WO2015130964A1 - Therapeutic compounds - Google Patents

Therapeutic compounds Download PDF

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Publication number
WO2015130964A1
WO2015130964A1 PCT/US2015/017820 US2015017820W WO2015130964A1 WO 2015130964 A1 WO2015130964 A1 WO 2015130964A1 US 2015017820 W US2015017820 W US 2015017820W WO 2015130964 A1 WO2015130964 A1 WO 2015130964A1
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WO
WIPO (PCT)
Prior art keywords
compound
membered
pharmaceutically acceptable
acceptable salt
groups
Prior art date
Application number
PCT/US2015/017820
Other languages
French (fr)
Inventor
Steven S. Bondy
Chien-Hung Chou
John O. Link
Winston C. Tse
Original Assignee
Gilead Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Priority to US15/121,643 priority Critical patent/US10202353B2/en
Publication of WO2015130964A1 publication Critical patent/WO2015130964A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • Retroviridae family include those of the subfamily Orthoretrovirinae and genera Alpharetrovirtis, Betaretrovirus, Gamaretrovirus, Deharetrovims, Epsi nretrovirtis, Lentivirus, and Spum ims which cause many human and animal diseases.
  • L ntivirus HiV- 1 infection In humans leads to depletion of T helper ceils and immune dysfunction, producing immunodeficiency and vuln rability to opportunistic infections.
  • Treating HIV-1 infections with highly active antiretroviraf therapies has proven to be effective at reducing viral load and significantly delaying disease progression (Hammer, 5.M., el aL; JAMA 2008, 300: 555-570), However, these treatments could lead to the emergence of HIV strains that are resistant to current therapies (Taiwo, 8.. International Journal of Infectious Diseases 2009, 13:552-559; Smith, R, I, et ai.. Science 2010, 327:697-701). Therefore, there is a need to discover new antiretroviral agents.
  • the present disclosure provides a compound of Formula (I):
  • ring A including the two carbon atoms to which it is fused to ring B, is a 5-6 membered monocyclic heteroaryl or pheny l, wherein any 5-6 membered heteroaryl or phenyl of A is optionally substituted with 1 , 2, or 3 Z l groups, wherein the Zr groups are the same or different;
  • ring B including the two carbon atoms to which it is fused to ring A, is a 5-7 membered monocyclic carbocycle, 6-10 membered bicyclic carbocycle, 5-7 membered monocyclic heterocyeie, or 6-10 membered bicychc heterocyde, wherein any 5-7 membered monocyclic carbocycle , 6-10 membered bicyclic carbocycle, 5-7 membered monocyclic heterocyde, or 6-10 bicyclic heterocycle of B is optionally substituted with 1, 2, 3, 4 or 5 Z 2 groups, wherein the Z 2 groups are the same or different;
  • R ! is phenyl, 5-6 membered monocyclic heteroaryl, 5-6-niembered monocyclic heterocycle, 9-10 membered bicyclic heterocycle, or 3-7 membered carbocycie, wherein any phenyl, 5-6 membered monocyclic heteroaryl 5-6-membered monocyclic heterocycle, 9-10 membered bicyclic heterocycle, or 3-7 membered carbocycie of R 5 is optionally substituted with 1, 2, 3, 4 or 5 Z 3 groups, wherein the Z 3 groups are the same or different;
  • R 2 is (Cr-Q)aikyi or 3-7 membered carbocycie, wherein any (CrCs)aikyl of R 2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • R 3 is phenyl, 9-10 membered bicyclic aryl, 5-7 membered monocyclic heterocycle, or 8- 10 membered bicyclic heterocycle, wherein any phenyl, 9-10 membered bicyclic aryl. 5-7 membered monocyclic heterocycle, or 8-10 membered bicyclic heterocycle of R 3 is optionally substituted with 1, 2. 3, 4 or 5 Z 4 groups, wherein the Z A groups are the same or different;
  • R 4 is H or (Ci-Cgjaikyl optionally substituted with 1 , 2, 3, 4 or 5 halo groups, which may be same or different;
  • each Z 1 is independently (Cf -CV a!kyl, (C C ⁇ lkeoyi, (C 2 ⁇ Cf)aikynyL 3-7 membered carbocycie, halo, -CN, -OR -OC(0)R pi , -OC(0) R qI R ri , -S(0) 2 OR
  • any 3-7 membered carbocycie of Z 1 is optionally substituted with 1, 2, 3. 4 or 5 halo groups or (Ci-Cgjalkyl, which may be same or different, and wherein any (Cj- C 6 )aikyl ? (CrQ)alkeriyi and (C 2 -C ⁇ s)alkynyi ofZ ! is optionally substituted with L 2, 3, 4 or 5 halo groups, which may be same or different;
  • each R ni is independently II or (C r Cs)alkyi
  • each R l is independently (Ci ⁇ C 6 )alkyl
  • each R ql and R ri is independently H or (CrCs)aikyi;
  • each Z 2 is Independently (C Q)aikyl, halo, oxo, or -OR" 2 , wherein any 3-7 membered carbocycie of Z is optionally substituted with I, 2, 3, 4 or 5 (CrQ)alkyl or halo groups, which may be same or different, and wherein any (C;-Q) ik i of Z 2 is optionally substituted with 1. 2, 3, 4 or 5 halo groups, which may be same or different;
  • each R" 2 is independently H, (Cj-C3 ⁇ 4)alkyL or (C 3 -C7)carbocycle; each Z 3 is independently (C]-Cs)alk l, halo, -CN, -OR" 3 , N0 2s or -C(O)N 3 r3 , wherein any (CrCg)alkyl of Z 3 is opiionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • each R" "' is independently H
  • each R q3 and R' 3 is independently H or (C r C 6 )alkyi;
  • each Z 4 is independently ⁇ C. -C6)alkyi, (C2-C & )alkenyl, (QrCjs)alkynyl, (CrC ⁇ earbocyele, halo, oxo, -CN, -OR" 4 , ⁇ GC(G)R p4 ⁇ -OC ⁇ 0)NR 4 R r4 , -SR n ?
  • any (C3-C7)carbocycle, of Z 3 is optionally substituted with 1, 2, 3, 4 or 5 halo groups or (Q- Cg)aikyl, and wherein any (Ci-Cgjalkyl, (CrC 6 )alkenyl and. (Ca-CV,)alkynyl of Z 4 is optionally substituted with L 2, 3 ? 4 or 5 halo groups, which may be same or different;
  • each R n4 is independently H or (C C 5 )alkyf
  • each r " is (Ci-C 5 )alkyi
  • each R q4 and R r4 is independently H or (C C 6 )alkyl
  • ring A including the two carbon atoms to which it is fused to ring B. is a 5-6 membered monocyclic hetcfoaryl or phenyl, wherein any 5-6 membered heteroar) ' ! or phenyl of A is optionally substituted with 1, 2, or 3 Z l groups, wherein the Z l groups are the same or different;
  • ring B including the two carbon atoms to which it is fused to ring A, is a 5-7 membered monocyclic earboeycle, 6-10 membered bicyclic earboeycle, 5-7 membered monocyclic heterocycle, or 6-10 membered bicyclic heterocycle, wherein any 5-7 membered monocyclic carbocycle , 6-10 membered bicyclic carbocycle, 5-7 membered .monocyclic heterocycle, or 6-10 bicyclic heterocycle of B is optionally substituted with 1 5 2, 3, 4 or 5 Z 2 groups, wherein the Z 2 groups are the
  • X is C or N; or the moiety wherein B is as defined above;
  • R is phenyl, 5-6 membered monocyclic h teroary!, 5-6-membered monocyclic heterocycle, 9-10 membered eyefie heterocycle, or 3-7 membered carbocycie, wherein any phenyl, 5-6 membered monocyclic heteroaryi, 5-6-mernbered monocyclic heterocycle, 9-10 membered bicyclic heterocycle, or 3-7 membered carbocycie of R' is optionally substituted with 1, 2, 3, or 5 Z 3 groups, wherein the Is groups are the same or different; or R' is
  • R 2 is (CrQ)aikyl or 3-7 membered carbocycie, wherein any (Ct-Cejalkyl of R 2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • R 3 is phenyl, 9-10 membered bicyclic aryl, 5-7 membered monocyclic heterocycle, or 8 ⁇ 10 membered bicyclic heterocycle, wherein any phenyl, 9-10 membered bicyclic aryl, 5-7 membered monocyclic heterocycle, or ⁇ -10 membered bicyclic heterocycle of R. 3 is optionally substituted with 1, 2, 3, 4 or 5 Z 4 groups, wherein the Z 4 groups are the same or different;
  • R 4 is H or (Ci-Q)alkyl optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • each Z 3 is independently (Cj-Cg)aik l, (C1 ⁇ 4 ⁇ )a!kenyl, (CrCs)alkynyl, 3-7 membered carbocycie, halo, -CN, -OR* 1 , -OC(0)R PI , -OC(0)NR Q , R FI , -SR* ! , -S ⁇ ()) ; ()I L
  • any 3-7 membered carbocycie of Z l is optionally substituted with I, 2, 3, 4 or 5 halo groups or (Ci-Cg)alkyl, which may be same or different, and wherein any (C R
  • C 6 )alkyl, ( ⁇ 1 ⁇ 4 1 ⁇ 4)alkenyl and (e 2 -C 6 )alkynyl of Z 5 is optionally substituted with L 2, 3, 4 or 5 halo groups, which may be same or different;
  • each R ri1 is independently II or (Ci-C 6 ⁇ alkyi
  • each R ! is independently (Cj-Ceja!kyi
  • each R ql and R d is independently H or (C r C 6 )alkyl
  • each Z 2 is independently (CrQOaikvi, halo, oxo.. or -OR "2 , wherein any 3-7 membered carbocycie of Z 2 is optionally substituted with 1, 2, 3, 4 or 5 (CrQ)alky1 or halo groups, which may be sanie or different and wherein any (CrQ)alkyl of Z 2 is optionally substituted with !, 2, 3 S 4 or 5 halo groups, which may be same or different;
  • each R ri2 is independently H 5 (C r C3 ⁇ 4alkyL (C ; -C ;i )haSoaik L or ( €rC? ⁇ earbo ⁇ ycie;
  • each Z 3 is independently (Ci ⁇ Q)alkyl, halo, -CN, -OR n3 ? NO 3 ⁇ 4 or ⁇ C(0) R. q3 R r3 , wherein any (CrC ⁇ alkyl of Z 3 is optionally substituted with 1, 2, 3, 4 or 5 halo groups., which may be same or different;
  • each R “ ' is independently H, (Cr 3 )alkyl, (Ci-Cyhaloalkyl, or (C 3 -C7)carboeycle;
  • each R' i3 and R r3 is independently H or (CrQ alkyi;
  • each " is independently (CrC 6 )alkyi, (C 2 -Cs)alkenyl, (C Q aikynyi, (Q ⁇ carbocycle, halo, oxo s -CN, ⁇ OR. a4 , -OC ⁇ 0) ⁇ , -OC(0) R 4 R rf , ⁇ SR 34 , -S(G)R p 5 -S(0) 2 OH s ⁇ S(0) 2 K p4 ?
  • any (C3 1 ⁇ 4)carboc e s of Z 5 is optionally substituted with 1, 2, 3, 4 or 5 halo groups or ( € ' ⁇ - C 6 )alkyi, and wherein any ⁇ C C 6 )alkyL (C 2 -C 6 )aikenyl and (CrCsJaikynyl of Z 4 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may he same or different;
  • each R Js4 is independently H or (Ci-Cg)aikyl
  • each R p4 is (C C3 ⁇ 4alk l;
  • each R q and R r * is independently H or (Ci ⁇ Cg)alkyl; or a pharmaceutically acceptable salt thereof.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof; and an additional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non- n cleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse
  • transcriptase an HIY nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXC 4 inhibitor, a gp! 20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIY integrase inhibitor, or combinations thereof.
