

Pyrazolone derivatives as nitroxyl donors Download PDF

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Publication number
WO2017070081A1
WO2017070081A1 PCT/US2016/057475 US2016057475W WO2017070081A1 WO 2017070081 A1 WO2017070081 A1 WO 2017070081A1 US 2016057475 W US2016057475 W US 2016057475W WO 2017070081 A1 WO2017070081 A1 WO 2017070081A1
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alkyl
compound
phenyl
methyl
membered
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English (en)
French (fr)
Inventor
Vincent Jacob Kalish
Lisa Marie Frost
Frederick Arthur Brookfield
Stephen Martin Courtney
Carl Leslie North
Matthew Robert CONROY
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Cardioxyl Pharmaceuticals Inc
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Cardioxyl Pharmaceuticals Inc
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Priority to EP16788365.1A priority Critical patent/EP3365328A1/en
Priority to CN201680072249.0A priority patent/CN108473439B/zh
Priority to JP2018519916A priority patent/JP6889704B2/ja
Priority to KR1020187014121A priority patent/KR20180063326A/ko
Priority to US15/769,160 priority patent/US10723704B2/en
Publication of WO2017070081A1 publication Critical patent/WO2017070081A1/en
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61K31/415—1,2-Diazoles
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    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • Nitroxyl has been shown to have positive cardiovascular effects in in vitro and in vivo models of failing hearts. However, at physiological pH, nitroxyl dimerizes to hyponitrous acid, which subsequently dehydrates to nitrous oxide. Owing to this metastability, nitroxyl for therapeutic use is typically generated in situ from donor compounds. A variety of compounds capable of donating nitroxyl have been described and proposed for use in treating disorders known or suspected to be responsive to nitroxyl. See, e.g. , U.S. Pat. Nos. 6,936,639, 7,696,373, 8,030,356, 8,268,890, 8,227,639, and 8,318,705, U.S. pre-grant publication nos. 2009/0281067, 2009/0298795, 201 1/0136827, and 201 1/0144067, PCT international publication no. WO 2013/059194, and Paolocci et al , Pharmacol.
  • nitroxyl donating compounds and compositions that are useful for the treatment of heart failure and that have a suitable safety profile.
  • nitroxyl donors that have increased solid state stability and, thus, are more amenable for oral administration.
  • the present disclosure relates to pyrazolone derivative compounds, pharmaceutical compositions comprising such compounds, kits comprising such compounds, and methods of using such compounds or pharmaceutical compositions.
  • a pyrazolone derivative compound of the disclosure is compound of formula (la)
  • C 4 perhaloalkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, -S(0) 2 -(5-, 6-, or 7- membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci-C 6 )alkylaminosulfonyl, and N,N-di(Ci-C6)alkylaminosulfonyl;
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • R 2 is (Ci-C 6 )alkyl
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • a pyrazolone derivative compound of the disclosure is compound of formula (lb)
  • C 4 perhaloalkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, -S(0) 2 -(5-, 6-, or 7- membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci-C6)alkylaminosulfonyl, and N,N-di(Ci-C6)alkylaminosulfonyl;
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl
  • R 2 is (Ci-C6)alkyl substituted with 1, 2 or 3 substituent(s) independently selected
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl
  • a pyrazolone derivative compound of the disclosure is compound of formula (Id)
  • R 1 is (Ci-C6)alkyl substituted with 1, 2 or 3 substituent(s) independently selected
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C6)alkyl
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • R 9 is (Ci-C 6 )alkyl
  • R 10 is not (Ci-C 6 )alkyl.
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl; R 8 is H,
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • a pyrazolone derivative compound of the disclosure is compound of formula (If)
  • R 2 is (Ci-C6)alkyl or phenyl, wherein said phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituent(s) independently selected from halo, cyano, (Ci-C6)alkyl, (Ci-C haloalkyl, (Ci-
  • C 4 perhaloalkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, -S(0) 2 -(5-, 6-, or 7- membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci-C6)alkylaminosulfonyl, and N,N-di(Ci-C6)alkylaminosulfonyl, wherein said (5-, 6-, or 7-membered)heterocycloalkyl is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from halo or (Ci-C6)alkyl; m is 1, 2 or 3; and
  • R is 5-methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • a pyrazolone derivative compound of the disclosure is compound of formula (Ig)
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C6)alkyl
  • a pyrazolone derivative compound of the disclosure is compound of formula (Ih)
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • a pyrazolone derivative compound of the disclosure is compound of formula (Ii)
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C6)alkyl
  • a pyrazolone derivative compound of the disclosure is compound of formula (Ij)
  • R 1 is (Ci-C 6 )alkyl
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl
  • R 3 is (Ci-C6)alkyl
  • R is 5-methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • a pyrazolone derivative compound of the disclosure is compound of formula (Ik)
  • R 1 is (5-, 6- or 7-membered)heterocycloalkyl
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl
  • R 3 is (Ci-C 6 )alkyl;
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • the invention includes the following:
  • C 4 perhaloalkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, -S(0) 2 -(5-, 6-, or 7- membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci-C 6 )alkylaminosulfonyl, and N,N-di(Ci-C6)alkylaminosulfonyl;
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • R 2 is (Ci-C 6 )alkyl
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • R 9 is (Ci-C 4 )alkyl.
  • R 3 is (Ci-C6)alkyl substituted with 1, 2 or 3 substituent(s) independently selected from -
  • R 2 is (Ci-C6)alkyl substituted with 1, 2 or 3 substituent(s) independently selected from -
  • (Ci-C4)perhaloalkoxy, -C( 0)-(5-, 6-, or 7-membered)heterocycloalkyl, (5-, 6-, or 7- membered)heterocycloalkyl, (Ci-C6)alkylsulfanyl, (Ci-C4)haloalkylsulfanyl, (Ci-
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C6)alkyl
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered
  • Ce)alkoxy, (Ci-C 4 )haloalkoxy, (Ci-C 4 )perhaloalkoxy, -C( 0)-(5-, 6-, or 7-membered)heterocycloalkyl, (5-, 6-, or 7-membered)heterocycloalkyl, (Ci-C6)alkylsulfanyl, (Ci-C 4 )haloalkylsulfanyl, (Ci- C 4 )perhaloalkylsulfanyl, (Ci-C6)alkylsulfinyl, (Ci-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl, (Ci- C 4 )haloalkylsulfinyl, (Ci-C 4 )haloalkylsulfonyl, (Ci-C 4 )perhaloalkylsulfinyl, (Ci-
  • R 2 is (Ci-C 2 )alkyl substituted with (5- or 6-membered)heteroaryl or phenyl; and R is hydrogen, -CO-(Ci-C6)alkyl, -CO-phenyl, -CO- benzyl, -CO-NH 2 or 5-methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R 3 is (Ci-C6)alkyl; and R is hydrogen, -CO-(Ci-C 6 )alkyl, -CO-phenyl, -CO-benzyl, -CO-NH 2 or 5-methyl-2-oxo-2H-l,3-dioxol-4- ylmethyl.
  • R 2 is (Ci-C 2 )alkyl substituted with (5- or 6-membered)heteroaryl or phenyl
  • R 3 is (Ci-C6)alkyl
  • R is hydrogen, -CO-(Ci-C6)alkyl, -CO- phenyl, -CO-benzyl, -CO-NH 2 or 5-methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl
  • R 2 is unsubstituted phenyl or phenyl substituted with a substituent selected from (Ci-C6)alkylsulfanyl, (Ci-C6)alkylsulfinyl, (Ci- C 6 )alkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , N-(Ci-C6)alkylaminosulfonyl, and NN-di(Ci- C6)alkylaminosulfonyl; and R 3 is (Ci-C6)alkyl.
  • R 2 is unsubstituted phenyl or phenyl substituted with a substituent selected from (Ci-C6)alkylsulfanyl, (Ci-C6)alkylsulfinyl, (Ci- C 6 )alkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , N-(Ci-C6)alkylaminosulfonyl, and NN-di(Ci- C6)alkylaminosulfonyl; and R 3 is methyl.
  • R is hydrogen, -CO-(Ci-C6)alkyl, -CO-phenyl, -CO-benzyl, -CO-NH 2 or 5- methyl-2-oxo-2H- 1 ,3-dioxol-4-ylmethyl.
  • R 2 is unsubstituted phenyl or phenyl substituted with a substituent selected from (Ci-C6)alkylsulfanyl, (Ci-C6)alkylsulfinyl, (Ci- C 6 )alkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , N-(Ci-C6)alkylaminosulfonyl, and NN-di(Ci- C6)alkylaminosulfonyl;
  • R 3 is (Ci-C6)alkyl; and R is hydrogen, -CO-(Ci-C6)alkyl, -CO-phenyl, -CO- benzyl, -CO-NH 2 or 5-methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R 2 is unsubstituted phenyl or phenyl substituted with a substituent selected from (Ci-C6)alkylsulfanyl, (Ci-C6)alkylsulfinyl, (Ci- C 6 )alkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , N-(Ci-C6)alkylaminosulfonyl, and N,N-di(Ci- C6)alkylaminosulfonyl; and R is hydrogen.
  • R 3 is (Ci-C6)alkyl; and R is hydrogen.
  • R 2 is unsubstituted phenyl or phenyl substituted with a substituent selected from (Ci-C6)alkylsulfanyl, (Ci-C6)alkylsulfinyl, (Ci- C 6 )alkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , N-(Ci-C 6 )alkylaminosulfonyl, and NN-di(Ci- C6)alkylaminosulfonyl; R 3 is (Ci-C6)alkyl; and R is hydrogen.
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, -(C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • (140) The compound of any one of the above (84) to (87), wherein X is CH 2 , O, NH, N(Ci-C 6 )alkyl, S, SO, or SO 2 ; n is 0, 1 or 2; and R is hydrogen, -CO-(Ci-C6)alkyl, -CO-phenyl, -CO-benzyl, -CO-NH 2 or 5-methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R is 5-methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • C 4 perhaloalkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, -S(0) 2 -(5-, 6-, or 7- membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci-C6)alkylaminosulfonyl, and N,N-di(Ci-C6)alkylaminosulfonyl;
  • R 2 is phenyl substituted with a substituent selected from (Ci-C 6 )alkylsulfenyl, (Ci-C 6 )alkylsulfinyl, (Ci-C 6 )alkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , N-
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl
  • R 1 is (Ci-C 6 )alkyl
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C6)alkyl;
  • R 3 is (Ci-C6)alkyl;
  • R is 5-methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl. (247) The compound of the above (246), wherein R 1 is (Ci-C4)alkyl.