  • One embodiment provides a method for treating a Retr viridae viral infection (e.g., an HIV viral infection) in a patient (e.g., a human), comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to the patient.
  • a Retr viridae viral infection e.g., an HIV viral infection
  • a patient e.g., a human
  • administering a compound of formula I, or a pharmaceutically acceptable salt thereof to the patient.
  • One embodiment provides a method for treating an HI V infection in a patient (e.g., human), comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an addi tional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HFV nucleoside inhibitor of reverse transcriptase, an HiV nucleotide inhibitor of reverse transcriptase, an HFV integrate inhibitor, a gp41 inhibitor, a CXCR.4 inhibitor, a g l20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrate inhibitor, or combinations thereof,
  • the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HFV nucleoside inhibitor of
  • One embodiment provides a compound of formula i, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g., for use In treating a Retroviridae viral infection (e.g., an HiV viral infection) or the proliferation of the HIV virus or AIDS in a patient (e.g., a human)).
  • a Retroviridae viral infection e.g., an HiV viral infection
  • a patient e.g., a human
  • One embodiment provides a compound of formula 1, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment of a Eeiroviridae viral infection, an Hi V virus infection, or AIDS.
  • One embodiment provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use m the manufacture of a medicament for treating a Retroviridae viral infection (e.g., an HIV viral infection) or the proliferation of the HIV virus or AIDS in a patient (e.g., a hmnmi)
  • a Retroviridae viral infection e.g., an HIV viral infection
  • a patient e.g., a hmnmi
  • One embodiment provides a compound of formula I, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrate inhibitor, a gp4!
  • a C.XCR4 inhibitor for use in a method for treating an HIV infection in patient (e.g., a human),
  • One embodiment provides processes and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof. Another embodiment provides processes and intermediates disclosed herein that are useful for preparing compounds of any one of formul s I, Ia s and lb, or salts thereof.
  • the present disclosure relates to, inter alia, compounds useful tor treating viral infections, in particular an HIV infection, pharmaceutical compositions thereof, processes for making the compounds, and methods of use thereof in treating viral infections, in particular an HIV (human immunodeficiency virus) infection.
  • HIV human immunodeficiency virus
  • Alkyl is a linear or branched saturated hydrocarbon.
  • an alky] group can have 1 to 8 carbon atoms (i.e., (CrCs)alkyl) or 1 to 6 carbon atoms (i.e.. (C ⁇ .- € ⁇ ; alkyl) or ! to 4 carbon atoms (i.e.. (CrC ⁇ a!kyl).
  • suitable alky! groups include, but are not limited to, methyl (Me, -C!3 ⁇ 4), ethyl (El ⁇ C3 ⁇ 4C3 ⁇ 4), !
  • aikenyl Is a linear or branched hydrocarbon with at least one carbon-carbon double bond.
  • an aikenyl group can have 2 to 8 carbon atoms (he,, Cj-Cg aikenyl), or 2 to 6 carbon atoms (i.e., € 2 ⁇ Ce aikenyl) or 2 to 4 carbon atoms (Le., C2-C4 aikenyl).
  • suitable aikenyl groups include, but are not limited to, ethylene or vinyl (-CH ⁇ CHa), allyl
  • Alkynyl is a linear or branched hydrocarbon with at least one carbon-carbon triple bond.
  • an alkynyl group can have 2 to 8 carbon atoms (i.e., € 2 -Cg alkyne,) or 2 to 6 carbon atoms (i.e., C 2 -C6 alkynyl) or 2 to 4 carbon atoms (i.e., C-rQ. alk n l .
  • suitable alkynyl groups include, but are not limited 10, acstylenyl (-CsCH), propargyl
  • halo or halogen as used herein refers to fi oro ( ⁇ F), chloro (-C1), bromo (-Br) and iodo ( ⁇ I).
  • haioalkyP refers to an aikyi as defined herein, wherein one or more hydrogen atoms of the alkyl are each independently replaced by a halo substituent
  • (Cr ⁇ Jhaioalkyi is a (Cj- alkyl wherein one or more of the hydrogen atoms of the (Ci-Cejalky!
  • haloalk ls include but are not limited to fiuoromethyl, fluorochloroin ethyl, difluoromethyl, difiuoroc oromeihyl, trifluoromethyl, 1,1,1-trifluoroethyi and pentafluoroethyl,
  • heteroalkyi refers to an alkyl in which one or more of the carbon atoms are each independently replaced with a heteroatom selected from the group consisting of O, N, S, and Si, A heteroatom may optionally be oxidized or alkylated. A heteroatom may be placed at any interior position of the heteroalkyi group or at a position at which the group is attached to the remainder of the molecule.
  • Examples include, but are not limited to, -CH 2 OCH3 ⁇ 4 -CH 2 CH 2 NHCH 3> -CH 2 C3 ⁇ 4N(CH 3 ) ⁇ C3 ⁇ 4 ⁇ CH 2 SCH 2 CH 3> -S ⁇ 0)CH 3 ⁇ 4 -C3 ⁇ 4C3 ⁇ 4S(0) 2 CH 3 , -CHCHOCH3,TMSi(CHj ⁇ j, -CH 2 aiNOC3 ⁇ 4.
  • aryl refers to any group derived from one or more aromatic rings, thai is, a single aromatic ring, a bicyclic or a multicyclic ring system.
  • Aryl groups include, but are not limited to, those groups derived from acenaphmylene, anthracene, azulene, benzene, cbrysene, a cyelopentadienyl anion, naphthalene, fjuoranthene, fiuorene, indane, perylene, phenalene, phenanthrene, pyreoe and the like.
  • an aryl group has from 6 to about 20 carbon atoms, for example from 6 to 20 carbon atoms, for example from 6 to 14 carbon atoms, for example from 6 to 10 carbon atoms, for example from about 6 to 10 carbon atoms.
  • heteroaryi refers to an aryl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom, as defined above, Heieroaryl groups include, but are not limited to, groups derived from aeridine, benzoimidazole, benzothiophene, benzoforars.
  • a heieroaryl group has from 5 to about 20 annular atoms, for example from 5 to 20 annular atoms, for example from 5 to 14 annular atoms, for example from 5 to 10 annular atoms.
  • heteroaryl includes single aromatic rings of from about 1 to 6 annular carbon atoms and about 1-4 annular heteroaioms selected from the group consisting of oxygen, nitrogen and sulfer.
  • the sulfur md nitrogen atoms may also be present In m oxidized form provided the ring is aromatic,
  • heterocyclyi or “heterocycle” as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring ⁇ i.e., at least one annular heteroatom selected from oxygen, nitrogen, and sulfur).
  • Heteroeycles include, but are not limited to, groups derived from azetidme, aziridirse, imidazo!idine, morpholine, oxirane (epoxide), ox.etane, piperazirie, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofurao, tetrah.ydrothiophene, dihydropyridme, tetrahydropyridsne, quinudidine, N-bromopyrrolIdine, N-chlorapiperidine, and the like.
  • the term “carbocycie” or “carbocyciyl” refers to a single saturated or partially unsaturated all carbon ring having 3 to 7 annular carbon atoms (i.e., (C3-C7)c boc cle) .
  • the term “carbocycie” or “carbocyciyl” also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocydio rings).
  • carbocycie Includes nsulticyelic carbocyles such as a bicycllc carbocycles (e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as bieyelo[3 J.Ojhexane and bicycIo[2.1. ijhexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 annular carbon atoms).
  • nsulticyelic carbocyles such as a bicycllc carbocycles (e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as bieyelo[3 J.Ojhexane and bicycIo[2.1. ijhexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 annular carbon atoms).
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirementsNon-limiiing examples of monocyclic carbocycles irs elude c clopropyl, cyclobutyl, cyelopentyL l ⁇ cycS peni-l ⁇ enyl s 1 ⁇ cyc3opent-2-enyl s l-eyclopent-S -euyl, cyclohexyl, I- cyclohcx ⁇ l ⁇ enyl, l ⁇ cyciohex-2 ⁇ enyl and l -cyclohex-3-enyl.
  • treatment is an approach for obtaining beneficial or desired results.
  • beneficial or desired results include, but are not limited to, alleviation of a symptom and/or di inishxaent of the extent of a symptom and/or pre venting worsening of a symptom associated with a disease or condition.
  • treatment includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival,
  • a sufficient or significant delay can, in effect encompass prevention, in that the individual does not develop the disease or condition.
  • a method that "delays" development of AIDS is a method that reduces the prohabi!ity of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method. Such comparisons may be based on clinical studies, using a statistically significant number of subjects.
  • the development of AIDS can be detected using known methods, such as confirming an individual's HIV* status and assessing the individual's T-cell count or other indication of AIDS
  • development such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits or groin, or presence of an opportunistic condition that is known to be associated with AIDS (e.g., a condition thai is generally not present in individuals with functioning immune systems hut does occur in AIDS patients).
  • Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence and onset,
  • an "at risk” individual Is an individual who is at risk of developing a condition to be treated, An individual “at risk” may or may not have detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment of methods described herein.
  • "At risk” denotes that an indi vidual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s). For example, individuals at risk for AIDS are those having HIV.
  • the term "effective amount” refers to an amount that is effective to elicit the desired biological or medical response, including the amou t of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the effective amount will vary depending on the compound, the disease,, and its severity and the age, weight, etc. of the subject to be treated.
  • the effective amount can include a range of amounts.
  • an effective amount may be in one or more doses, i.e., a single dose or muidple doses may be required to achieve the desired treatment endpoint
  • An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conj unction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • ring A including the two carbon atoms to which it is fused to ring B, is a 5-6 membered monocyclic heteroary! or phenyl wherein any 5-6 membered heieroar ) or phenyl of A is optionally substituted with 1, 2, or 3 Z l groups, wherein the Z 1 groups are the same or different;
  • B including the two carbon atoms to which it is fused to ring A, is a 5-7 membered monocyclic carbocycie, 6-10 membered bicyclic carbocycie, 5-7 membered monocyclic heterocyele, or 6-10 membered bicyclic hetereeycle, wherein any 5-7 membered monocyclic carbocycie , 6-10 membered bicyclic carbocycie, 5-7 membered monocyclic heterocyele, or 6-10 bicyclic heteroeycle of B Is optionally substituted with 1, 2, 3, 4 or 5 Z" groups, wherein the Z 2 groups are the same or different;
  • X is C or N
  • R is phenyl, 5-6 membered monocyclic heieroary!, 5-6-membered monocyclic heteroeycle, 9-10 membered bicyclic heteroeycle, or 3-7 membered carbocycie, wherein any phenyl, 5-6 membered monocyclic heteroar h 5-6-menibered monocyclic heteroeycle. 9-10 memfoered bicyclic heteroeycle, or 3-7 membered carbocycie of R ! is optionally substituted with 1, 2, 3, 4 or 5 1 ' groups, wherein the 7f groups are the same or different;
  • R 2 is (CrC 6 )alk l or 3-7 membered carbocycie, wherein any (Cri3 ⁇ 4alkyi of R 2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • R 3 is phenyl, 9- 10 membered bicyclic aryl, 5-7 membered monocyclic heteroeycle, or 8- 10 membered bicyclic heteroeycle, wherein any phenyl, 9-10 membered bicyclic aryl, 5-7 membered monocyclic heteroeycle, or 8-10 membered bicyclic heteroeycle of 3 is optionally substituted with l s 2, 3, 4 or 5 Z groups, wherem the Z 4 groups are the same or different;
  • each ?. ⁇ is independently (C Q ' Jalkyi (C;rC1 ⁇ 4)aIkenyi, (Ca-C ⁇ aikynyl, 3-7 membered carbocycie, halo, -CN, -OR nS , -OC(0)R pl , -OC(0)NR ql R ri , ⁇ SR n! , -S(0)R pl , -S ⁇ (%GH, -S(0) 2 R pl s -S(0 ⁇ >NR ql R d 5 ⁇ NR qi R i3 ⁇ 4 , -NR nt COR pi , ⁇ NR nl C0 2 R pi ? ⁇ NR n 1 CO R q ' R r 1 ,
  • any 3-7 membered carbocycie of Z 3 is optionally substituted with 1, 2, 3, 4 or 5 halo groups or (C r C 6 )aikyl, which may be same or different, and wherein any (C; ⁇ C 6 )alkyl, iCV(1 ⁇ 4)a?kenyi and ⁇ G ⁇ Cya ikynyl of Z ⁇ is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • each R ni is independently H or ⁇ C C 6 )alkyl
  • each R l and R rt is independently H or (C 3 -C 6 )alkyl
  • each 7 is independently (C; -Chalky i, halo, oxo, or ⁇ OR i , wherein any 3-7 membered carbocycie of Z 2 is optionally substituted with 1, 2, 3, 4 or 5 (C Ce k l or halo groups, which may be same or different, and wherein any (Cj-Cejalkyi of Z 2 Is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • each K.* 2 Is independently R (C r C>)aikvi, ⁇ C ⁇ C 3 )haloaikyL or (C 3 -C?)car ocyde: each Z 3 is independently (C f -3 ⁇ 4)alky], halo, -CN, -OR :,3 5 NO3 ⁇ 4 or ⁇ C ⁇ 0)NR 3 R F3 5 wherein any (CrCg)aikyi of Z 3 is opiionaiiy substituted with 1 , 2. 3, 4 or 5 balo groups, which may be same or different;
  • each R" 3 is independently H, ⁇ C C ⁇ alk l, (Ci-C3)haloalkyl, or (C3-C 7 )carbocycle;
  • each 3 ⁇ 4: - and R 1'" ' is independently H or (C r C 6 )aikyl;
  • each Z 4 is independently (Ci-C 6 )alkyl, (C 2 -C ⁇ )&lkmyl, (Q-C ⁇ aikynyj, (C3- € 7 )carboeycfe, halo, oso, -CN, ⁇ 0 ⁇ -OC(0)R P4 , -OC(0) S 4 R i4 , -SR !!4 5 -S(0)R p4 s ⁇ S(0) 2 OH, -8(0) ⁇ , -S(0) 2 M ⁇ s -NR R r *, -NR ⁇ COR ⁇ , R' ⁇ CO.R ⁇ , -NR ,l CONR 4 R f4 , - R R4 S(0) 2 R P * -NR" 4 S(0) 2 OR ⁇ 5 - ⁇ ⁇ 4 8 ⁇ 0)2»3 ⁇ 4 ⁇ , NC3 ⁇ 4 -C(0)R N4 , ⁇ CXG)OR !I4 5 or -C(0)NR R R S wherein
  • Z 5 is optionally substituted with I , 2, 3, 4 or 5 halo groups or ( € ⁇ .- € 6 )alkyl and wherein any (C ; -Cs)alkyl ; (C 2 -C 6 )alkenyl and (QrCgklkynyl of Z 4 is optionally substituted with 1» 2, 3, 4 or 5 halo groups, which may be same or different;
  • each R N4 is independently H or (CrQ-,)aikyl
  • each R 554 is (C C 6 )aikyl
  • each R Q4 and R R4 is independently H or (Q-C 6 )alkyl
  • ring A including the two carbon atoms to which it is fused to ring B, is a 5-6 membered monocyclic heteroaryl or phenyl, wherein any 5-6 membered heteroaryl or phenyl of A is optionally substituted with L 2, or 3 Z s groups, wherein the l) groups are the same or different;
  • ring B including the two carbon atoms to which it is fused to ring A, is a 5-7 membered monocyclic earboeycle, 6-10 membered bicyclic earboeycle, 5-7 membered monocyclic heterocycle, or 6-10 membered bicyclic heterocycle, wherein any 5-7 membered monocyclic earboeycle , 6-10 membered bicyclic earboeycle, 5-7 membered monocyclic heterocycle, or 6-10 bicyclic heterocycle of B is optionally substituted with 1, 2, 3, 4 or 5 7? groups, wherein the Z 2 groups are the same or different;
  • X is C or N; or the moiety wherein B is as defined above;
  • R ! ' is phenyl, 5-6 membered monocyclic heteroaryl, 5 ⁇ 6 ⁇ membered. monocyclic hcterocy e, 9-10 membered bicyclic heierocycie, or 3-7 membered carbocyele, wherein any phenyl, 5-6 membered monocyclic heteroaryl, 5-6 ⁇ membered monocyclic heterocycle, 9-10 membered bicyclic hete.rocycle, or 3-7 membered carbocyele of R i is optionally substituted with I, 2, 3, 4 or 5 Z 3 groups, wherein the Z 3 groups are the same or different; or R 5 is
  • benzoihiofuranyi is which any of the rings are optionally substituted with 1, 2, or 3 7/ groups;
  • R 3 is phenyl, 9 ⁇ I0 membered bicyclic aryl, 5-7 membered monocyclic heterocycle, or 8 ⁇ 10 membered bicyclic heterocycle, wherein any phenyl 9-10 membered bicyclic aryt 5-7 membered monocyclic heterocycle, or 8-10 membered bicyclic heterocycle of R J is optionally substituted with I, 2, 3, 4 or 5 Z 4 groups, wherein the Z 4 groups are the same or different;
  • R 4 is H or (Cj-Cgjalkyi optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • each Z 1 is independently (Ci «)alkyl, (Cr3 ⁇ 4)aiksrtyl, (Cs-C ⁇ alkynyl, 3-7 membered carbocyele, halo, -CN, -OR ni s -OC(0)R pl 5 -OC(0)NR ql R rt , ⁇ SR nl , ⁇ S(0)R pl s -S(0) 2 OH, -S(0) 2 R p, s -S(0 ⁇ ? NR qi R ri , ⁇ NR qf R ri , -NR al COR pI , -N ⁇ CO ⁇ , -NR Bl CONR q5 R rf ,
  • any 3-7 membered carbocyele of Z 1 is optionally substituted with I, 2, 3, 4 or 5 halo groups or (Ci-Q)aik l, which may be same or different, and wherein any (C ⁇ ⁇ C 6 )alkyl 5 (C 2 -C 6 )alkenyl and (C 2 ⁇ C 6 )alkynyl of Z 1 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • each R" J is independently H or (CrQ,)alkyl
  • each R p! is independen ly ( €r € 6 )alkyl
  • each R Qi and R' is independently H or (C C 6 )alkyl
  • each Z 2 is independently (CrCs)alkyl, halo, oxo, or -OR" 2 , wherein any 3-7 membered carbocyele of Z 2 is optionally substituted with 1, 2, 3, 4 or 5 (C Qtelkyl or halo groups, which may be same or different, and wherein any (Ci -Chalky! of Z 2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • each R" 2 is independently H, (C] -C3)aikyi, (Ci-C3)haioalkyl, or (C3 ⁇ C 7 )earbocycie;
  • each Z 3 is independently (C C 6 )alkyl, halo, -CM, -OR" 3 , NO Z; or -C(0)NR q3 R r3 , wherein any (CrC 6 )alkyl of Z 3 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • each ⁇ * is independently H, ( € €3 ⁇ 4k3 ⁇ 4yl or ( € . r €: carhocy e;
  • each R q3 and 3 is independently H or (Ci ⁇ C 6 )aikyf
  • each Z 4 is independently ⁇ C.-C 6 )alkyl, (C 2 -Q)alkenyl 5 (CrCgJaikynyi, (CrC ⁇ carbocycle, halo, oxo, -CN, -OR" 4 , -OC(G)R p4 , ⁇ OC(0)N q R r s -S(0) 2 OH, -S(0) 2 R p4 s -5(C3 ⁇ 4NR q R r 5 - q R r4 ?
  • each R n4 is independently H or (Ci ⁇ €3 ⁇ 4a!kyl
  • each is (C r C 6 )alkyl
  • each R 3 ⁇ 4 nd R r is independently H or (Cr i)a!kyi; or a pharmaceutically acceptable salt thereof.
  • ring A including the two carbon atoms to which it is fused to ring B, is a 5-6 membered monocyclic heteroaryl or phenyl, wherein any 5-6 membered heteroaryl or phenyl of A is optionally substituted with I, 2, or 3 Z !
  • ring B including the two carbon atoms to which it Is fused to ring A, is a 5-7 membered monocyclic carbocycle, 6-10 membered bicyclic carbocycle, 5-7 membered monocyclic heterocycie, or 6-10 membered bicyclic heterocycie, wherein any 5-7 membered monocyclic carbocycle , 6-10 membered bicyclic carbocycle, 5-7 membered monocyclic heterocycie, or 6-10 bicydic heterocycle of B is optionally substituted with 1, 2, 3, 4 or 5 Z 2 groups, wherein the Z 2 groups are the same or different;
  • X is C or N
  • R 1 is phenyl, 5-6 membered monocyclic heteroaryl, 5 ⁇ 0-mernbered monocyclic heterocycle, 9-10 membered bicydic heterocycle, or 3-7 membered carbocycle, wherein any phenyl, 5-6 membered monocyclic heteroaryl, 5 ⁇ 6 ⁇ membered monocyclic heterocycle, 9-10 membered hicyclic heterocycle, or 3-7 membered carbocycle of R ! Is optionally substituted with I , 2, 3, 4 or 5 Z 3 groups, wherein the Z J groups are the same or different;
  • R 7' is (Cj-C6)aikyl or 3-7 membered carbocycle, wherein any (Ci-Q)aikyi of R 2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
  • R 3 is phenyl, 9-10 membered bicydic aryl, 5-7 membered monocyclic heterocycle, or 8 ⁇ 10 membered bicydic heterocycle, wherein any phenyl, 9-10 membered hicyclic aryl 5-7 membered monocyclic heterocycle, or 8-1.0 membered hicyclic heterocycle of R J is optionally substituted with i 2, 3, 4 or 5 Z 4 groups, wherein the Z 4 groups are the same or different;
  • R 4 is H or (CrCg)alkyl optionally substituted with 1 , 2, 3, 4 or 5 halo groups, which may foe same or different;
  • each Z 3 is independently (CrC g )alkyi, (C 2 -C6)alkenyl 5 (C 2 -C6)alkynyl, 3-7 membered carbocycle, halo, -CN, -OR" 5 , -OC(0)R pl , -OC(0)NR ql R rl s -SR n l , -S(0)R p3 , -S(0) 2 OH, •S(Q) 2 R ⁇ , -S(0) 2 NR qS R ri , -NR q! R r! , -NR nI COR pI , ⁇ R n! C0 2 R pi s - R ⁇ CONR ⁇ R' 1 ,
  • any 3-7 membered carbocyeie of Z 1 is optionally substituted with 1, 2, 3, 4 or 5 halo groups or (Ci-C ⁇ alkyl, which may be same or different, and wherein any (Cp Qiaikyl, (OrC ⁇ alkenyl and (C 2 -C 3 )alkynyl ofZ* is optionally substituted with L 2, 3, 4 or 5 halo groups, which may be same or different;
  • each R n! is independently H or ⁇ C
  • each R l is independently (C;-Q)aSky
  • each R ql and R d is independently H or (C r C 6 )a!kyl
  • each Z 2 is independently (Cr Oalkyl halo, oxo, or -OR nA .