  • R 1 is (5-, 6- or 7-membered)heterocycloalkyl
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl; R 3 is (Ci-C6)alkyl; and
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C 4 )alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered
  • composition of the above (283), wherein the at least one pharmaceutically acceptable excipient is selected from lactose, macrocrystalline cellulose, croscarmellose, or any mixture thereof.
  • kits for treating and/or preventing a disease or condition responsive to nitroxyl therapy comprising a compound of any one of the above (1), (18), (40), (62), (84), ( 164), ( 178), (196), (218), (246), (256) or (275), or a pharmaceutical composition of any of the above (283) to (286); and instructions for use of the kit.
  • the kit of the above (298), wherein the disease or condition is selected from cardiovascular diseases, ischemia/reperfusion injury, cancerous disease, and pulmonary hypertension.
  • a “pharmaceutically acceptable salt” refers to a salt of any therapeutic agent disclosed herein, which salt can include any of a variety of organic and inorganic counter ions known in the art and which salt is pharmaceutically acceptable.
  • various exemplary embodiments of counter ions are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.
  • a pharmaceutically acceptable salt can include as a counter ion, by way of example, an organic or inorganic acid, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.
  • Illustrative salts include, but are not limited to, sulfate, citrate, acetate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
  • a salt can be prepared from a compound of any one of the formulae disclosed herein having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl-N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower-alkyl amines), such as mono-, bis-, or tris-(2- hydroxyethyl)amine, 2-hydroxy-fert-butylamine, or tris-(hydroxymethyl)methylamine, NN-di-lower- alkyl-N-(hydroxy-lower-alkyl)-amines, such as NN-dimethyl-N-(
  • a salt can also be prepared from a compound of any one of the formulae disclosed herein having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • Suitable acids include hydrogen sulfate, citric acid, acetic acid, hydrochloric acid (HQ), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, phosphoric acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • “Pharmaceutically acceptable excipient” refers to any substance, not itself a therapeutic agent, used as a carrier, diluent, adjuvant, binder, and/or vehicle for delivery of a therapeutic agent to a patient, or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a compound or pharmaceutical composition into a unit dosage form for administration.
  • Pharmaceutically acceptable excipients are known in the pharmaceutical arts and are disclosed, for example, in Gennaro, Ed., Remington: The Science and Practice of Pharmacy, 20 th Ed. (Lippincott Williams & Wilkins, Baltimore, MD, 2000) and Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, D.C., (e.g.
  • pharmaceutically acceptable excipients can provide a variety of functions and can be described as wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners.
  • Examples of pharmaceutically acceptable excipients include without limitation: (1) sugars, such as lactose, glucose and sucrose, (2) starches, such as corn starch and potato starch, (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, and croscarmellose, such as or eroscarmeUose sodium, (4) powdered tragacanth, (5) malt, (6) gelatin, (7) talc, (8) excipients, such as cocoa butter and suppository waxes, (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol, (12) esters, such as e
  • Unit dosage form refers to a physically discrete unit suitable as a unitary dosage for a human or an animal. Each unit dosage form can contain a predetermined amount of a therapeutic agent calculated to produce a desired effect.
  • a “patient” refers to an animal, such as a mammal, including but not limited to a human. Hence, the methods disclosed herein can be useful in human therapy and veterinary applications.
  • the patient is a mammal.
  • the patient is a human.
  • Effective amount refers to such amount of a therapeutic agent or a pharmaceutically acceptable salt thereof, which in combination with its parameters of efficacy and potential for toxicity, as well as based on the knowledge of the practicing specialist, should be effective in a given therapeutic form. As is understood in the art, an effective amount can be administered in one or more doses.
  • beneficial or desired results include but are not limited to inhibiting and/or suppressing the onset and/or development of a condition or reducing the severity of such condition, such as reducing the number and/or severity of symptoms associated with the condition, increasing the quality of life of those suffering from the condition, decreasing the dose of other medications required to treat the condition, enhancing the effect of another medication a patient is taking for the condition, and/or prolonging survival of patients having the condition.
  • Prevent refers to reducing the probability of developing a condition in a patient who does not have, but is at risk of developing a condition.
  • a patient “at risk” may or may not have a detectable condition, and may or may not have displayed a detectable condition prior to the treatment methods disclosed herein.
  • At risk denotes that a patient has one or more so- called risk factors, which are measurable parameters that correlate with development of a condition and are known in the art. A patient having one or more of these risk factors has a higher probability of developing the condition than a patient without such risk factor(s).
  • Positive inotrope refers to an agent that causes an increase in myocardial contractile function.
  • exemplary positive inotropes are a fteto-adrenergic receptor agonist, an inhibitor of phosphodiesterase activity, and calcium-sensitizers.
  • Zteto-adrenergic receptor agonists include, among others, dopamine, dobutamine, terbutaline, and isoproterenol. Analogs and derivatives of such compounds are also included within positive inotropes.
  • U.S. Pat. No. 4,663,351 discloses a dobutamine prodrug that can be administered orally.
  • a condition that is "responsive to nitroxyl therapy” includes any condition in which administration of a compound that donates an effective amount of nitroxyl under physiological conditions treats and/or prevents the condition, as those terms are defined herein.
  • a condition whose symptoms are suppressed or diminished upon administration of nitroxyl donor is a condition responsive to nitroxyl therapy.
  • PH Pulmonary hypertension
  • MPAP mean pulmonary arterial pressure
  • (Ci-C6)alkyl refers to saturated linear and branched hydrocarbon structures having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • alkyl residue having a specific number of carbons when named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, "propyl” includes ⁇ -propyl and zso-propyl and "butyl” includes «-butyl, sec-butyl, z ' so-butyl and tert- butyl.
  • (Ci-C6)alkyl groups include methyl, ethyl, ⁇ -propyl, zso-propyl, «-butyl, fert-butyl, «-hexyl, and the like.
  • “(C 2 -C6)alkyl” refers to saturated linear and branched hydrocarbon structures having 2, 3, 4, 5, or 6 carbon atoms.
  • alkyl residue having a specific number of carbons When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, "propyl” includes ⁇ -propyl and zso-propyl and "butyl” includes «-butyl, sec-butyl, z ' so-butyl and fert-butyl.
  • Examples of (C 2 -C6)alkyl groups include ethyl, ⁇ -propyl, zso-propyl, «-butyl, fert-butyl, «-hexyl, and the like.
  • (Ci-C alkyl) refers to saturated linear and branched hydrocarbon structures having 1, 2, 3, or 4 carbon atoms. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, "propyl” includes ⁇ -propyl and zso-propyl and "butyl” includes «-butyl, sec-butyl, /so-butyl and fert-butyl. Examples of (Ci-C alkyl groups include methyl, ethyl, ⁇ -propyl, / ' so-propyl, «-butyl, fert-butyl, and the like.
  • (C 2 -C4)alkenyl refers to a straight-chain or branched unsaturated hydrocarbon radical having 2, 3, or 4 carbon atoms and a double bond in any position, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methylethenyl, 1 -methyl- 1-propenyl, 2 -methyl -2-propenyl, 2- methyl- 1-propenyl, 1 -methyl -2-propenyl, and the like.
  • (C3-C6)cycloalkyl refers to a saturated cyclic hydrocarbon containing 3, 4, 5, or 6 ring carbon atoms.
  • Examples of (C3-C6)cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • (Ci-C perhaloalkyl” refers to a (Ci-C alkyl group wherein every hydrogen atom is replaced by halo, each halo being independently selected.
  • Examples of (Ci-C perhaloalkyl groups include -CF 3 , -CC1 3 , -CF 2 CF 3 , -CC1 2 CF 3 , -CC1FCC1F 2 , -CF(CF 3 ) 2 , -CBr(CF 3 )(CFCl 2 ), and the like.
  • (Ci-C haloalkyl) refers to a (Ci-C alkyl group wherein at least one hydrogen atom is replaced by halo but wherein the (Ci-C haloalkyl contains few halos than a (Ci-C perhaloalkyl having the same number of carbon atoms as the (Ci-C haloalkyl.
  • Each halo of a (Ci-C haloalkyl is independently selected.
  • Examples of (Ci-C haloalkyl groups include -CHF 2 , -CH 2 F, - CHFC1, -CH 2 CF 3 , -CHC1CHF 2 , -CHFCHC1F, -CH(CF 3 ) 2 , -CH(CF 3 )(CH 3 ), -CBr(CHF 2 )(CHCl 2 ), and the like.
  • (Ci-C6)alkoxy refers to -0-(Ci-C6)alkyl.
  • Examples of (Ci-C6)alkoxy groups include methoxy, ethoxy, propoxy, «-propoxy, zso-propoxy, butoxy, «-butoxy, sec-butoxy, fert-butoxy, pentoxy, hexyloxy, and the like.
  • (Ci-C alkoxy) refers to -0-(Ci-C4)alkyl.
  • Examples of (Ci-C4)alkoxy groups include methoxy, ethoxy, propoxy, «-propoxy, zso-propoxy, butoxy, «-butoxy, sec-butoxy, fert-butoxy, and the like.
  • (Ci-C4)haloalkoxy refers to -0-(Ci-C4)haloalkyl.
  • Examples of (Ci-C4)haloalkoxy groups include -OCHF 2 , -OCH 2 F, -OCHFC1, -OCH 2 CF 3 , -OCHClCHF 2 , -OCHFCHC1F, - OCH(CF 3 ) 2 , -OCH(CF 3 )(CH 3 ), -OCBr(CHF 2 )(CHCl 2 ), and the like.
  • (Ci-C4)perhaloalkoxy refers to -0-(Ci-C4)perhaloalkyl.
  • Examples of (Ci-C4)perhaloalkoxy groups include -OCF 3 , -OCCl 3 , -OCF 2 CF 3 , -0CC1 2 CF 3 , -0CC1FCC1F 2 , - OCF(CF 3 ) 2 , -OCBr(CF 3 )(CFCl 2 ), and the like.
  • (Ci-C6)alkylsulfanyl refers to -S-(Ci-C6)alkyl.
  • Examples of (Ci-C6)alkylsulfanyl groups include methylsulfanyl, ethylsulfanyl, propylsulfanyl, «-propylsulfanyl, zso-propylsulfanyl, butylsulfanyl, «-butylsulfanyl, sec-butylsulfanyl, fert-butylsulfanyl, pentylsulfanyl, hexylsulfanyl, and the like.