  • my 3-7 membered carbocycle of Z 2 is optionally substituted with 1, 2, 3, 4 or 5 (CrCs)alkyl or halo groups, which, may be same or different, and wherein any iC; ⁇ C i: )sikyl o 2 is optionally substituted with L 2, 3, 4 or 5 alo groups, which may be same or different;
  • each R r,2 is independently 3 ⁇ 4 (C 3 ⁇ C 3 )aikyl, (C 5 -C 3 )haloalkyl, or (C 3 -C 7 )carbocycle; each £ is independently (C C. ⁇ )a1kyl, halo, -CN, -OR* 3 , N0 2 , or -C(0)NB.
  • q 3 ⁇ 4 r3 s wherein any (Ci-Cg)alkyS of Z 3 is optionally substituted with 1 , 2, 3, 4 or 5 halo groups, which may be same or different;
  • each R n3 is independently H, (CrC ⁇ alkyl, (Ci-C3)haio lk l s or (C3-C7)carbocycle;
  • each R q'! and R r3 is independently H or (C r C fj )alkyl
  • each Z 4 is indepeadently (CrCs)alkyL ⁇ C 2 -C 6 ⁇ alkenyl 5 (C 2 1 ⁇ 4)aikynyL ⁇ C 3 -Cr)carbocydft, halo, oxo, -CN, -O * -OC(0)R p s ⁇ QC(0)NR q R f4 , -SR" ⁇ -S(G)R i 4 s ⁇ S(0) a O3 ⁇ 4 ⁇ S ⁇ C3) 2 R p4 , -S(0) 2 NR. ⁇ i4 R.
  • any (C3 ⁇ 4-C7)carbocyele ; of 7. ⁇ is optionally substituted with 1, % 3, 4 or 5 halo groups or ((. " ⁇ - Cg)alkyl. and wherein any (Cj -Ch lk !, and ⁇ C?-Q, ⁇ a!kynyi of Z 4 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which ma be same or different;
  • each R n4 is Independently H or (Q -Q;)alkyl:
  • each is (C C 6 )alkyI
  • each R c and R' 4 is independently H or (O.-Q)alkyl
  • compositions detailed herein may comprise a compound of Formula (I) in a racemie or nou-racemic mixture of stereoisomers or may comprise a compound of Formula (I) as a substantially pure isomer (e.g., as the (S)-Isomer at one or more stereoceniers).
  • the 5-6 membered heteroaryl of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms.
  • ring A is a 5-6 membered monocyclic heteroaryl wherein the 5-6 membered heteroaryl of A comprises 1 -2 nitrogen atoms and 3-4 carbon atoms in the ring, and wherein any 5-6 membered heteroaryl of A is optionally substituted with one or two Z groups, in certain instances, ring A, including the two carbon atoms to which it is fused to ring B, Is a 5-6 mernbered monocyclic heteroaryi, wherein the 5-6 membered heteroaryi of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring, and wherein any 5-6 membered heteroaryi of A is optionally substituted with one or two Z 1 groups; and X is N.
  • the 5-6 membered heteroaryi of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring. In certain instances, the 5-6 membered heteroaryi of A comprises 2 annular nitrogen atoms and 3 annular carbon atoms.
  • ring A is a 5-6 membered monocyclic heteroaryi or phenyl, wherein the 5-6 membered heteroaryi of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring, and wherein any 5-6 membered heteroaryi or phenyl of A.
  • ring A Is a 5-6 membered monocyclic heteroaryi or phenyl, wherein the 5-6 membered heteroaryi of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring, and wherein any 5-6 membered heteroaryi or phenyl of A is optionally substituted with 1 or 2 Z l groups.
  • ring A Is a 5-6 membered monocyclic heteroaryi, wherein the 5-6 membered hsteroaryl of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring, and wherein any 5-6 membered heteroaryi of A is optionally substituted with 1 , 2, or 3 Z 1 groups.
  • X is N
  • ring A is a 5-6 membered monocyclic heteroaryi, wherein the 5-6 membered heteroaryi of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms In the ring, and wherein any 5-6 membered heteroaryi of A is optionally substituted with 1 or 2 Z l groups, in one such variation, X is N.
  • Y is CZ or N; Z is CZ lB or N; and each Z is independently H or Z ⁇ In certain embodiments, Y is N. In certain embodiments, Y is CZ , wherein " is H, In certain embodiments, Y is CZ ia , wherein Z 3a is 7; . In certain embodiments, Y is CZ l, ⁇ wherein Z 5 is I and ; is an optionally substituted (C 3 -C 6 )aikyi (e.g., - €H 3 and --CF 3 ) 5 halo, or -NR qt R rt (e.g., -N3 ⁇ 4). In certain embodiments, Z is N.
  • Z is CZ ia , wherein Z ia is H, In certain embodiments, Z is CZ is , wherein Z is Z 3 ⁇ 4 . In certain embodiments, Z is €Z la , wherein Z i is Z 3 amiZ 3 is an optionally substituted ( €rC f ,)alkyl (e.g., -C3 ⁇ 4 and -CF; $ ) > halo, or -NR ! R r; (e.g., ⁇ MH 2 ). It is understood that any Y moiety may be combined with any Z moiety the same as if each and every combination were specifically and individually listed.
  • Y is N and Z is CZ ls where Z 3 ⁇ 4a is Z 1 (e.g., an optionally substituted ⁇ C: -Chalky! ⁇ .
  • Z 3 ⁇ 4a is Z 1 (e.g., an optionally substituted ⁇ C: -Chalky! ⁇ .
  • B i these embodiments may be any 8 moiety as detailed herein.
  • each Z 1a is independently H or z
  • each Z 5a is H.
  • Z la is Z ⁇
  • Z ia is Z 1 and Z 1 is an optionally substituted (C C 6 )aiky1 (e.g., -C3 ⁇ 4 and ⁇ -CF 3 )» halo, or -NR ⁇ R ⁇ (e.g., -N3 ⁇ 4).
  • B in these embodiments may be any B moiety as detailed herein.
  • Z 5a is independently H or Z ⁇
  • Z ia is H
  • Z 1 a is z
  • Z ia is Z l and Z ! Is an optionally substituted (CrC 6 )aikyl (e.g., - €'3 ⁇ 4 md-CFs), haio, or - R 3 ⁇ 4i R ri (e.g., ⁇ NH 2 ).
  • .B in these embodiments may be any B moiety as detailed herein,
  • the moiety ( 8 ] ? is or , B in these embodiments may be any B moiety as detailed herein,
  • Z 18 is independently H or Z s ; and each Z ia is independently H or Z 2 .
  • Z u is H and each Z 2a is H.
  • Z Ss is Z ! and Z l is a optionally substituted (Ci-Ce)alky ⁇ (e.g., - €3 ⁇ 4 and -CFj), halo, or -NR l R ri (e.g., -NH3 ⁇ 4).
  • Z Ia isTMCP 3
  • at least one Z 2& is an optionally substituted ( € .
  • rQ)a1kyl e.g., -C3 ⁇ 4 and -CF;?
  • halo or oxo.
  • at least one Z 2a is halo (e.g., fluoro).
  • two Z 3 ⁇ 4 are halo (e.g., fkora) and two Z 2s are hydrogen,
  • R is FJ.
  • a compound of Formula (I) is a com ound of Formula (lb):
  • Z !a is H or Z ! .
  • the compounds contain l s 2, 3, 4 or 5 Z 3 moiety, in one aspect, the compounds contain 1 or 2 Z 1 moiety, in certain embodiments of Formula (I), (la), and (lb), Z 1 is independently ⁇ ' C C3 ⁇ 4a]kyl, halo, -OH, or -NR3 ⁇ 4 ri , wherein any (Q-C ⁇ alkyl of 7. ⁇ Is optionally substituted with 1, 2, 3, 4 or 5 halo groups.
  • Z ! is independently (C C 6 )alkyl, halo, -OH, or ⁇ R q 'R r!
  • Z x is independently an optionally substituted (C; ⁇ C 6 )alkyl (e.g., -C3 ⁇ 4 and ⁇ CF 3 ), halo, or -NR 3 ⁇ 4l rt (e.g., -N3 ⁇ 4),
  • Z 1 is H, ⁇ CF 3 ⁇ 4 or OH. In certain instances, Z 1 is ⁇ CI3 ⁇ 4.
  • ring B is a 5-7 membered monocyclic carbocycle,. or 6-10 membered hicyciic carbocycle, wherein any 5-7 membered monocyclic carbocycle or 6-10 membered bicyelic carbocycle of B is optioaally substituted with 1, 2, 3, 4 or 5 Z 2 groups
  • ting B is a 5-7 membered monocyclic carbocycle, or 6-10 membered bicyclle carbocycle, wherein any 5-7 membered monocyclic carbocycle or 6-10 membered bicyelic carbocycle of B is optionally substituted with 1, 2, or 3 Z 2 groups
  • ring B is a 5-7 membered monocyclic carbocycle, or 6-10 membered bicyelic carbocycle, wherein any 5-7 membered monocyclic carbocycle or 6-10 membered bicyelic carbocycle of B is optional
  • ring B is a 6-7 membered monocyclic carbocycle, or 6 membered bicyelic carbocycle, wherein any 6-7 membered monocyclic carbocycle or 6 membered bicycile carbocycle of B is optionally substituted with L 2, 3, 4 or 5 Z 2 groups, in certain embodiments, ring B is a 6-7 membered monocyclic carbocycle, or 6 membered bicyelic carbocycle, wherein any 6-7 membered monocyclic carbocycle or 6 membered bicyelic carbocycle of B is optionally substituted with 1.
  • ring B is a 6-7 membered monocyclic carbocycle, or 6 membered bicyclle carbocycle, wherein any 6-7 membered monocyclic carbocycle or 6 membered bicyelic carbocycle of B is optionally substituted with I or 2 Z" groups.
  • ring B is a 6-10 membered bicyelic carbocycle, or 6-10 membered bicyelic heteroeycle, wherein any 6-10 membered bicyelic carbocycle or 6-10 bicyclle heteroeycle of B is optionally substituted with 1, 2, 3, 4 or 5 Z 2 groups, in certain embodiments, ring B is a 6-10 membered bicyclle carbocycle, or 6-10 membered bicyclle heteroeycle, wherein any 6-10 membered bicyelic carbocycle or 6-10 bicyclic heterocycle of B is optionally substituted with 1, 2, or 3 2/ groups, in certain embodiments, ring B is a 6-10 membered bicyclic carbocycie, or 6-10 membered bicyclic heieroc cle, wherein any 6-10 membered bicyclic carbocycie or 6-10 bicyclic heteroeycle of B is optionally substituted with 1
  • ring B is a 6-10 membered bicyclic carbocycie, whereia any 6-10 membered bicyclic carbocycie of B is optionally substituted with 1, 2, 3, 4 or 5 Z 2 groups, in certain embodiments, ring B is a 6-10 membered bicyclic carbocycie, wherein any 6-10 membered bicyclic carbocycie of B is optionally substituted with 1, 2, or 3 Z 2 groups, In certain embodiments, ring B is a 6-10 membered bicyclic carbocycie, wherein any 6-10 membered bicyclic carbocycie of B is optionally substituted with 1 or 2 Z 2 groups.
  • ring B is a 6-7 membered bicyclic- carbocycie, wherein any 6-7 membered bicyclic carbocycie is optionally substituted with 1, 2, 3, 4 or 5 Z 2 groups
  • ring B is a 6-7 membered bicyclic carbocycie, wherein any 6-7 membered bicyclic carbocycie is optionally substituted with 1, 2, or 3 Z 2 groups
  • ring B is a 6-7 membered bicyclic carbocycie, wherein any 6-7 membered bicyclic carbocycie is optionally substituted with 1 or 2 Z 2 groups.
  • ring B is bicyclop. L0]hex ⁇ 2 ⁇ cue, wherein bieyclo[3,LQJhex-2-ene is optionally substituted with 1, 2, 3, 4 or 5 Z 2 groups, in. certain embodiments, ring B is bicyc1o[3-L0]hex-2-ene, wherein bicyclo[3.h0]hex ⁇ 2 ⁇ ene is optionally substituted, with 1, 2, or 3 Z 2 groups, in certain embodiments, ring B is
  • ring B is a 6-7-membered monocyclic carbocycie.
  • ring B including the two carbon atoms to which it is fused to ring A, is a 6-membered bicyclic carbocycie.
  • ring B is a 6-membered monocyclic heteroc cie.
  • ring B is a IQ-membered bicyclic heterocycie.
  • ring B is
  • each Z " is independently ( €j-Q)alkyL halo, oxo, or -OR ", wherein my (CrQ)alkyl of Z 1 is optionally substituted with 1, 2, or 3 halo groups.
  • Z 2 is an optionally substituted (C C 6 )alkyl (e.g., -CF3 ⁇ 4 and -CF 3 ), balo, or oxo.
  • each Z 2 is independently methyl, fiuoro, oxo, or OH, In certain embodiments of Formula (I), (la), and (lb), each Z 2 is
  • R is phenyl, 9-10-membered bicyclic heterocycle, or 5-6 membered monocyclic heteroaryl, wherein any phenyl, 9-10-membered bicyclic heterocycle, or 5-6 membered monocyclic heteroaryl of R. ; Is optionally substituted with h 2, 3, 4, or 5 Z 3 groups, in certain embodiments, ! is phenyl or 5-6 membered monocyclic heteroaryl, wherein any phenyl or 5-6 membered monocyclic heteroaryl of R 1 is optionally substituted with 1, 2, or 3 Z 3 groups.
  • R l is phenyl or 5-6 membered monocyclic heteroaryl, wherein any phenyl or 5-6 membered monocyclic heteroaryl of R 1 is optionally substituted with 1 or 2 Z 3 groups.
  • R 1 is phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 Z 3 groups. In certain embodiments, R 1 is phenyl, wherein the phenyl is optionally substituted with 1 or 2 Z 3 groups.
  • R is tetrahydrofuranyl, which is optionally substituted with 1, 2, or 3 Z 3 groups
  • R l is cyclobutyi, which is optionally substituted with i, 2, or 3 7 groups
  • the compounds contain at least one Z moiety.
  • each Z 3 is independently (C Q)alkyl, halo, -CM, - N ⁇ 3 ⁇ 4, or
  • each Z 3 is independently (Cj-Csjaikyl, halo, -CM, - NO3 ⁇ 4 or -e(0) R q3 R r3 , wherein any (C r C 6 )alkyi of Z 3 is optionally substituted with 1, 2, or 3 halo groups.
  • each Z 3 is independently methyl, fluoro, bfomo, chloro, CN, N ⁇ 1 ⁇ 4, ⁇ C(0)N3 ⁇ 4 or -CF 3
  • each Z 3 is fiuoro.
  • R l is:
  • R 2 is (C Q > )alkyl.
  • R 2 is optionally substituted with
  • R 3 is phenyl, 9-10 membered bicyc!ic aryl, or 8-10 membered bicyclic heteroeycle, wherein any phenyl, 9- 0 membered bicyclic aryl or ⁇ -10 niembered bicyclic heierocycle of R 5 is optionally substituted with L 2 or 3 Z 4 groups.
  • R 3 is phenyl or 9-10 membered bicyclic aryl, wherein any phenyl or 9-10 membered bicyclic aryl of R 4 is optionally substituted with I, 2 or 3 Z* groups.
  • R 3 is phenyl, naphthyl or isoindoJm-I -one, wherein any phenyl, naphthyl, or isoindorin-l-one of R 4 is optionally substituted with I, 2 or 3 Z 4 groups.
  • R 3 is phenyl, wherein the phenyl of II 4 is optionally substituted with 1, 2 or 3 Z 4 groups.
  • the compounds contain at least one Z 4 moiety.
  • the compounds contain 1 , 2, or 3 Z 4 moiety.
  • the compounds contain 2 Z 4 moieties, in certain embodiments of Formula (I), (l ), and (lb), the compounds contain 1 Z 4 moiety, in certain embodime ts of Formula (I), (la), and (lb), each Z 4 is independently (C r C3 ⁇ 4alkyl s halo, -CM, -OR "4 .
  • each Z is independently (C-.-Q > )alkyl, halo, -CN, -OR" 4 , -NR ⁇ R' , or oxo, wherein any ( €r € ? ,)alkyl, of Z 4 is optionally substituted with 1. 5 2, or 3 halo groups,
  • each 2 4 is independently (Cj- C 6 )alkyl, halo, -CN, -0(Ci-C 6 )a!kyl ⁇ -N((C r C 6 )alk.yl) 2 , or oxo,
  • each Z 4 is independently methyl, -OCH 3 , fluoro, chloro, - t'CHjJj, or oxo,
  • R 3 is:
  • R 4 is H. 0081 j It is understood that any variable for ring B of Formula (I) and (la) may be combined with any variable of 4 of Formula (I) and (la) the same as if each and every combination were specifically and individually listed.
  • ring B is an optionally substituted 6-7 member earbocycle and R 4 is hydrogen.
  • ring B is a 6-7 member earbocycle substituted with ⁇ € ' F : , and 4 is hydrogen.
  • any variable for ring B of Formula (I) and (la) may be combined with any variable of R 5 of Formula ( ) and (la) the same as if each and even,- combination were specifically and individually listed.
  • ring B is an optionally substituted 6-7 member earbocycle and R : is optionally substituted and is phenyl pyridinyl, thiofuranyl, imidazoly!, benzothioforanyl, thiazolyl pyrazoJyl,
  • ring B is an optionally substituted 6-7 member earbocycle and R ! is optionally substituted and is phenyl
  • ring B is a 6-7 member earbocycle substituted with - €F 3 and is optionally substituted and is phenyl, pyridmyi, thiofuranyl, imidazolyl, benzotWofuranyl, tbiazolyl, pyrazolyl, tetrahydrofuranyl, or cyelobutyi.
  • ring B is a 6-7 membered earbocycle substituted with - €3 ⁇ 4 and R: is optionally substituted and is phenyl.
  • any variable for ring B of Formula (I) and (la) may be combined with any variable of R ' of formula (i) and (la) the same as if each and every combination were specifically and individually listed.
  • ring B Is an optionally substituted 6-7 membered earbocycle and is (CrCs)alkyl ⁇ such as methyl.
  • ring B is a 6-7 membered earbocycle substituted with -CF 3 and R 2 Is (Cs ⁇ i3 ⁇ 4alkyl, such as methyl
  • any variable for ring B of Formula (I) and (la) may be combined with any variable of R J of Formula (I) and (la) the same as If each and every combination were specifically and individually listed.
  • ring B is an optionally substituted 6-7 member earbocycle and R J is phenyl, naphthyl or isoindoiin-l- one, wherein any phenyl naphthyl, or isoindolin-1- ⁇ ⁇ ⁇ of R 4 is optionally substituted with I, 2 or 3 Z 4 groups.
  • ring B is a 6-7 member earbocycle substituted with -CF 3 and R 3 Is phenyl, naphthyl or isomdob ° n ⁇ l ⁇ one, wherein any phenyl naphthyl, or isomdolin-i- one of R 4 Is optionally substituted with I, 2 or 3 Z 4 groups.
  • any variable for R 2 of Formula (I) and (la) may be combined with any variable of R 3 of Formula (I) and (la) the same as if each and every combination were specifically and individually listed.
  • 2 is (CrCg)alkyl, such as m thyl and R 3 is phenyl, naphthyl or isoindolin-l-one, wherein, any phenyl, naphthyl, or isoindolm-l -one of R 4 is optionally substituted with 1. 2 or 3 Z groups,
  • the compounds may have any one or more of the following structural features:
  • ring B is a 5-7 membered monocyclic carbocycle (e.g., eycloheptane, cyclohexane and cyelopentane) optionally substituted with 1, 2, 3, 4 or 5 Z 2 groups (e.g., - CH;3 ⁇ 4,-Cl: ' i, -OH, halo or oxo), such as uiisubstiMed eyclohexane or a mono-or di- substituted cyelohexane:
  • R 4 is H
  • R* is phenyl, 9-10-membered bicyclic heterocycle (e.g., tetrahydrofuranyl), 5-6 membered monocyclic heteroaryl (e.g., pyridinyl, tMoferanyl, iraidazoly!, henzothiofuranyi, thiazolyl, pyrarolyl), or 3-7 member earbocyele (e.g., cyclobutyi), wherein any phenyl, 9-lG-membered bicyclic heterocycle, 5-6 membered monocyclic heteroaryl or 3-7 member carbocycle of R 5 is optionally substituted with one or more Z 3 groups;
  • bicyclic heterocycle e.g., tetrahydrofuranyl
  • 5-6 membered monocyclic heteroaryl e.g., pyridinyl, tMoferanyl, iraidazoly!, henzothiofuranyi, thiazolyl,
  • R 2 Is (C r C 6 )alkyl (e.g., methyl);
  • R '5 is phenyl or 9-10 membered bicyclic aryl, wherein any phenyl or 9» 10
  • membered bicyclic aryl of R 4 is optionally substituted with I , 2 or 3 Z 4 groups (e.g., phenyl, naphthyl, or isomdolin-I -one).
  • the compounds conform to at least one of features (a)-(e). In another variation, the compounds conform to two or more (and in certain variations, ail) of features (a) ⁇ (e). In a particular variation, the compounds conform to feature (a). In another variation, the compounds confirm to feature (a) and (b). embodiments of Formula (I) and (la), where the moiety
  • the compounds may have any one or more of the following structural features:
  • ring A is a 5-6 membered heteroary! ring (e.g., a 5-6 membered heteroaryi ring bearing 1-2 annular nitrogen atoms and 3-4 annular carbon atoms) optionally substituted with 1, 2, or 32/ groups (e.g., ⁇ CI- ,- ⁇ 3 ⁇ 4 halo or -N3 ⁇ 4).
  • ring A may be a 5 membered heteroaryi containing 2 annular nitrogen atoms, e.g., pyrazolyl (e.g., -CF; substituted pyrazolyl) arid imidazolyl (e.g., » N3 ⁇ 4 substituted imidazoiyl);
  • R 1 is phenyl, 9 0-membered bicyclic heterocycle (e.g., teirahydrofuranvl), 5-6 membered monocyclic heteroaryi (e.g., pyridmyl, thiofurasiyl, imidazolyl, benzothiofurarryl, thiazolyl, pyrazolyl), or 3-7 member earbocyeie (e.g., eyclobutyl), wherein any phenyl. 9-1 ⁇ membered bicyclic heterocycle, 5-6 membered monocyclic heteroary! or 3-7 member e rbocyc!e of 5 is optionally substituted with 1, 2, 3, 4. or 5 Z 3 groups;
  • 9-1 ⁇ membered bicyclic heterocycle, 5-6 membered monocyclic heteroary! or 3-7 member e rbocyc!e of 5 is optionally substituted with 1, 2, 3, 4. or 5 Z 3 groups;
  • R 2 is (CrC f i)alkyl; (e.g., methyl);
  • R 3 is phenyl or 9-10 membered bicyclic aryl, wherein any phenyl or 9-10
  • membered bicyclic aryl of R 4 is optionally substituted with 1, 2 or 3 Z 4 groups (e.g., phenyl, naphthyl, or isoindo!m-l-one).
  • the compounds conform to at least one of features (a)-(e). In another variation, the compounds conform to two or more (and in certain variations, all) of features (a) ⁇ (e). in a particular variation, the compounds conform to feature (a). In another variation, the compounds conform to features (a) and (b).
  • the compound of Formula (! ⁇ , (la), or (lb), is selected from a compoun of Form ula (II)
  • R l , Z l& , Z 2 , and Z 4 are as defined herein.