  • (Ci-C4)haloalkylsulfanyl refers to -S-(Ci-C4)haloalkyl.
  • Examples of (Ci- C4)haloalkylsulfanyl groups include -SCHF 2 , -SCH 2 F, -SCHFC1, -SCH 2 CF 3 , - SCHC1CHF 2 , -SCHFCHC1F, -SCH(CF 3 ) 2 , -SCH(CF 3 )(CH 3 ), -SCBr(CHF 2 )(CHCl 2 ), and the like.
  • “(Ci-C4)perhaloalkylsulfanyl” refers to -S-(Ci-C4)perhaloalkyl.
  • Examples of (Ci- C4)perhaloalkylsulfanyl groups include -SCF3, -SCCI3, -SCF2CF3, -SCCI2CF3, - SCCIFCCIF2, -SCF(CF 3 ) 2 , -SCBr(CF 3 )(CFCl 2 ), and the like.
  • (Ci-C6)alkylsulfinyl refers to -S(0)-(Ci-C6)alkyl.
  • Examples of (Ci-C6)alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, propylsulfinyl, «-propylsulfinyl, wo-propylsulfinyl, butylsulfinyl, «-butylsulfinyl, sec-butylsulfinyl, fert-butylsulfinyl, pentylsulfinyl, hexylsulfinyl, and the like.
  • (Ci-C6)alkylsulfonyl refers to -S(0) 2 -(Ci-C6)alkyl.
  • Examples of (Ci-C6)alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, «-propylsulfonyl, zso-propylsulfonyl, butylsulfonyl, «-butylsulfonyl, sec-butylsulfonyl, fert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, and the like.
  • (C3-C6)cycloalkylsulfonyl refers to -S(0) 2 -(C3-C6)cycloalkyl.
  • Examples of (C3- C6)cycloalkylsulfonyl groups include -S(0)2-cyclopropyl, -S(0)2-cyclobutyl, -S(0)2- cyclopentyl, -S(0)2-cyclohexyl, and the like.
  • (Ci-C4)perhaloalkylsulfinyl refers to -S(0)-(Ci-C4)perhaloalkyl.
  • Examples of (Ci- C 4 )perhaloalkylsulfinyl groups include -S(0)-CF 3 , -S(0)-CC1 3 , -S(0)-CF 2 CF 3 , -S(0)-CC1 2 CF 3 , -S(O)- CCIFCCIF2, -S(0)-CC1FCC1F 2 , -S(0)-CC1FCC1F 2 , -S(0)-CF(CF 3 ) 2 , -S(0)-CBr(CF 3 )(CFCl 2 ), and the like.
  • (Ci-C4)perhaloalkylsulfonyl refers to -S(0) 2 -(Ci-C4)perhaloalkyl.
  • Examples of (Ci- C4)perhaloalkylsulfonyl groups include -S(0)2-CF3, -S(0)2-CCl3, -S(0)2-CF2CF3, -S(0)2- CCI2CF3, -S(0) 2 -CC1FCC1F 2 , -S(0) 2 -CC1FCC1F 2 , -S(0) 2 -CC1FCC1F 2 , -S(0) 2 -CF(CF 3 )2, -S(0) 2 - CBr(CF 3 )(CFCl 2 ), and the like.
  • (Ci-C4)haloalkylsulfinyl refers to -S(0)-(Ci-C4)haloalkyl.
  • Examples of (Ci- C 4 )haloalkylsulfinyl groups include -S(0)-CHF 2 , -S(0)-CH 2 F, -S(0)-CHFC1, -S(0)-CH 2 CF 3 , -S(O)- CHCICHF2, -S(0)-CHFCHC1F, -S(0)-CH(CF 3 ) 2 , -S(0)-CH(CF 3 )(CH 3 ), -S(0)-CBr(CHF 2 )(CHCl 2 ), and the like.
  • (Ci-C4)haloalkylsulfonyl refers to -S(0) 2 -(Ci-C4)haloalkyl.
  • Examples of (Ci- C 4 )haloalkylsulfonyl groups include -S(0) 2 -CHF 2 , -S(0) 2 -CH 2 F, -S(0) 2 -CHFC1, -S(0) 2 - CH2CF3, -S(0) 2 -CHC1CHF 2 , -S(0) 2 -CHFCHC1F, -S(0) 2 -CH(CF 3 )2, -S(0) 2 -CH(CF 3 )(CH 3 ), -S(0) 2 - CBr(CHF 2 )(CHCl 2 ), and the like.
  • N-(Ci-C 6 )alkylaminosulfonyl refers to -S(0) 2 -NH-(Ci-C 6 )alkyl.
  • Examples of N-(Ci- C 6 )alkylaminosulfonyl groups include -S(0) 2 -NH-methyl, -S(0) 2 -NH-ethyl, -S(0) 2 -NH- «- propyl, -S(0) 2 -NH-/so-propyl, -S(0) 2 -NH- «-butyl, -S(0) 2 -NH-sec-butyl, -S(0) 2 -NH-/so-butyl, -S(0) 2 - NH-fert-butyl, -S(0) 2 -NH- «-hexyl, and the like.
  • N,N-di(Ci-C6)alkylaminosulfonyl refers to -S(0) 2 -N-((Ci-C6)
  • Ce)alkyl is independently selected.
  • Examples of NN-di(Ci-C6)alkylaminosulfonyl groups are independently selected.
  • (5-, 6-, or 7-membered)heterocycloalkyl refers to a saturated or partially unsaturated, monocyclic -heterocycle ring of 5, 6, or 7 members, comprising 1, 2, 3, or 4 ring heteroatoms each independently selected from nitrogen, oxygen, and sulfur, wherein said nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocycloalkyl group can be attached to the parent structure through a carbon or a heteroatom.
  • Examples of (5-, 6-, or 7-membered)heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, tetrahydro-oxazinyl, tetrahydrofuranyl, thiolanyl, dithiolanyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranone, ⁇ -butyrolactone, 2H-pyranyl, 4H- pyranyl, dioxolanyl, tetrahydropyranyl, dioxanyl, dihydrothiophenyl, morpholinyl, thiomorpholinyl, oxazinyl, tetrahydro-oxazinyl, 1,2,3-triazinanyl, and the like.
  • (5- or 6-membered)heteroaryl refers to a monocyclic aromatic heterocycle ring of 5 or 6 members, i.e. , a monocyclic aromatic ring comprising at least one ring heteroatom, e.g. , 1, 2, 3, or 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur.
  • the (5- or 6- membered)heteroaryl comprises a nitrogen or sulfur atom(s)
  • the nitrogen atom or sulfur atom(s) are optionally oxidized to form the N-oxide or S-oxide(s).
  • a (5- or 6-membered)heteroaryl group can be attached to the parent structure through a carbon or heteroatom.
  • Examples of (5- or 6- membered)heteroaryls include pyridyl, pyrrolyl, pyrazolyl, furyl, imidazolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl, thiophenyl, and the like.
  • (C6-Cio)aryl refers to a monovalent aromatic hydrocarbon group which may be monocyclic, bicyclic or tricyclic, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3, 4, 5, 6 or 7 ring members.
  • Examples of (C6-Cio)aryl groups include without limitation phenyl, naphthyl, indanyl, indenyl and tetralinyl. In some embodiments, the aryl is phenyl.
  • a compound of the disclosure can contain one, two, or more asymmetric centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • the disclosure encompasses compounds with all such possible forms, as well as their racemic and resolved forms or any mixture thereof, unless specifically otherwise indicated.
  • isotopes present in the compounds of the disclosure include isotopes of hydrogen (e.g., 2 H and 3 H), carbon (e.g., 13 C and 14 C), nitrogen (e.g., 15 N) and oxygen (e.g., 17 0 and 18 0).
  • isotopes of hydrogen e.g., 2 H and 3 H
  • carbon e.g., 13 C and 14 C
  • nitrogen e.g., 15 N
  • oxygen e.g., 17 0 and 18 0.
  • One aspect of the disclosure provides a compound of formula (la) or a pharmaceutically acceptable salt thereof, wherein:
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl
  • R 2 is (Ci-C 6 )alkyl;
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • the present disclosure relates to a compound of formula (la) and the attendant definitions, wherein R 1 is unsubstituted phenyl.
  • R 1 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 1 in connection with formula (la).
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is methylsulfanyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is trifluoromethylsulfanyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is methylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is methylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is cyclopropylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C/ haloalkylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfinyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -NR 6 R 7 . In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is - S(0) 2 -phenyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -(5-, 6-, or 7-membered)heterocycloalkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-di(Ci-C6)alkylaminosulfonyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-dimethylaminosulfonyl.
  • R 2 is (Ci-C4)alkyl.
  • R 2 is methyl, ethyl, propyl, or butyl.
  • R 2 is methyl, ethyl, or propyl.
  • R 2 is methyl, ethyl, or butyl.
  • R 2 is methyl, propyl, or butyl.
  • R 2 is ethyl, propyl, or butyl. In another embodiment, R 2 is methyl or ethyl. In another embodiment, R 2 is methyl or propyl. In another embodiment, R 2 is methyl or butyl. In another embodiment, R 2 is ethyl or propyl. In another embodiment, R 2 is ethyl or butyl. In another embodiment, R 2 is propyl or butyl. In another embodiment, R 2 is methyl. In another embodiment, R 2 is ethyl. In another embodiment, R 2 is propyl. In another embodiment, R 2 is zso-propyl. In another embodiment, R 2 is butyl. In another embodiment, R 2 is fert-butyl.
  • R 9 is phenyl is methyl, ethyl or propyl.
  • R 9 is methyl or ethyl.
  • R 9 is methyl.
  • R 9 is ethyl.
  • the present disclosure relates to a compound of formula (la) and the attendant definitions, wherein R is hydrogen, -CO-methyl, -CO-ethyl, -CO-benzyl, -CO-phenyl or 5- methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R is hydrogen or 5-methyl-2-oxo- 2H-l,3-dioxol-4-ylmethyl.
  • R is hydrogen.
  • R is 5- methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R is -CO-methyl or -CO-ethyl.
  • R is -CO-methyl. In another embodiment, R is -CO-ethyl. In another embodiment, R is -CO-benzyl or -CO-phenyl. In another embodiments, R is -CO-benzyl. In another embodiment, R is -CO-phenyl. In another embodiment, R is -CO-NH 2 . In each of the above embodiments in this paragraph, R is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment. In various embodiments of each of the above embodiments in this paragraph, the substituent
  • Another aspect of the disclosure provides a compound of formula (lb)
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • R 3 is (Ci-C6)alkyl substituted with 1, 2 or 3 substituent(s) independently selected
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • the present disclosure relates to a compound of formula (lb) and the attendant definitions, wherein R 1 is H.
  • R 1 is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents.
  • R 1 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • R 1 is phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • the substitutents are selected from among those disclosed above for R 1 in connection with formula (lb).
  • R 1 is (Ci-C 4 )alkyl.
  • R 1 is methyl, ethyl, propyl, or butyl.
  • R 1 is methyl, ethyl, or propyl.
  • R 1 is methyl, ethyl, or butyl.
  • R 1 is methyl, propyl, or butyl.
  • R 1 is ethyl, propyl, or butyl.
  • R 1 is methyl or ethyl.
  • R 1 is methyl or propyl.
  • R 1 is methyl or butyl. In another embodiment, R 1 is ethyl or propyl. In another embodiment, R 1 is ethyl or butyl. In another embodiment, R 1 is propyl or butyl. In another embodiment, R 1 is methyl. In another embodiment, R 1 is ethyl. In another embodiment, R 1 is propyl. In another embodiment, R 1 is zso-propyl. In another embodiment, R 1 is butyl. In another embodiment, R 1 is fert-butyl.
  • the alkyl is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • the present disclosure relates to a compound of formula (lb) and the attendant definitions, wherein R 1 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents, the substitutents being selected from among those disclosed above for R 1 in connection with formula (lb).
  • R 1 is unsubstituted (5- or 6-membered)heteroaryl.
  • R 1 is monosubstituted (5- or 6-membered)heteroaryl.
  • R 1 is disubstituted (5- or 6- membered)heteroaryl.
  • R 1 is trisubstituted (5- or 6-membered)heteroaryl.
  • the present disclosure relates to a compound of formula (lb) and the attendant definitions, wherein R 1 is unsubstituted phenyl.
  • R 1 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 1 in connection with formula (lb).
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfinyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -NR 6 R 7 . In another embodiment, R 1 is phenyl substituted with 1, 2, or 3
  • R 1 independently selected substituent(s), at least one of which is -S(0) 2 -phenyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is - S(0) 2 -(5-, 6-, or 7-membered)heterocycloalkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-di(Ci-C6)alkylaminosulfonyl.
  • C 4 perhaloalkylsulfinyl, (Ci-C 4 )perhaloalkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, - S(0) 2 -(5-, 6-, or 7-membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci- C6)alkylaminosulfonyl, and NN-di(Ci-C6)alkylaminosulfonyl.
  • the present disclosure relates to a compound of formula (lb) and the attendant definitions, wherein, R 2 is (C1-C4) alkyl.
  • R 2 is methyl, ethyl, propyl, or butyl.
  • R 2 is methyl, ethyl, or propyl.
  • R 2 is methyl, ethyl, or butyl.
  • R 2 is methyl, propyl, or butyl.
  • R 2 is ethyl, propyl, or butyl.
  • R 2 is methyl or ethyl.
  • R 2 is methyl or propyl.
  • R 2 is methyl or butyl. In another embodiment, R 2 is ethyl or propyl. In another embodiment, R 2 is ethyl or butyl. In another embodiment, R 2 is propyl or butyl. In another embodiment, R 2 is methyl. In another embodiment, R 2 is ethyl. In another embodiment, R 2 is propyl. In another embodiment, R 2 is zso-propyl. In another embodiment, R 2 is butyl. In another embodiment, R 2 is fert-butyl.
  • the alkyl is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • the present disclosure relates to a compound of formula (lb) and the attendant definitions, wherein R 2 is unsubstituted phenyl.
  • R 2 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 2 in connection with formula (lb).
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (5-, 6-, or 7-membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfanyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is methylsulfanyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C/ haloalkylsulfinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfonyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0)2-NR 6 R 7 . In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is - S(0)2-phenyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0)2-(5-, 6-, or 7-membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-di(Ci-C6)alkylaminosulfonyl.
  • C 4 perhaloalkylsulfinyl, (Ci-C 4 )perhaloalkylsulfonyl, -S(0) 2 -NH 2 , , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, -S(0) 2 -(5-, 6-, or 7-membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci- C6)alkylaminosulfonyl, and NN-di(Ci-C6)alkylaminosulfonyl.
  • the present disclosure relates to a compound of formula (lb) and the attendant definitions, wherein R 3 is (Ci-C6)alkyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 3 in connection with formula (lb). In another embodiment, R 3 is (Ci-C6)alkyl substituted with a substituent selected from among those disclosed above for R 3 in connection with formula (lb). In another embodiment, R 3 is (Ci-C4)alkyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 3 in connection with formula (lb).
  • R 3 is (Ci-C4)alkyl substituted with a substitutent selected from among those disclosed above for R 3 in connection with formula (lb).
  • R 3 is (Ci-C 2 )alkyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 3 in connection with formula (lb).
  • R 3 is (Ci-C 2 )alkyl substituted with a substituent selected from among those disclosed above for R 3 in connection with formula (lb).
  • the present disclosure relates to a compound of formula (lb) and the attendant definitions, wherein R is hydrogen, -CO-methyl, -CO-ethyl, -CO-benzyl, -CO-phenyl or 5- methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R is hydrogen or 5-methyl-2-oxo- 2H-l,3-dioxol-4-ylmethyl.
  • R is hydrogen.
  • R is 5- methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R is -CO-methyl or -CO-ethyl.
  • R is -CO-methyl. In another embodiment, R is -CO-ethyl. In another embodiment, R is -CO-benzyl or -CO-phenyl. In another embodiments, R is -CO-benzyl. In another embodiment, R is -CO-phenyl. In another embodiment, R is -CO-NH2. In each of the above embodiments in this paragraph, R is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • the substituent is -halo, -NH2, -NHCH3, -CF3 or -OCH3 or the substituents are independently selected from -halo, -Nth, -NHCH3, -CF 3 or -OCH 3 .
  • Another aspect of the disclosure provides a compound of formula (Ic)
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • R 2 is (Ci-C6)alkyl substituted with 1, 2 or 3 substituent(s) independently selected from
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, - (C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • the present disclosure relates to a compound of formula (Ic) and the attendant definitions, wherein R 1 is H.
  • R 1 is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents.
  • R 1 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • R 1 is phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • the substitutents are selected from among those disclosed above for R 1 in connection with formula (Ic).
  • R 1 is (Ci-C4)alkyl.
  • R 1 is methyl, ethyl, propyl, or butyl.
  • R 1 is methyl, ethyl, or propyl.
  • R 1 is methyl, ethyl, or butyl.
  • R 1 is methyl, propyl, or butyl.
  • R 1 is ethyl, propyl, or butyl.
  • R 1 is methyl or ethyl.
  • R 1 is methyl or propyl.
  • R 1 is methyl or butyl.
  • R 1 is ethyl or propyl. In another embodiment, R 1 is ethyl or butyl. In another embodiment, R 1 is propyl or butyl. In another embodiment, R 1 is methyl. In another embodiment, R 1 is ethyl. In another embodiment, R 1 is propyl. In another embodiment, R 1 is zso-propyl. In another embodiment, R 1 is butyl. In another embodiment, R 1 is fert-butyl.
  • the alkyl is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • the present disclosure relates to a compound of formula (Ic) and the attendant definitions, wherein R 1 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents, the substitutents being selected from among those disclosed above for R 1 in connection with formula (Ic).
  • R 1 is unsubstituted (5- or 6-membered)heteroaryl.
  • R 1 is monosubstituted (5- or 6-membered)heteroaryl.
  • R 1 is disubstituted (5- or 6- membered)heteroaryl.
  • R 1 is trisubstituted (5- or 6-membered)heteroaryl.
  • the present disclosure relates to a compound of formula (Ic) and the attendant definitions, wherein R 1 is unsubstituted phenyl.
  • R 1 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 1 in connection with formula (Ic).
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (5-, 6-, or 7-membered)heterocycloalkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfanyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfinyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0)2-NR 6 R 7 . In another embodiment, R 1 is phenyl substituted with 1, 2, or 3
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-di(Ci-C6)alkylaminosulfonyl.
  • N-NR 4 R 5 N-(Ci-C6)alkylaminosulfonyl, or N,N-di(Ci-C6)alkylaminosulfonyl.
  • the present disclosure relates to a compound of formula (Ic) and the attendant definitions, wherein R 2 is (Ci-C6)alkyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 2 in connection with formula (Ic).
  • R 2 is (Ci-C6)alkyl substituted with a substituent selected from among those disclosed above for R 2 in connection with formula (Ic).
  • R 2 is (Ci-C4)alkyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 2 in connection with formula (Ic).
  • R 2 is (Ci-C4)alkyl substituted with a substitutent selected from among those disclosed above for R 2 in connection with formula (Ic).
  • R 2 is (Ci-C 2 )alkyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 2 in connection with formula (Ic).
  • R 2 is (Ci-C2)alkyl substituted with a substituent selected from among those disclosed above for R 2 in connection with formula (Ic).
  • the present disclosure relates to a compound of formula (Ic) and the attendant definitions, wherein R 3 is (Ci-C6)alkyl. In another embodiment, R 3 is (5- or 6- membered)heteroaryl. In another embodiment, R 3 is phenyl. In another embodiment, R 3 is
  • R 9 is (Ci-C 6 )alkyl, (Ci-C 6 )alkyl substituted with phenyl or phenyl and R 10 is selected from (Ci-C6)alkyl.
  • R 3 is (Ci-G alkyl.
  • R 3 is methyl, ethyl, propyl, or butyl.
  • R 3 is methyl, ethyl, or propyl.
  • R 3 is methyl, ethyl, or butyl.
  • R 3 is methyl, propyl, or butyl.
  • R 3 is ethyl, propyl, or butyl.
  • R 3 is methyl or ethyl.
  • R 3 is methyl or propyl.
  • R 3 is methyl or butyl.
  • R 3 is ethyl or propyl. In another embodiment, R 3 is ethyl or butyl. In another embodiment, R 3 is propyl or butyl. In another embodiment, R 3 is methyl. In another embodiment, R 3 is ethyl. In another embodiment, R 3 is propyl. In another embodiment, R 3 is zso-propyl. In another embodiment, R 3 is butyl. In another embodiment, R 3 is fert-butyl.