  • each Z 2 is independently (Ci-Cg)alkyl ⁇ halo, oxo, or -OR" 2 , wherein any (Cj-Cejaikyi of Z 2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups.
  • each Z 2 is independently ( €i-C6)alkyi, halo, oxo, or -OR" 2 , wherein any (Cr € & )aikyl of Z 2 is optionally substituted with 1, 2, or 3 halo groups. In certain embodiments., 7?
  • each Z 2 is independently methyl, fluoro, oxo, or OH.
  • each Z 2 is independently methyl, fluoro, or OH,
  • R ! is phenyl, 9-10 ⁇ memhered bicyciie heterocycle, 5-6 membered monocyclic heteroary! or 3-7 member carbocycie, wherein any phenyl, 9-1 O-membered bieyclic heterocycle, 5-6 membered monocyclic heteroaryl or 3-7 member carbocycie of R 1 is optionally substituted with I, 2, 3, 4, or 5 Z 3 groups.
  • R ! is phenyl, 9-10 ⁇ memhered bicyciie heterocycle, 5-6 membered monocyclic heteroary! or 3-7 member carbocycie, wherein any phenyl, 9-1 O-membered bieyclic heterocycle, 5-6 membered monocyclic heteroaryl or 3-7 member carbocycie of R 1 is optionally substituted with I, 2, 3, 4, or 5 Z 3 groups.
  • iV is phenyl or 5-6 membered monocyclic heteroaryl, wherein any phenyl or 5-6 membered monocyclic heteroaryl of R 1 is optionally substituted with 1, 2, or 3 Z 3 groups.
  • R 3 ⁇ 4 is phenyl or 5-6 membered monocyclic heteroaryl, wherein any phenyl or 5-6 membered monocyclic heteroaryl of R 3 ⁇ 4 is optionally substituted with 1 or 2 Z 3 groups, fW94J
  • R l is phenyl wherein the phenyl is optionally substituted with I or 2 Z 3 groups
  • R ! is pyridinyl, thiofuranyl, imidazotyi, benzothio&ranyl, thiazolyl, or pyrazoiyl, in which any of the ring are optionally substituted with I , 2, or 3 Z 3 groups.
  • R l is tetrahydrofUranyl, which is optionally substituted with 1, 2, or 3 Z 3 groups.
  • R ! is c ciobutyf, which is optionally substituted with I, 2, or 3 Z 3 groups.
  • the compounds contain at least one Z 3 moiety.
  • each Z 3 is independently (C;-C 6 )aikyl halo, -CN, - N0 2 ⁇ or -C(0) R 3 R i3 ⁇ wherein any (Ci-C «)alkyl of Z 3 is optionally substituted with I, 2 S 3, 4 or 5 halo groups.
  • each Z 3 is independently (C OOalk L halo, -CM, - NO 3 ⁇ 4 or -C ⁇ 0)NR q R r3 s wherein any (CrCi )alkyI of Z 3 is optionally substituted with 1, 2, or 3 halo groups.
  • each Z 3 is independently methyl, fluoro, bromo, chloro, CN, N ⁇ 3 ⁇ 4, -C(0)NH 2s or ⁇ CF 3 .
  • each Z 3 is fluoro.
  • R ! is:
  • the compounds contain 2 Z 4 moieties, In certain embodiments of Formula (II), the compounds contain 1 Z 4 moiety. In certain embodiments of Formula (II), each Z 4 is independently (C ⁇ ⁇ Ce)&lkyi, halo, -CN. -OR i:4 ,
  • each Z 4 is independently (Ci ⁇ C 6 )aikyl, halo, -CN, -OR" 4 , or oxo, wherein an ⁇ CrQ)alkyl, of Z 4 is optionally substituted with 1 , 2, or 3 halo groups.
  • each Z 4 is independently (Ci- € ⁇ -,)aIkyl 3 halo, - CN, -0(C Q)alkyL -N((Ci ⁇ C 6 )aikyl) 2s or oxo,
  • each Z 4 is independently methyl, -() €3 ⁇ 4, fluoro, chioro, ⁇ N(CI3 ⁇ 4)2, or oxo,
  • Z is is H or Z 1 , wherem each 7 is independently (C C 6 )alky!, halo, -OH, or ⁇ NK ql R ! wherein any (G-C 6 )alkyi ofZ ? Is optionally substituted with 1 , 2, or 3 halo groups.
  • each Z 1 is independently -CF 3 , halo, -OH, or -NH 2 - 3 ⁇ 4i
  • each Z 5 is independently -CF3 ⁇ 4 or -OR
  • the present disclosure provides the following compounds or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides the following compounds or a pharmaceutically acceptable salt thereof. 40
  • the compounds ofForm.uk (I), (la), or (lb), such as Compounds 1-35 or lz-35z, may be prepared and/or formulated as pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid.
  • Non-limiting examples of pharmaceutically acceptable sails include sulfates, pyrosulfales, bi sulfates, sulfites.
  • pro ylsulfonates besylates, xylencsuifonates, naphthalene- 1 -sulfonates, naphthalene-2- suifonates, phenylacetates, phenylpropionates, phenylbutyrat.es, citrates, lactates, ⁇ - hydroxybutyrates, glycolates, tartrates, and mandeiates. Lists of other suitable pharmaceutically acceptable salts are found in Remington The Science and Practice of Pharmacy.. 21 st Edition, lippincott Williams and Wiikins, Philadelphia, Pa., 2006.
  • solvate refers to an aggregate that comprises one or more molecules of a compound of fee invention with one or more molecules of solvent
  • the solvent may be water, in which case the solvate may be a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as a hydrate, including a monohydrate. dihydrate, hemihydrate, sesqulhydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compound of the invention may be true solvates, while in other eases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent,
  • tills invention also includes any compound provided herein that may be enriched at any or ail atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( 2 H or D),
  • Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemie mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present disclosure,
  • the compounds of the present disclosure may be compounds according to Formula (I), (la), or (lb) with one or more chiral centers, which may be either of the (R) or (S) configuration, or which may comprise a mixture thereof
  • the carbon to which R 4 and the carbon to which - CHj-R 1 are connected may be either of the R or S configurations.
  • R 4 is a substituent other than H
  • the carbon to which R 4 s connected is a chiral center and may be either of the R or S configuration.
  • the carbon to which s connected to is a chiral center and may be either of the R or S configuration .
  • Form ula L R 4 is H and the chiral center is of the S configuration
  • the present disclosure includes both racemie mixtures of a compound of Formula I and isolated isomers of Formula L Where more than one chiral center is present in a compound of fee present disclosure, some, none, or all of the chiral centers may be eaantiomerically enriched. Thus, mixtures of a compound of Formula I may he racemie with respect to one or more chiral centers and/or enantiomericaiiy enriched with respect to one or more chiral centers.
  • the compounds disclosed herein are .formulated with, conventional carriers (e.g., inactive ingredient or exeipieni material) which will be selected la accord with ordinary practice. Tablets will contain excipients including glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic.
  • Ail formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as ED I ' A. carbohydrates such as dextrin, hydroxyatkytceirulose, hydroxyaikylfflethytediulose, stearic acid and the like.
  • One embodiment provides the formulation as a solid dosage form including a solid oral dosage form.
  • the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
  • compositions comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients.
  • the earrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co,, Easton, PA), Such methods include the step of bringing into association the active ingredient with inactive ingredients (e.g., a carrier, pharmaceutical excipients, etc) which constitutes one or more accessory ingredients.
  • inactive ingredients e.g., a carrier, pharmaceutical excipients, etc
  • the formulations are prepared by uniformly and Intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations described herein that are suitable for oral administration may be presented as discrete units including bisi not limited to capsules, cachets or tablets each containing a predetermined am ount of the active ingredient,
  • compositions disclosed herein comprise one o more compounds disclosed herein together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be In any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersibie powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydraie, croscarraeilose sodium, povidone, calc um or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, rmerocrystal!mc cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearaie, stearic acid or talc.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydraie, croscarraeilose sodium, povidone, calc um or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as cellulose, rmerocrystal!mc cellulose, starch, gelatin or a
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption m the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • a dosage form for oral administration to humans contains approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material),
  • a dosage form, (e.g., for oral administration to humans) contains: .from 1.0 mg to 1000 mg or from 50 mg to 1000 mg or from .100 mg to 1000 mg or from 200 mg to .1000 mg or from 300 mg to 1000 mg or from 10 mg to 800 mg or from 10 mg to 600 mg or from 10 mg to 500 mg or from 10 mg to 400 mg or from 10 mg to 300 mg or from 50 mg to 800 mg or from 100 mg to 600 mg or from ISO mg to 500 mg or from 200 mg to 400 mg or from 50 mg to 500 mg or from 10 mg to 300 mg or from 50 mg to 300 mg or from 10 mg to 200 mg or from 50 mg to 200 mg or from 100
  • a dosage form tor oral administration to humans contains at least any of 10, 25, 50, 100, ISO, 200, 250 or 300 mg and no more than 500 or 800 or 1000 mg of active material (e.g., from at least 50 mg to no more than 500 mg).
  • a dosage form for oral administration to humans contains at least any of 10, 23, 50, 100, ISO, 200, 250 or 300 mg or no more than 500 or 800 or 1000 mg of active material
  • a dosage form for oral administration to humans contains any of 10, 25, 50, 100, ISO, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of active material
  • a dosage form in an amount provided herein may be administered to a patient (e.g., a human in need thereof? in accordance with a dosing regimen provided herein, such as once, twice or thrice daily dosing.
  • a dosing regimen provides for administratio of at least 10 mg and no more than 1,000 mg of active material (e.g., a compound of any of Formula (I), (la), or (lb)) daily, and it is understood that the amount may he provided in any suitable dosage form and amount (e.g., 500 mg twice daily or 1,000 mg once daily would provide the same amount of 1,000 mg/day dosing).
  • the invention embraces once daily dosing to an individual (e.g,, a human in need thereof) of a dosage form of compound (e.g., a compound of any of Formula (I), (la), or (lb)) containing at least 50 mg and not more than 300 mg of compound.
  • the carrier material varies from about 5 to about 95% of the total compositions (weightrwdght).
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • a formulation comprising an active ingredient provided herein (a compound of any one of Formul (I), (la), or (lb), such as any one of Compounds 1-35 or J.z- 35z or a pharmaceutical salt thereof) in one variation does not contain an agent that affects the rate at which the active ingredient is metabolized,
  • compositions comprising a compound of any one of Formula (I), (la), or (Ufa) in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of any one of Formula ( ⁇ ), (la), or (lb) or any other active ingredient administered separately, sequentially or simultaneously with a compound of any one of formula ( ⁇ ), (la), or (lb).
  • any of the methods, kits, articles of manufacture and the like detailed herein in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of any one of Formula ( ⁇ ), (ia), or (lb) or any other active ingredient administered separately, sequentially or simultaneously wife a compound of any one of Formula (I), (la), or (lb),
  • a compound of any one of Formula (I), (la), or (lb), such as any one of Compounds 1-35 or lz ⁇ 35z is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HiV,
  • the tablet can contain another active ingredient for treating HiV, such as an HIV protease inhibiting compound, an HIV non-nucleoslde inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HiV integrase inhibitor, a gp 1 inhibitor, a CXCR.4 inhibitor, a gpi20 inhibitor, a CCR5 inhibitor, a capsid polymerizatio inhibitor, or a non-catalytic site HIV integrase inhibitor, and combinations thereof
  • such tablets are suitable for once daily dosing.
  • Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylacticaily (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinicia using conventional dose escalation studies.
  • a method of inhibiting the proliferation of the HIV virus in an individual in need thereof comprising administering a compound of any of Formula (I), (la), (lb) or (II), or a pharmaceutically acceptable salt thereof, to the individual.
  • a compound of any of Formula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof, for use in such a method is provided herein.