  • the present disclosure relates to a compound of formula (Ic) and the attendant definitions, wherein R is hydrogen, -CO-methyl, -CO-ethyl, -CO-benzyl, -CO-phenyl or 5- methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R is hydrogen or 5-methyl-2-oxo- 2H-l,3-dioxol-4-ylmethyl. In another embodiment, R is hydrogen. In another embodiment, R is 5- methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl. In another embodiment, R is -CO-methyl or -CO-ethyl. In another embodiment, R is -CO-methyl. In another embodiment, R is -CO-ethyl. In another embodiment, R is -CO-benzyl or -CO-phenyl. In another embodiments, R is -CO-benzyl. In another embodiment, R is -CO-phenyl. In another embodiment, R is -CO-NH 2 .
  • R is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • the substituent is -halo, - NH2, -NHCH3, -CF3 or -OCH3 or the substituents are independently selected from -halo, -NH2, - NHCH 3 , -CF 3 or -OCH 3 .
  • Another aspect of the disclosure provides a compound of formula (Id)
  • R 1 is (Ci-C6)alkyl substituted with 1, 2 or 3 substituent(s) independently selected from
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl
  • C 4 perhaloalkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, -S(0) 2 -(5-, 6-, or 7- membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci-C 6 )alkylaminosulfonyl, and N,N-di(Ci-C6)alkylaminosulfonyl;
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C6)alkyl;
  • R is hydrogen, -COH, -CO-(Ci-C 6 )alkyl, -CO-(C 2 -C 4 )alkenyl, -CO-phenyl, -CO-benzyl, -CO- cyclopentyl, -CO-cyclohexyl, -CO-(5-, 6-, or 7-membered)heterocycloalkyl, -CO-benzyloxy, -CO-O- (Ci-C 6 )alkyl, -CO-NH 2 , -CO-NH-(Ci-C 4 )alkyl, or -CO-N((Ci-C 4 )alkyl) 2 , wherein said -(Ci-C 6 )alkyl, -(C 2 -C4)alkenyl, phenyl, benzyl, cyclopentyl, cyclohexyl, -(5-, 6-, or 7-membered)he
  • the present disclosure relates to a compound of formula (Id) and the attendant definitions, wherein R 1 is (Ci-C6)alkyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 1 in connection with formula (Id). In another embodiment, R 1 is (Ci-C6)alkyl substituted with a substituent selected from among those disclosed above for R 1 in connection with formula (Id). In another embodiment, R 1 is (Ci-C4)alkyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 1 in connection with formula (Id).
  • R 1 is (Ci-C alkyl substituted with a substitutent selected from among those disclosed above for R 1 in connection with formula (Id).
  • R 1 is (Ci-C2)alkyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 1 in connection with formula (Id).
  • R 1 is (Ci-C2)alkyl substituted with a substituent selected from among those disclosed above for R 1 in connection with formula (Id).
  • the present disclosure relates to a compound of formula (Id) and the attendant definitions, wherein R 2 is unsubstituted phenyl.
  • R 2 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 2 in connection with formula (Id).
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (5-, 6-, or 7-membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfanyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0)2-NR 6 R 7 .
  • R 2 is phenyl substituted with 1, 2, or 3
  • R 2 is independently selected substituent(s), at least one of which is -S(0)2-phenyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is - S(0)2-(5-, 6-, or 7-membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-di(Ci-C6)alkylaminosulfonyl.
  • the present disclosure relates to a compound of formula (Id) and the attendant definitions, wherein R 3 is (Ci-C6)alkyl. In another embodiment, R 3 is (5- or 6- membered)heteroaryl. In another embodiment, R 3 is phenyl. In another embodiment, R 3 is
  • R 9 is (Ci-C 6 )alkyl, (Ci-C 6 )alkyl substituted with phenyl or phenyl and R 10 is selected from (Ci-C6)alkyl.
  • R 3 is (Ci-C4)alkyl.
  • R 3 is methyl, ethyl, propyl, or butyl.
  • R 3 is methyl, ethyl, or propyl.
  • R 3 is methyl, ethyl, or butyl.
  • R 3 is methyl, propyl, or butyl.
  • R 3 is ethyl, propyl, or butyl.
  • R 3 is methyl or ethyl.
  • R 3 is methyl or propyl.
  • R 3 is methyl or butyl.
  • R 3 is ethyl or propyl. In another embodiment, R 3 is ethyl or butyl. In another embodiment, R 3 is propyl or butyl. In another embodiment, R 3 is methyl. In another embodiment, R 3 is ethyl. In another embodiment, R 3 is propyl. In another embodiment, R 3 is zso-propyl. In another embodiment, R 3 is butyl. In another embodiment, R 3 is fert-butyl.
  • R 3 is
  • R 9 is tert-butyl and R 10 is (Ci-C 6 )alkyl.
  • R 3 is
  • R 9 is tert-butyl and R 10 is (Ci-C 4 )alkyl.
  • R 3 is
  • R 9 is (C 2 )alkyl substituted with phenyl and R 10 is ethyl.
  • the present disclosure relates to a compound of formula (Id) and the attendant definitions, wherein R is hydrogen, -CO-methyl, -CO-ethyl, -CO-benzyl, -CO-phenyl or 5- methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R is hydrogen or 5-methyl-2-oxo- 2H-l,3-dioxol-4-ylmethyl. In another embodiment, R is hydrogen. In another embodiment, R is 5- methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl. In another embodiment, R is -CO-methyl or -CO-ethyl. In another embodiment, R is -CO-methyl. In another embodiment, R is -CO-ethyl. In another embodiment, R is -CO-benzyl or -CO-phenyl. In another embodiments, R is -CO-benzyl. In another embodiment, R is -CO-phenyl. In another embodiment, R is -CO-NH 2 .
  • R is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • the substituent is -halo
  • -NH2, -NHCH3, -CF3 or -OCH3 or the substituents are independently selected from -halo, -Nth,
  • Another aspect of the disclosure provides a compound of formula (Ie)
  • R 11 is H, (Ci-C6)alkyl or phenyl, wherein said alkyl and said phenyl are unsubstituted or substituted with 1, 2, 3, 4, or 5 substituent(s) independently selected from halo, (Ci-C6)alkyl, (Ci-C4)haloalkyl, (Ci-C4)perhaloalkyl, (Ci-C6)alkoxy, (Ci-C4)haloalkoxy, (Ci-C4)perhaloalkoxy, -
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein R 1 is H.
  • R 1 is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents.
  • R 1 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • R 1 is phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • the substitutents are selected from among those disclosed above for R 1 in connection with formula (Ie).
  • R 1 is (Ci-C 4 )alkyl.
  • R 1 is methyl, ethyl, propyl, or butyl.
  • R 1 is methyl, ethyl, or propyl.
  • R 1 is methyl, ethyl, or butyl.
  • R 1 is methyl, propyl, or butyl.
  • R 1 is ethyl, propyl, or butyl.
  • R 1 is methyl or ethyl.
  • R 1 is methyl or propyl.
  • R 1 is methyl or butyl. In another embodiment, R 1 is ethyl or propyl. In another embodiment, R 1 is ethyl or butyl. In another embodiment, R 1 is propyl or butyl. In another embodiment, R 1 is methyl. In another embodiment, R 1 is ethyl. In another embodiment, R 1 is propyl. In another embodiment, R 1 is zso-propyl. In another embodiment, R 1 is butyl. In another embodiment, R 1 is fert-butyl.
  • the alkyl is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein R 1 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents, the substitutents being selected from among those disclosed above for R 1 in connection with formula (Ie).
  • R 1 is unsubstituted (5- or 6-membered)heteroaryl.
  • R 1 is monosubstituted (5- or 6-membered)heteroaryl.
  • R 1 is disubstituted (5- or 6- membered)heteroaryl.
  • R 1 is trisubstituted (5- or 6-membered)heteroaryl.
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein R 1 is unsubstituted phenyl.
  • R 1 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 1 in connection with formula (Ie).
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (5-, 6-, or 7-membered)heterocycloalkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfanyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfinyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0)2-NR 6 R 7 . In another embodiment, R 1 is phenyl substituted with 1, 2, or 3
  • R 1 independently selected substituent(s), at least one of which is -S(0)2-phenyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is - S(0)2-(5-, 6-, or 7-membered)heterocycloalkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-di(Ci-C6)alkylaminosulfonyl.
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein R 1 is monosubstituted phenyl substituted with halo, (Ci-C6)alkyl, (Ci- C haloalkyl, (Ci-G perhaloalkyl, (Ci-C6)alkoxy, (Ci-G haloalkoxy, (Ci-
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein X is CH 2 , O, S, SO, or S0 2 .
  • X is CH 2 , O, S, or SO.
  • X is CH 2 , S, SO, or S0 2 .
  • X is CH 2 , O, SO, or S0 2 .
  • X is CH 2 , O, S, or S0 2 .
  • X is O, S, SO or S0 2 .
  • X is CH 2 .
  • X is O.
  • X is S.
  • X is SO.
  • X is S0 2 .
  • X is NH.
  • X is N(Ci-C6)alkyl.
  • X is N(CO)phenyl.
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein m is 1. In another embodiment, m is 2. In another embodiment, m is 3. In another embodiment, m is 4. In another embodiment, m is 5.
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In another embodiment, n is 4. In another embodiment, n is 5. In one embodiment, the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein m+n is 1. In another embodiment, m+n is 2. In another embodiment, m+n is 3.
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein R 11 is H.
  • R 11 is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents.
  • R 11 is phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • the substitutents are selected from among those disclosed above for R 11 in connection with formula (Ie).
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein R 11 is (Ci-C alkyl.
  • R 11 is methyl, ethyl, propyl, or butyl. In another embodiment, R 11 is methyl, ethyl, or propyl. In another embodiment, R 11 is methyl, ethyl, or butyl. In another embodiment, R 11 is methyl, propyl, or butyl. In another embodiment, R 11 is ethyl, propyl, or butyl. In another embodiment, R 11 is methyl or ethyl. In another embodiment, R 11 is methyl or propyl. In another embodiment, R 11 is methyl or butyl. In another embodiment, R 11 is ethyl or propyl. In another embodiment, R 11 is ethyl or butyl.