  • the individual In need thereof is a human who has been infected with HIV.
  • the indi vidual in need thereof Is a human who has been infected with HIV but who has not developed AIDS.
  • the individual in need thereof is an individual at risk for developing AI DS
  • the individual in need thereof is a human who has been infected with HIV and who has developed AIDS
  • a compound of any of Formula (I), (la), (lb), or ( ⁇ ), or a pharmaceutically acceptable salt thereof is administered to the individual separately, sequentially or simultaneously with another active ingredient for treating HiV, such as an HIV protease inhibiting compound, an HIV non-nucleoside Inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 Inhibitor, a gp!20 inhibitor, a CC S Inhibitor, a capsid polymerization inhibitor, or a noin -catalytic site HIV integrate inhibitor and combinations thereof,
  • One embodiment provides a method for treating a Reiroviridae viral infection (e.g., an HIV viral infection) in an individual (e.g. , a human), comprising administering a compound of any of Form ula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof, to the individual,
  • a Reiroviridae viral infection e.g., an HIV viral infection
  • an individual e.g. , a human
  • administering a compound of any of Form ula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof, to the individual,
  • One embodiment provides a method tor inhibiting the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS in an individual (e.g., a human), comprising adm inistering a compound of any of Formula Formula ( ⁇ ), (la), (lb), or (II), or a
  • One embodiment provides a method for treating an HIV infection k an individual (e.g., a human), comprising administering a compound of any of Formula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof, to the individual
  • One embodiment provides a method for treating an HIV infection in an individual (e.g., a human), comprising administering to the individual In need thereof a therapeutically effective amount of a compound of any of Formula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of an additional therapeutic agent, wherein the therapeutic agent is an HIV protease inhibiting compound, an HIV non-nueleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV iotegra.se inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp!20 inhibitor, a CCR5 Inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HI integrase inhibitor and combinations thereof Also provided herein is a compound of my of Formula (I), (la), (lb), or (I
  • lll j One embodiment provides a compound of any of Formula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g., for use in treating a Reiroviridae viral infection (e.g., an HIV viral infection) or the proliferation of the HIV virus or AIDS or delaying the onset of AIDS irs an individual (e.g., a human)).
  • a Reiroviridae viral infection e.g., an HIV viral infection
  • the proliferation of the HIV virus or AIDS or delaying the onset of AIDS irs an individual e.g., a human
  • One embodiment provides a compound of any of Formula (1), (la), (lb), or ( ⁇ ), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a Reiroviridae viral infection (e.g., an HIV viral infection) or the proliferation of the HIV virus or AIDS or delaying the onset of AIDS in an individual (e.g., a human).
  • a Reiroviridae viral infection e.g., an HIV viral infection
  • One embodiment provides a compound of any of Formula (I), (la), (ib), or (II), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of the proliferation of a Reiroviridae virus, an HIV virus or AIDS or for use in the therapeutic treatment of delaying the onset of AIDS.
  • One embodiment provides the use of a compound of any of Formula (I). (la), (Ib), or (II), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for a Reiroviridae virus Infection (e.g., an HIV virus infection) in an individual (e.g., a human).
  • the administration is to an Individual (e.g., a human) In need of the treatment.
  • the administration Is to an individual (e.g., a human) who is at risk of developing AIDS,
  • One or more compounds disclosed, herein are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like, It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An advantage of the compounds disclosed herein is that, they are orally bloavailabie and can be dosed orally.
  • the compound such as a compound of any of Formula (I), (la), (ib), or (H) may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • the compound is administered on a daily or intermittent schedule for the duration of the individual's Site,
  • the dosage or dosing frequenc of a compound of any of Formula (I), (la), (Ib), or (II) may be adjusted over the course of the treatment e.g., based on the judgment of the
  • the compound may be administered to at; individual in an effective amount. in one aspect the compound is administered once daily. In one aspect, the compound is administered twice a day. In one aspect, the compound Is administered three times daily, it is understood that the compound, may be administered in any dosage amount provided herein, such as a dosage amount that would provide at least 10 mg day dosing and no more than 1 5 000 mg/day dosing. Once daily oral dosing is embraced, such as by administering a dosage form containing from 50 mg to 300 mg of compound.
  • the invention provides a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection. Also provided herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in such a method.
  • a compound as disclosed herein e.g., a compound of any of Formula (I), (la), (Ib) 5 or (II) or a pharmaceutically acceptable salt thereof
  • may be combined with one or more additional therapeutic agents in any dosage amount of the compound e.g., from 50 mg to 300 mg of compound.
  • a method for treating or preventing an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.
  • a compound disclosed hereto, or a pharmaceutically acceptable salt thereof for use in such a method.
  • the invention provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, In combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • the therapeutic agent used in combination with the compound disclosed herein can be any and- HIV agent,
  • combination pharmaceutical agents comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents are provided.
  • One embodiment provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent, and a phanBaeeutieafly acceptable carrier, in one embodiment the additional therapeutic agent may be an anti-HIV agent.
  • the additional therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds (HIV protease inhibitors), HIV non -nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide Inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or ailosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp4I inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp!20 inhibitors, G6PD and NADH-oxtdase inhibitors, capsid polymerization inhibitors or capsld disrupting compounds such as those disclosed In US 2013/0165489 (University of Pennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drug for treating HIV, and combinations thereof.
  • One embodiment provides a pharmaceutical composition comprising a compound disclosed herein; and an additional therapeutic agent wherein the additional therapeutic agent is an HI protease inhibiting compound, an HIV non-nuc!eoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HI V nucleotide inhibitor of reverse transcriptase, an HIV integrase Inhibitor, a gp41 inhibitor, a CXC 4 inhibitor, a p!20 inhibitor, a CC 5 inhibitor, a capsld polymerization inhibitor, or a non-catalytic site HIV Integrase Inhibitor and combinations thereof.
  • the additional therapeutic agent is an HI protease inhibiting compound, an HIV non-nuc!eoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HI V nucleotide inhibitor of reverse transcriptase, an HIV integrase Inhibitor, a gp41 inhibitor, a
  • the additional therapeutic agent is selected from one or more of:
  • HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mossenavir (DMP-450), JE-214? (AG1776), L-756423, RO0334649, ⁇ -272, DPC-681, DPC-684, GW64Q385X, DG17, PPL-100, DG35, and AG
  • HIV non-nucteoside or non-nucieotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DFC-083.
  • HIV nucleoside inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosme, sta udirse, zaleitabine, lamivudine, ahacav!r, amdoxovir, elvueitabine, alovudine, MiV-210, ⁇ -FT €, D ⁇ d4FC, emtricitabine, phosphatide, fozivudine tidoxil, apricitibme (AVX754), amdoxovir, KP-1 61, GS-9131 (Gilead Sciences) and fosalvudirie tidoxil (formerly HDP 99.0003);
  • H1Y nucleotide inhibitors of reverse transcriptase selected from the group consisting of tenofovir, tenofovir disoproxii fumarate, tenofovir disoproxii hemifo arate, tenofovir disoproxii, tenofovir atafen amide fumarate, tenofovir alafenanride hemifumarate, tenofovir aiafenamide, GS-7340 (Gilead Sciences).
  • GS- 148 Gilead Sciences
  • adefovir, adefovir dipivoxii CMX-001 (C merix) and CMX-157 (Chinierix)
  • f is integrase Inhibitors selected from the group consisting of curcumin, derivatives ofeure min, chicoric acid, derivatives of chicoric acid, , 5 -dicaf&oy Iqu ins c acid, derivatives of 3,5-dieaffeoylquinIc acid, aurintriearboxyiic acid, derivatives of aurintri arboxyiic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, iyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-I360, AR-177.
  • L-870812, and L-870810 raitegravir, BMS-538158, GS 364735C, BMS-707035, MK-2048.
  • HIV non-catalytic site or allosteric, ubengrase inhibitors (NCINl) including, but not limited to, BI-224436, CX05 I 6, CX0S045, CXI.4442, compounds disclosed in WO
  • gp41 inhibitors selected from the group consisting of en&vir ide, sifuvirtide, aibuvirtide, FB006M, and TRi-1 .144;
  • CC 5 inhibitors selected from the group consisting of aplaviroe, vkriviroc, maraviroc, cenicriviroc, PRO- 140, INCB15050, PF-232798 (Pfizer), and CCRSmAbOOA;
  • CD4 attachment inhibitors selected from the group consisting of ibalizumah (T B- 355) and BMS-068 (B S-663068);
  • pharmacokinetic enhancers selected from the group consisting of cobieistat, ritonavir, and SPI-452;
  • other drugs for treating H!V selected from the group consisting of B AS- 100, SP1- 452, REP 9, 5 ⁇ -0 ⁇ , TNX-3S5, DES6, ODN-93, ODN-1 12, VGV-1, PA- 57 (tevirirnat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-22I HIV, DEBIO-025, BAY 50-4798, MDX01G (ipilimumab), PBS 119, AI.G 889, and PA-1050040 (PA-040),
  • a compound disclosed herein, or a pharmaceuticall acceptable salt thereof is combined with two, three, four or more additional therapeutic agents.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with, two additional therapeutic agents.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents.
  • the two, three four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can he selected from different classes of therapeutic agents.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleotide inhibitor of reverse transcriptase and an HIV non ⁇ nucleoside inhibitor of reverse transcriptase.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an RW nucleotide inhibitor of reverse transcriptase, an HIV non-nueleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound,
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof s combined with an HIV nucleotide inhibitor of reverse transcriptase, an HIV non -nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with tenofovir, tenofovir disoproxil furnarate, tenofovir disoproxil. hemifumarate, ienofovir disoproxil, ienofovir alafena ide fum&raie, ienofovir alafenamide hemifumarate, or ienofovir aiafenanwde.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with ienofovir disoproxil fumarate, ienofovir disoproxil hemifumarate, or ienofovir a!afenamide.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with emtricitabine, abacavir or lamivudine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one of: tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil henufumarate, tenofovir disoproxil, ienofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir aiafenamlde and one of: emtricitabine, abacavir or lamivudine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one of: tenofovir disoproxil fumarate, tenofovir disoproxil Iienii&marate, ienofovir alafenamide fumarate, or ienofovir aiafenamlde and one of: emtricitabine or abacavir,
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-30 mg tenofovir aiafenamlde fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5- 10; 545; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound as disclosed herein e.g., a compound of any of Formula (I), (la), (lb), or ( ⁇ ) or a pharmaceutically acceptable salt thereof
  • the agents provided herein may be combined with the agents provided herein in any dosage amount of the compound (e.g., from SO mg to 300 mg of compound) the same as if each combination of dosages were specifically and individually listed.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 200- 250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil arid 200 mg emtricitabine.
  • a compound disclosed herei is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemi fumarate, or tenofovir disoproxil and 200 mg cmtricitabine.
  • a compound as disclosed herein e.g., a compound of any of Formula (I), (la), (Ih), or (II) or a pharmaceutically acceptable salt thereof
  • one or more of the compounds disclosed herein are combined with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient.
  • a pharmaceutical composition including one or more of the compounds disclosed herein combined with one or more other active therapeutic agents is provided.
  • the compounds disclosed herein are combined with one or more ot er active therapeutic agents in a solid dosage form.
  • the combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administsriid m two or more admhvsinnkws.
  • one or more of the compounds disclosed herein are coadministered with one or more other active therapeutic agents.
  • Co-administration of a compound disclosed herein with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more other active therapeutic agents, such that therapeutically effective amounts of disclosed herein and one or more other active therapeutic agents are both present in the body of the patient,
  • the present application provides a method for treating an H V infectio comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents such as those disclosed above. Also provided is a compound disclosed herein, or a
  • the invention also provides a product comprising a compound disclosed, herein, or a pharmaceutically acceptable salt or co-crystal thereof, and an additional therapeutic agent such as those disclosed above as a combined preparation for simultaneous, separate or sequential use in therapy (e.g., in treating an HIV infection).