  • R 11 is propyl or butyl. In another embodiment, R 11 is methyl. In another embodiment, R 11 is ethyl. In another embodiment, R 11 is propyl. In another embodiment, R 11 is zso-propyl. In another embodiment, R 11 is butyl. In another embodiment, R 11 is fert-butyl. In each of the embodiments listed in this paragraph, the alkyl is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein R 11 is unsubstituted phenyl.
  • R 11 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 11 in connection with formula (Ie).
  • R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl.
  • R 11 is unsubstituted phenyl.
  • R 11 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 11 in connection with formula
  • R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfanyl. In another embodiment, R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl. In another embodiment, R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl. In another embodiment, R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl.
  • R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl. In another embodiment, R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfinyl. In another embodiment, R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl.
  • R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfinyl. In another embodiment, R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfonyl. In another embodiment, R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -NR 6 R 7 . In another embodiment, R 11 is phenyl substituted with 1, 2, or 3
  • R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -(5-, 6-, or 7-membered)heterocycloalkyl.
  • R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is
  • R 11 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is NN-di(Ci-C6)alkylaminosulfonyl.
  • N-NR 4 R 5 N-(Ci-C6)alkylaminosulfonyl, or N,N-di(Ci-C 6 )alkylaminosulfonyl.
  • the present disclosure relates to a compound of formula (Ie) and the attendant definitions, wherein R is hydrogen, -CO-methyl, -CO-ethyl, -CO-benzyl, -CO-phenyl or 5- methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R is hydrogen or 5-methyl-2-oxo- 2H-l,3-dioxol-4-ylmethyl.
  • R is hydrogen.
  • R is 5- methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • R is -CO-methyl or -CO-ethyl.
  • R is -CO-methyl. In another embodiment, R is -CO-ethyl. In another embodiment, R is -CO-benzyl or -CO-phenyl. In another embodiments, R is -CO-benzyl. In another embodiment, R is -CO-phenyl. In another embodiment, R is -CO-NH 2 . In each of the above embodiments in this paragraph, R is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment. In various embodiments of each of the above embodiments in this paragraph, the substituent is -halo,
  • -NH 2 , -NHCH3, -CF3 or -OCH3 or the substituents are independently selected from -halo, -NH 2 ,
  • Another aspect of the disclosure provides a compound of formula (If)
  • C 4 perhaloalkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, -S(0) 2 -(5-, 6-, or 7- membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci-C 6 )alkylaminosulfonyl, and N,N-di(Ci-C6)alkylaminosulfonyl, wherein said (5-, 6-, or 7-membered)heterocycloalkyl is
  • R is 5-methyl-2-oxo-2H-l,3-dioxol-4-ylmethyl.
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein m is 1. In another embodiment, m is 2. In another embodiment, m is 3.
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein R 2 is methyl, ethyl, propyl, or butyl.
  • R 2 is methyl, ethyl, or propyl.
  • R 2 is methyl, ethyl, or butyl.
  • R 2 is methyl, propyl, or butyl.
  • R 2 is ethyl, propyl, or butyl.
  • R 2 is methyl or ethyl.
  • R 2 is methyl or propyl.
  • R 2 is methyl or butyl.
  • R 2 is ethyl or propyl.
  • R 2 is ethyl or butyl. In another embodiment, R 2 is propyl or butyl. In another embodiment, R 2 is methyl. In another embodiment, R 2 is ethyl. In another embodiment, R 2 is propyl. In another embodiment, R 2 is zso-propyl. In another embodiment, R 2 is butyl. In another embodiment, R 2 is fert-butyl.
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein R 2 is unsubstituted phenyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is chloro.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is fluoro.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci- C6)alkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is methyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is perfluoromethyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is methoxy. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perfluoroalkoxy.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (5-, 6-, or 7-membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (5-, 6-, or 7-membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is morpholinyl, piperidinyl or piperazinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is morpholinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is piperidinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is piperazinyl.
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfanyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is methylsulfanyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is trifluoromethylsulfanyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is methylsulfinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is methylsulfonyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C/ haloalkylsulfinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci- C haloalkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is perhalomethylsulfinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is perfluoromethylsulfinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is perhalomethylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is perfluoromethylsulfonyl .
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -NR 6 R 7 .
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 - N(CH3)(CH 2 CH 2 OCH3), -S(0)2-NH(CH 2 CH 2 OCH3), -S(0) 2 -N(CH 3 ) 2 or -S(0) 2 -NH(CH 3 ) .
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -phenyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -(5-, 6-, or 7- membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -morpholinyl, -S(0) 2 -piperidinyl or -S(0) 2 -piperazinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -morpholinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 - piperidinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -piperazinyl.
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is NN-di(Ci-C6)alkylaminosulfonyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is NN- dimethy laminosulfonyl .
  • R 2 is phenyl wherein the phenyl is unsubstituted or substituted with 1, 2, or 3 substituent(s) independently selected from chloro, fluoro, bromo, trifluoromethyl, methyl, butyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, phenylsulfonyl, methylsulfonylcarbamyl, methoxy, carboxyl, methylsulfonylcarbamyl, formamidopropanoic acid, formamidoacetic acid, methoxycarbonyl, morpholinylcarbonyl, 4,4- difluoropiperidinylcarbonyl, trifluorome
  • R 2 is phenyl wherein the phenyl is unsubstituted or substituted with 1, 2, or 3 substituent(s) independently selected from 2-chloro, 3- chloro, 4-chloro, 5-chloro, 2-fluoro, 3-fluoro, 4-fluoro, 5-fluoro, 2-bromo, 3-bromo, 4-bromo, 5-bromo, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 2-methyl, 3 -methyl, 4-methyl, 5 -methyl, 2- butyl, 3 -butyl, 4-butyl, 5 -butyl, 4-methylsulfanyl, 2-methylsulfinyl, 4-methylsulfinyl, 3-methylsulfonyl, 4-methylsulfonyl, 4-ethylsulfonyl, 4-propylsulfonyl, 2-methoxy, 4-methoxy, 2-trifluoromethoxy, 4- trifluoromethoxy, 4-
  • R 2 is monosubstituted phenyl substituted with chloro, fluoro, bromo, methyl, butyl, trifluoromethyl, methoxy, trifluoromethoxy, mo holinyl, piperazinyl, methylpiperazinyl, carboxyl, methylsulfonylcarbamyl, formamidopropanoic acid, formamidoacetic acid, methoxycarbonyl, mo holinylcarbonyl, 4,4-difluoropiperidinylcarbonyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, trifluoromethylsulfanyl, trifluoromethylsulfinyl, trifluoromethylsulfonyl, phenylsulfonyl, mo ⁇ holinylsulfonyl, 4,4- difluor
  • R 2 is monosubstituted phenyl substituted with 2-chloro, 3-chloro, 4-chloro, 5-chloro, 2- fluoro, 3-fluoro, 4-fluoro, 5-fluoro, 4-bromo, 2-methyl, 3 -methyl, 4-methyl, 5 -methyl, 4-butyl, 4-t- butyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 5-trifluoromethyl, 2-methoxy, 3- methoxy, 4-methoxy, 2-trifluoromethoxy, 4-trifluoromethoxy, 3-mo ⁇ holin-4-yl, 3-(piperazin-l-yl), 3- (4-methylpiperazin-l-yl), 4-carboxyl, 4-methylsulfonylcarbamyl, 4-formamidopropanoic acid, 4- formamidoacetic acid, 4-methoxycarbonyl, 4-mo ⁇ holinylcarbonyl, 4-(4,4- difluoropiperi
  • R 2 is disubstituted phenyl, each substituent being independently selected from halo, (Ci-C6)alkyl, (Ci- C4)perhaloalkyl, (Ci-C6)alkoxy, (5-, 6-, or 7-membered)heterocycloalkyl, (Ci-C6)alkylsulfinyl, (Ci- C6)alkylsulfonyl and -NR 4 R 5 .
  • R 2 is disubstituted phenyl, each substituent being independently selected from chloro, fluoro, methyl, trifluoromethyl, methoxy, morpholinyl, piperazinyl, methylpiperazinyl, methylsulfinyl, methylsulfonyl, methoxyethyl(methyl)amino and dimethylamino.
  • R 2 is disubstituted phenyl, each substituent being disubstituted phenyl, each substituent being
  • R 2 is trisubstituted phenyl, each substituent being independently selected from halo, (Ci-C6)alkyl, and (Ci- C6)alkylsulfonyl. In another embodiment, R 2 is trisubstituted phenyl, each substituent being independently selected from fluoro, methyl and methylsulfonyl.
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein R 2 is selected from unsubstituted phenyl, 4-chlorophenyl, 2- chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, 2- fluorophenyl, 4-fluorophenyl, 4-bromophenyl, 2-chloro-4-fluorophenyl, 2-methylphenyl, 4- butylphenyl, 4-7-butylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 2-methoxyphenyl, 2- trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-carboxyl, 4- carbamylphenyl, 4-phenyl(formamido)propanoic acid, 4-phenyl(formamid
  • R 2 is unsubstituted phenyl. In another embodiment, R 2 is 4-chlorophenyl. In another embodiment, R 2 is 2-chlorophenyl. In another embodiment, R 2 is 3-chlorophenyl. In another embodiment, R 2 is 2,3- dichlorophenyl. In another embodiment, R 2 is 2,4-dichlorophenyl. In another embodiment, R 2 is 3,5- dichlorophenyl. In another embodiment, R 2 is 2-fluorophenyl. In another embodiment, R 2 is 4- fluorophenyl. In another embodiment, R 2 is 4-bromophenyl. In another embodiment, R 2 is 2-chloro-4- fluorophenyl. In another embodiment, R 2 is 2-methylphenyl.
  • R 2 is 4- butylphenyl. In another embodiment, R 2 is 4-i-butylphenyl. In another embodiment, R 2 is 3,5- dimethylphenyl. In another embodiment, R 2 is 4-methoxyphenyl. In another embodiment, R 2 is 2- methoxyphenyl. In another embodiment, R 2 is 2-trifluoromethoxyphenyl. In another embodiment, R 2 is 4-trifluoromethoxyphenyl. In another embodiment, R 2 is 4-methoxycarbonylphenyl. In another embodiment, R 2 is 4-carboxylphenyl. In another embodiment, R 2 is 4-carbamylphenyl. In another embodiment, R 2 is 4-phenyl(formamido)propanoic acid.
  • R 2 is 4- phenyl(formamido)acetic acid. In another embodiment, R 2 is 4-N,N-dimethylcarbamylphenyl. In another embodiment, R 2 is 4-cyclopropylsulfonylphenyl. In another embodiment, R 2 is 4- phenylsulfonyl. In another embodiment, R 2 is 4-(4,4-difluoropiperidin-l-yl)sulfonylphenyl. In another embodiment, R 2 is 4-(isopropylsulfonimidoyl)phenyl. In another embodiment, R 2 is 4- ⁇ 1 ⁇ -4- sulfonylphenyl.
  • R 2 is 4-mo ⁇ holine-4-carbonylphenyl. In another embodiment, R 2 is 4-(4,4-difluoropiperidine-l-carbonyl)phenyl. In another embodiment, R 2 is 3- mo holinyl-4-methylsulfonylphenyl. In another embodiment, R 2 is 3-(methoxyethyl)methylamino-4- methylsulfonylphenyl. In another embodiment, R 2 is 3,5-difluoro-4-methylsulfonylphenyl. In another embodiment, R 2 is 3,5-difluoro-4-methylsulfonylphenyl. In another embodiment, R 2 is 2-ethoxy-4- fluorophenyl.
  • R 2 is 3-fluoro-4-methoxyphenyl. In another embodiment, R 2 is 2-trifluoromethylphenyl. In another embodiment, R 2 is 3-trifluoromethylphenyl. In another embodiment, R 2 is 4-trifluoromethylphenyl. In another embodiment, R 2 is 3,5- bis(trifluoromethyl)phenyl. In another embodiment, R 2 is 3-methylsulfonylphenyl. In another embodiment, R 2 is 4-methylsulfanylphenyl. In another embodiment, R 2 is 4- trifluoromethylsulfanylphenyl. In another embodiment, R 2 is 2-methylsulfinylphenyl. In another embodiment, R 2 is 4-methylsulfinylphenyl.
  • R 2 is 3-fluoro-4- methylsulfinylphenyl. In another embodiment, R 2 is 3-methyl-4-methylsulfinylphenyl. In another embodiment, R 2 is 4-methylsulfonylphenyl. In another embodiment, R 2 is 4-ethylsulfonylphenyl. In another embodiment, R 2 is 4-isopropylsulfonylphenyl. In another embodiment, R 2 is 4-morpholine-4- methylsulfonylphenyl. In another embodiment, R 2 is 3-(4-methylpiperazin-l-yl)-4- methylsulfonylphenyl.
  • R 2 is 3-piperazin-l-yl-4-methylsulfonylphenyl. In another embodiment, R 2 is 3-methoxy-4-methylsulfonylphenyl. In another embodiment, R 2 is 3- trifluoromethyl-4-methylsulfonylphenyl. In another embodiment, R 2 is 3-fluoro-4- methylsulfonylphenyl. In another embodiment, R 2 is 3-chloro-4-methylsulfonylphenyl. In another embodiment, R 2 is 3 -methyl -4-methylsulfonylphenyl. In another embodiment, R 2 is 3,5-dimethyl-4- methylsulfonylphenyl.
  • R 2 is 3-(dimethylamino)-4-methylsulfonylphenyl.
  • R 2 is 4-trifluoromethylsulfinylphenyl.
  • R 2 is 4- trifluoromethylsulfonylphenyl.
  • R 2 is 4-phenyl(methyl)oxo- 6 -sulfanylidene- 2,2,2-trifluoroacetamide.
  • R 2 is 4-methylsulfonimidoylphenyl.
  • R 2 is 4-isopropylsulfonimidoylphenyl.
  • R 2 is 4-NN- dimethylaminosulfonylphenyl.
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein m is 1 and R 2 is unsubstituted phenyl. In another embodiment, m is 2 and R 2 is unsubstituted phenyl. In another embodiment, m is 3 and R 2 is unsubstituted phenyl. In another embodiment, m is 1 and R 2 is monosubstituted phenyl, e.g., selected from among the monosubstituted R 2 phenyl groups disclosed above in connection with the compounds of formula (If).
  • m is 2 and R 2 is monosubstituted phenyl, e.g., selected from among the monosubstituted R 2 phenyl groups disclosed above in connection with the compounds of formula (If).
  • m is 3 and R 2 is monosubstituted phenyl, e.g., selected from among the monosubstituted R 2 phenyl groups disclosed above in connection with the compounds of formula (If).
  • m is 1 and R 2 is disubstituted phenyl, e.g., selected from among the disubstituted R 2 phenyl groups disclosed above in connection with the compounds of formula (If).
  • m is 2 and R 2 is disubstituted phenyl, e.g., selected from among the disubstituted R 2 phenyl groups disclosed above in connection with the compounds of formula (If).
  • m is 3 and R 2 is disubstituted phenyl, e.g. , selected from among the disubstituted R 2 phenyl groups disclosed above in connection with the compounds of formula (If).
  • m is 1 and R 2 is trisubstituted phenyl, e.g. , selected from among the trisubstituted R 2 phenyl groups disclosed above in connection with the compounds of formula (If).
  • m is 2 and R 2 is trisubstituted phenyl, e.g. , selected from among the trisubstituted R 2 phenyl groups disclosed above in connection with the compounds of formula (If).
  • R 1 is m is 3 and R 2 is trisubstituted phenyl, e.g., selected from among the trisubstituted R 2 phenyl groups disclosed above in connection with the compounds of formula (If).
  • the present disclosure relates to a compound of formula (If) and the attendant definitions, wherein m is 1 and R 2 is methyl.
  • m is 1 and R 2 is ethyl.
  • m is 1 and R 2 is propyl.
  • m is 1 and R 2 is zso-propyl.
  • m is 1 and R 2 is butyl.
  • m is 1 and R 2 is fert-butyl.
  • m is 2 and R 2 is methyl.
  • m is 2 and R 2 is ethyl.
  • m is 2 and R 2 is propyl.
  • m is 2 and R 2 is zso-propyl. In another embodiment, m is 2 and R 2 is butyl. In another embodiment, m is 2 and R 2 is fert-butyl. In another embodiment, m is 3 and R 2 is methyl. In another embodiment, m is 3 and R 2 is ethyl. In another embodiment, m is 3 and R 2 is propyl. In another embodiment, m is 3 and R 2 is zso-propyl. In another embodiment, m is 3 and R 2 is butyl. In another embodiment, m is 3 and R 2 is fert-butyl.
  • Another aspect of the disclosure provides a compound of formula (Ig)
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C6)alkyl
  • the present disclosure relates to a compound of formula (Ig) and the attendant definitions, wherein R 1 is H.
  • R 1 is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents.
  • R 1 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • R 1 is phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • the substitutents are selected from among those disclosed above for R 1 in connection with formula (Ig).
  • R 1 is (Ci-C4)alkyl.
  • R 1 is methyl, ethyl, propyl, or butyl.
  • R 1 is methyl, ethyl, or propyl.
  • R 1 is methyl, ethyl, or butyl.
  • R 1 is methyl, propyl, or butyl.
  • R 1 is ethyl, propyl, or butyl.
  • R 1 is methyl or ethyl.
  • R 1 is methyl or propyl.
  • R 1 is methyl or butyl.
  • R 1 is ethyl or propyl. In another embodiment, R 1 is ethyl or butyl. In another embodiment, R 1 is propyl or butyl. In another embodiment, R 1 is methyl. In another embodiment, R 1 is ethyl. In another embodiment, R 1 is propyl. In another embodiment, R 1 is zso-propyl. In another embodiment, R 1 is butyl. In another embodiment, R 1 is fert-butyl.
  • the alkyl is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • R 1 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents, the substitutents being selected from among those disclosed above for R 1 in connection with formula (Ig).
  • R 1 is unsubstituted (5- or 6-membered)heteroaryl.
  • R 1 is monosubstituted (5- or 6-membered)heteroaryl.
  • R 1 is disubstituted (5- or 6- membered)heteroaryl. In another embodiment, R 1 is trisubstituted (5- or 6-membered)heteroaryl.
  • the present disclosure relates to a compound of formula (Ig) and the attendant definitions, wherein R 1 is unsubstituted phenyl.
  • R 1 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 1 in connection with formula (Ig).
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (5-, 6-, or 7-membered)heterocycloalkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfanyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfinyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0)2-NR 6 R 7 . In another embodiment, R 1 is phenyl substituted with 1, 2, or 3
  • R 1 independently selected substituent(s), at least one of which is -S(0)2-phenyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is - S(0)2-(5-, 6-, or 7-membered)heterocycloalkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-di(Ci-C6)alkylaminosulfonyl.
  • the present disclosure relates to a compound of formula (Ig) and the attendant definitions, wherein R 1 is monosubstituted phenyl substituted with halo, (Ci-C6)alkyl, (Ci- C haloalkyl, (Ci-C perhaloalkyl, (Ci-C6)alkoxy, (Ci-C haloalkoxy, (Ci-
  • the present disclosure relates to a compound of formula (Ig) and the attendant definitions, wherein R 2 is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents.
  • R 2 is (5- or 6- membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • R 2 is phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • the substitutents are selected from among those disclosed above for R 2 in connection with formula (Ig).
  • R 2 is (Ci-G alkyl.
  • R 2 is methyl, ethyl, propyl, or butyl.
  • R 2 is methyl, ethyl, or propyl.
  • R 2 is methyl, ethyl, or butyl.
  • R 2 is methyl, propyl, or butyl.
  • R 2 is ethyl, propyl, or butyl.
  • R 2 is methyl or ethyl.
  • R 2 is methyl or propyl.
  • R 2 is methyl or butyl.
  • R 2 is ethyl or propyl. In another embodiment, R 2 is ethyl or butyl. In another embodiment, R 2 is propyl or butyl. In another embodiment, R 2 is methyl. In another embodiment, R 2 is ethyl. In another embodiment, R 2 is propyl. In another embodiment, R 2 is zso-propyl. In another embodiment, R 2 is butyl. In another embodiment, R 2 is fert-butyl.
  • the alkyl is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • the present disclosure relates to a compound of formula (Ig) and the attendant definitions, wherein R 2 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents, the substitutents being selected from among those disclosed above for R 2 in connection with formula (Ig).
  • R 2 is unsubstituted (5- or 6-membered)heteroaryl.
  • R 2 is monosubstituted (5- or 6-membered)heteroaryl.
  • R 2 is disubstituted (5- or 6- membered)heteroaryl.
  • R 2 is trisubstituted (5- or 6-membered)heteroaryl.
  • the present disclosure relates to a compound of formula (Ig) and the attendant definitions, wherein R 2 is unsubstituted phenyl.
  • R 2 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 2 in connection with formula (Ig).
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (5-, 6-, or 7-membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfanyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0) 2 -NR 6 R 7 .
  • R 2 is phenyl substituted with 1, 2, or 3
  • R 2 is independently selected substituent(s), at least one of which is -S(0) 2 -phenyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is - S(0) 2 -(5-, 6-, or 7-membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-di(Ci-C6)alkylaminosulfonyl.
  • C 4 perhaloalkylsulfinyl, (Ci-C 4 )perhaloalkylsulfonyl, -S(0) 2 -NH 2 , , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, - S(0) 2 -(5-, 6-, or 7-membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci- C6)alkylaminosulfonyl, and NN-di(Ci-C6)alkylaminosulfonyl.
  • Another aspect of the disclosure provides a compound of formula (Ih)
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl
  • the present disclosure relates to a compound of formula (Ih) and the attendant definitions, wherein R 2 is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents.
  • R 2 is (5- or 6- membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • R 2 is phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • the substitutents are selected from among those disclosed above for R 2 in connection with formula (Ih).
  • R 2 is (Ci-G alkyl.
  • R 2 is methyl, ethyl, propyl, or butyl.
  • R 2 is methyl, ethyl, or propyl.
  • R 2 is methyl, ethyl, or butyl.
  • R 2 is methyl, propyl, or butyl.
  • R 2 is ethyl, propyl, or butyl.
  • R 2 is methyl or ethyl.
  • R 2 is methyl or propyl.
  • R 2 is methyl or butyl.
  • R 2 is ethyl or propyl. In another embodiment, R 2 is ethyl or butyl. In another embodiment, R 2 is propyl or butyl. In another embodiment, R 2 is methyl. In another embodiment, R 2 is ethyl. In another embodiment, R 2 is propyl. In another embodiment, R 2 is zso-propyl. In another embodiment, R 2 is butyl. In another embodiment, R 2 is fert-butyl.
  • the alkyl is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • R 2 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents, the substitutents being selected from among those disclosed above for R 2 in connection with formula (Ih).
  • R 2 is unsubstituted (5- or 6-membered)heteroaryl.
  • R 2 is monosubstituted (5- or 6-membered)heteroaryl.
  • R 2 is disubstituted (5- or 6- membered)heteroaryl. In another embodiment, R 2 is trisubstituted (5- or 6-membered)heteroaryl.
  • the present disclosure relates to a compound of formula (Ih) and the attendant definitions, wherein R 2 is unsubstituted phenyl.
  • R 2 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 2 in connection with formula (Ih).
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (5-, 6-, or 7-membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfanyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl. In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfinyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfonyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0)2-NR 6 R 7 .
  • R 2 is phenyl substituted with 1, 2, or 3
  • R 2 is independently selected substituent(s), at least one of which is -S(0)2-phenyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is - S(0)2-(5-, 6-, or 7-membered)heterocycloalkyl.
  • R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is In another embodiment, R 2 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-di(Ci-C6)alkylaminosulfonyl.
  • the present disclosure relates to a compound of formula (Ih) and the attendant definitions, wherein R 2 is monosubstituted phenyl substituted with halo, (Ci-C6)alkyl, (Ci- C haloalkyl, (Ci-G perhaloalkyl, (Ci-C6)alkoxy, (Ci-G haloalkoxy, (Ci-
  • the present disclosure relates to a compound of formula (Ih) and the attendant definitions, wherein R 3 is (Ci-C6)alkyl.
  • R 3 is (5- or 6- membered)heteroaryl.
  • R 3 is phenyl.
  • R 3 is (Ci-C4)alkyl.
  • R 3 is methyl, ethyl, propyl, or butyl.
  • R 3 is methyl, ethyl, or propyl.
  • R 3 is methyl, ethyl, or butyl.
  • R 3 is methyl, propyl, or butyl.
  • R 3 is ethyl, propyl, or butyl.
  • R 3 is methyl or ethyl.
  • R 3 is methyl or propyl.
  • R 3 is methyl or butyl.
  • R 3 is ethyl or propyl. In another embodiment, R 3 is ethyl or butyl. In another embodiment, R 3 is propyl or butyl. In another embodiment, R 3 is methyl. In another embodiment, R 3 is ethyl. In another embodiment, R 3 is propyl. In another embodiment, R 3 is zso-propyl. In another embodiment, R 3 is butyl. In another embodiment, R 3 is fert-butyl.
  • R 9 is tert-bu yl and R 10 is (Ci-C 4 )alkyl.
  • R 3 is
  • the present disclosure relates to a compound of formula (Ih) and the attendant definitions, wherein m is 1. In another embodiment, m is 2. In another embodiment, m is 3.
  • Another aspect of the disclosure provides a compound of formula (Ii)
  • C 4 perhaloalkylsulfonyl, -S(0) 2 -NH 2 , -S(0) 2 -NR 6 R 7 , -S(0) 2 -phenyl, -S(0) 2 -(5-, 6-, or 7- membered)heterocycloalkyl, -NR 4 R 5 , N-(Ci-C6)alkylaminosulfonyl, and N,N-di(Ci-C6)alkylaminosulfonyl;
  • R 4 , R 5 , R 6 and R 7 are each independently H or (Ci-C 6 )alkyl;
  • the present disclosure relates to a compound of formula (Ii) and the attendant definitions, wherein R 1 is H.
  • R 1 is (Ci-C6)alkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents.
  • R 1 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • R 1 is phenyl, wherein the phenyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently selected substituents.
  • the substitutents are selected from among those disclosed above for R 1 in connection with formula (Ii).
  • R 1 is (Ci-G alkyl.
  • R 1 is methyl, ethyl, propyl, or butyl.
  • R 1 is methyl, ethyl, or propyl.
  • R 1 is methyl, ethyl, or butyl.
  • R 1 is methyl, propyl, or butyl.
  • R 1 is ethyl, propyl, or butyl.
  • R 1 is methyl or ethyl.
  • R 1 is methyl or propyl.
  • R 1 is methyl or butyl.
  • R 1 is ethyl or propyl. In another embodiment, R 1 is ethyl or butyl. In another embodiment, R 1 is propyl or butyl. In another embodiment, R 1 is methyl. In another embodiment, R 1 is ethyl. In another embodiment, R 1 is propyl. In another embodiment, R 1 is zso-propyl. In another embodiment, R 1 is butyl. In another embodiment, R 1 is fert-butyl.
  • the alkyl is unsubstituted in one embodiment, monosubstituted in another embodiment, disubstituted with two independently selected substitutents in an additional embodiment, or trisubstituted with three independently selected substitutents in a further embodiment.
  • the present disclosure relates to a compound of formula (Ii) and the attendant definitions, wherein R 1 is (5- or 6-membered)heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1, 2 or 3 independently selected substituents, the substitutents being selected from among those disclosed above for R 1 in connection with formula (Ii).
  • R 1 is unsubstituted (5- or 6-membered)heteroaryl.
  • R 1 is monosubstituted (5- or 6-membered)heteroaryl.
  • R 1 is disubstituted (5- or 6- membered)heteroaryl.
  • R 1 is trisubstituted (5- or 6-membered)heteroaryl.
  • the present disclosure relates to a compound of formula (Ii) and the attendant definitions, wherein R 1 is unsubstituted phenyl.
  • R 1 is phenyl substituted with 1, 2 or 3 independently selected substituent(s), the substitutents being selected from among those disclosed above for R 1 in connection with formula (Ii).
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G haloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (5-, 6-, or 7-membered)heterocycloalkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfanyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkylsulfanyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (C3-C6)cycloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfinyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfinyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C4)perhaloalkylsulfonyl. In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is -S(0)2-NR 6 R 7 . In another embodiment, R 1 is phenyl substituted with 1, 2, or 3
  • R 1 independently selected substituent(s), at least one of which is -S(0)2-phenyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is - S(0)2-(5-, 6-, or 7-membered)heterocycloalkyl.
  • R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is In another embodiment, R 1 is phenyl substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is N,N-di(Ci-C6)alkylaminosulfonyl.
  • the present disclosure relates to a compound of formula (Ii) and the attendant definitions, wherein R 1 is monosubstituted phenyl substituted with halo, (Ci-C6)alkyl, (Ci- C4)haloalkyl, (Ci-C4)perhaloalkyl, (Ci-C6)alkoxy, (Ci-C4)haloalkoxy, (Ci-
  • the present disclosure relates to a compound of formula (Ii) and the attendant definitions, wherein R 3 is (Ci-C6)alkyl.
  • R 3 is (5- or 6- membered)heteroaryl.
  • R 3 is phenyl.
  • R 3 is (Ci-C4)alkyl.
  • R 3 is methyl, ethyl, propyl, or butyl.
  • R 3 is methyl, ethyl, or propyl.
  • R 3 is methyl, ethyl, or butyl.
  • R 3 is methyl, propyl, or butyl.
  • R 3 is ethyl, propyl, or butyl.
  • R 3 is methyl or ethyl.
  • R 3 is methyl or propyl.
  • R 3 is methyl or butyl.
  • R 3 is ethyl or propyl. In another embodiment, R 3 is ethyl or butyl. In another embodiment, R 3 is propyl or butyl. In another embodiment, R 3 is methyl. In another embodiment, R 3 is ethyl. In another embodiment, R 3 is propyl. In another embodiment, R 3 is zso-propyl. In another embodiment, R 3 is butyl. In another embodiment, R 3 is fert-butyl.
  • the present disclosure relates to a compound of formula (Ii) and the attendant definitions, wherein m is 1. In another embodiment, m is 2. In another embodiment, m is 3. In another embodiment, m is 2 and the lactone ring is not fused to a phenyl ring.
  • m is 2 and the lactone ring is fused to a phenyl ring, wherein said fused phenyl ring is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently substituent(s), the substituent(s) being selected from among those disclosed above for m in connection with formula (Ii).
  • the fused phenyl ring is substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is halo.
  • the fused phenyl ring is substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkyl.
  • the fused phenyl ring is substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C haloalkyl. In another embodiment, the fused phenyl ring is substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-G perhaloalkyl. In another embodiment, the fused phenyl ring is substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C6)alkoxy. In another embodiment, the fused phenyl ring is substituted with 1, 2, or 3 independently selected substituent(s), at least one of which is (Ci-C perhaloalkoxy.

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