  • kits comprising a compound of arty of Formula (I), (la), (lb), or (II), or a pharmaceuticall acceptable salt thereof,
  • the kit may further comprise instructions for use, e.g., for use In Inhibiting an HIV protease, such as for use k treating an HIV infection or AIDS.
  • the instructions for use are generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable.
  • kits comprising one or more containers comprising a compound of any of Formula (I), (la), (ib), or (0), or a pharmaceutically acceptable salt thereof.
  • Optionally associated with such contamer(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice reflects approval by the agency for the manufacture, use or sale for human administration,
  • Each component if there is more than one component
  • kits may be packaged in separate containers or some components can be combined in one container where cross- reactivity and shelf life permit.
  • the kits may be in unit dosage forms, bulk packages (e.g., rauiti-dose packages) or sub-unit doses. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies),
  • articles of manufacture comprising a unit dosage of a compound of any of Formula (I), (la), (ib), or (II), or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein.
  • suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • the embodiments are also directed to processes and intermediates useful .for preparing the subject compounds or pharmaceutically acceptable salts thereof,
  • any of the processes for preparation of the subjec t compounds it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 4 th ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • Scheme 1 shows a representative synthesis of the compounds of the embodiments.
  • the carboxyl group of Compound 1 ⁇ A can react with the amino group of Compound 1-B through standard coupling conditions to produce Compound 1-C.
  • the carboxyl group of Compound 1-A can be activated to facilitate reaction with an amine, Activating agents for carboxyl groups include, but are not limited to, various phosphorus compounds, carbodiimides, and c oroformates. in certain instances, an activating agent for a carboxyl group is isobutyl chlorofomiate,
  • Compound 1-C is then deproteeted to remove the amino protecting group PG 1 .
  • the protecting group PG is a Boc-group, which cars be removed with TFA,
  • suitable protecting groups for amino groups and the procedure for removal of the protecting group can be found in T, W. Greene and P. G, M. Wats, "Protective Groups in Organic Synthesis," 4* ed, 5 Wiley, New York 2006.
  • the amino group of Compound 1-C can react with the carboxyl group of Compound 1-C through standard peptide coupling conditions to produce a compound of Formula (I).
  • Reagents such as EDCi/HOBt, HOBt, PyBOP, HATU, or BEM (Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. Carplno, L. A.; EhFaham, A, I Am. Chem. Soc. 1995, 1 17, 5401. Li, P.; Xu, J, C, I Pept. Res.
  • the present disclosure provides a process of preparing a compound of the present disclosure, the process involving:
  • the above processes farther involve the step of forming a salt of a compound of the present disclosure.
  • Embodiments are directed to the other processes described herein; and to the product prepared by any of the processes described herein.
  • the present disclosure provides for intermediates used to make a compound of the Formula (I), (la). (lb), or (II), The intermediates are contemplated as failing within the scope of the present invention.
  • BEP :::: 2-bromo -ethyl pyridinium teirailuoroborate
  • Boc ieri-butoxy carbosyl
  • COMU ' (l ⁇ cya3 ⁇ 4o-2-etlioxy-2-oxoethylidenaminooxy)dImethylamino-mo ⁇ holirio- carbenium hexafluorophosphate
  • DMPU 1 ⁇ dImeihyl ⁇ 3,4,5,6 etrahydro « 2 ⁇ lH)"pyrim5dkone
  • EDC 1 -ethyl ⁇ 3-(3-dimethylamlnopropyl) carbodiimlde
  • HCV hepatitis C virus
  • HMDS hexameihy!disila2ari.e(azide)
  • MI-Iz mega He tz
  • NMP N-meihyipyn-oiidmone
  • PE petroleum ether
  • TBAF terra- ⁇ buty!ammonium fluoride
  • TMSOTf trimethylsilyl trifluororaethanesulfonate
  • TPAP ietraprop I amnion i u m perruihcnate
  • reaction mixture was diluted with EiOAe (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was separated and was concentrated to dryness in vacuo. The residue was purified by flash column chromatography (Rf; 03, 20%
  • Compound 4 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)-2-((iert ⁇ butoxycarbonyi)amino) ⁇ 3 ⁇ (3 J 5-dir orophenyl)propariolc acid for IA and substituting 4 ⁇ raeihoxy-N-methylanilsfie for N- ethyhmlme to provide 7 mg of title compound, MS (m z) 551 [ ⁇ -l .
  • Compound 12 was prepared according to the method presented for the synthesis of Example 1 utilizing (S) ⁇ 2 ⁇ ((teri-butoxycarbonyl)amkto)-3-(liI-pyrazol-l-yI)propanoic acid for 1A to provide 20 mg of title compound, MS ⁇ m/z) 475 [M+H] + ,
  • Compoimd 18 was prepared accordmg io the meihod presented for the synthesis of Example 1 utilizing (S)-2-((teit-b «toxycarboiiyi)ammo)-3- ⁇ 3-carbamoylphenyl)propanoic acid for ⁇ A to provide I 1 mg of title compound.
  • Compound 19 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)-3-(3-bromophenyl) ⁇ 2 ⁇ ((iert-buioxycarbonyl)amHio)propanoic acid, for 1A to provide 5 nig of title compound.
  • Compound 28 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)-2-((tert-buioxycarbony!)amino)-3-(3,5-difliioropheriyi)propaiioie acid for 1A and substituting 4-fluorO"N ⁇ meihyIaniiirie for N-methylamline to pro vide 17 mg of title compound. MS (m/z) 551 [M+H] ⁇ .
  • the title compound was prepared from 25E according to the method presented for the synthesis of 3!D in Example 31 to provide title compound.
  • Test A Antiviral assay in MT4 Cells
  • Test B Cytotoxicity assay
  • the compounds demonstrate >10% inhibition at 2 ⁇ . In one embodiment, the compounds demonstrate >30% inhibition at 2 ⁇ , In one embodiment, the compounds demonstrate >50% inhibition at 2 ⁇ In one embodiment, the compoimds demonstrate >70% inhibition at 2 ⁇ , In one embodiment, the compounds demonstrate >75% inhibition at 2 ⁇ , In one embodiment, the compounds demonstrate >S0% inhibi tion at 2 ⁇ . In one embodiment, the compounds demonstrate >85% inhibition at 2 ⁇ . ⁇ one embodiment, the compounds demonstrate >90% inhibition at 2 ⁇ . In one embodiment, the compounds demonstrate >95% inhibition at 2 uM. It is to be understood that the compounds disclosed herein cars be grouped according to their % inhibition as described above,
  • a compound is of any formulae provided herein, wherein the compound exhibits from 85% ⁇ IGQ% inhibition of virus-induced cell killing at 2 ⁇ . In other embodiments, a compound is of any formulae provided herein wherein the compound exhibits from 50-100, 60-100, 70-100, 80-100, or 90-100% inhibition of virus-induced cell killing at 2 ⁇ .
  • % Inhibition may be evaluated by techniques known in the art.
  • a compound is of any formulae provided herein wherein the compound exhibits from 85% ⁇ iO0% Inhibition of virus-induced cell killing at 2 ⁇ as measured by the method provided in the Test A and Test B sections discussed above.

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Abstract

Compounds of Formula I: or salts thereof are disclosed. Also disclosed are pharmaceutical compositions comprising a compound of Formula I, processes for preparing compounds of Formula I, intermediates useful for preparing compounds of Formula I and therapeutic, methods for treating a Retroviridae viral infection, in particular infection caused by the HIV virus.

Description

THERAPEUTIC COMPOUNDS
BACKGROUND
[0001 j Positive-single stranded RNA viruses comprising fee Retroviridae family include those of the subfamily Orthoretrovirinae and genera Alpharetrovirtis, Betaretrovirus, Gamaretrovirus, Deharetrovims, Epsi nretrovirtis, Lentivirus, and Spum ims which cause many human and animal diseases. Among the L ntivirus, HiV- 1 infection In humans leads to depletion of T helper ceils and immune dysfunction, producing immunodeficiency and vuln rability to opportunistic infections. Treating HIV-1 infections with highly active antiretroviraf therapies (HAART) has proven to be effective at reducing viral load and significantly delaying disease progression (Hammer, 5.M., el aL; JAMA 2008, 300: 555-570), However, these treatments could lead to the emergence of HIV strains that are resistant to current therapies (Taiwo, 8.. International Journal of Infectious Diseases 2009, 13:552-559; Smith, R, I, et ai.. Science 2010, 327:697-701). Therefore, there is a need to discover new antiretroviral agents.
SUMMARY
[0Θ02) In one aspect, the present disclosure provides a compound of Formula (I):
Figure imgf000002_0001
I
wherein;
ring A, including the two carbon atoms to which it is fused to ring B, is a 5-6 membered monocyclic heteroaryl or pheny l, wherein any 5-6 membered heteroaryl or phenyl of A is optionally substituted with 1 , 2, or 3 Zl groups, wherein the Zr groups are the same or different; ring B, including the two carbon atoms to which it is fused to ring A, is a 5-7 membered monocyclic carbocycle, 6-10 membered bicyclic carbocycle, 5-7 membered monocyclic heterocyeie, or 6-10 membered bicychc heterocyde, wherein any 5-7 membered monocyclic carbocycle , 6-10 membered bicyclic carbocycle, 5-7 membered monocyclic heterocyde, or 6-10 bicyclic heterocycle of B is optionally substituted with 1, 2, 3, 4 or 5 Z2 groups, wherein the Z2 groups are the same or different;
X Is C or N;
R! is phenyl, 5-6 membered monocyclic heteroaryl, 5-6-niembered monocyclic heterocycle, 9-10 membered bicyclic heterocycle, or 3-7 membered carbocycie, wherein any phenyl, 5-6 membered monocyclic heteroaryl 5-6-membered monocyclic heterocycle, 9-10 membered bicyclic heterocycle, or 3-7 membered carbocycie of R5 is optionally substituted with 1, 2, 3, 4 or 5 Z3 groups, wherein the Z3 groups are the same or different;
R2 is (Cr-Q)aikyi or 3-7 membered carbocycie, wherein any (CrCs)aikyl of R2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
R3 is phenyl, 9-10 membered bicyclic aryl, 5-7 membered monocyclic heterocycle, or 8- 10 membered bicyclic heterocycle, wherein any phenyl, 9-10 membered bicyclic aryl. 5-7 membered monocyclic heterocycle, or 8-10 membered bicyclic heterocycle of R3 is optionally substituted with 1, 2. 3, 4 or 5 Z4 groups, wherein the ZA groups are the same or different;
R4 is H or (Ci-Cgjaikyl optionally substituted with 1 , 2, 3, 4 or 5 halo groups, which may be same or different;
each Z1 is independently (Cf -CV a!kyl, (C C^ lkeoyi, (C2~Cf)aikynyL 3-7 membered carbocycie, halo, -CN, -OR -OC(0)Rpi, -OC(0) RqIRri,
Figure imgf000003_0001
-S(0)2OR
Figure imgf000003_0002
-NRB,S(0)2Rp , -NRaiS(0)2ORp5, ~NRJi:S(0)2MR fRri, N<¾, -C(G)R!li,
Figure imgf000003_0003
or
-C(0)NRqiRd, wherein any 3-7 membered carbocycie of Z1 is optionally substituted with 1, 2, 3. 4 or 5 halo groups or (Ci-Cgjalkyl, which may be same or different, and wherein any (Cj- C6)aikyl? (CrQ)alkeriyi and (C2-C<s)alkynyi ofZ! is optionally substituted with L 2, 3, 4 or 5 halo groups, which may be same or different;
each Rni is independently II or (CrCs)alkyi;
each R l is independently (Ci~C6)alkyl;
each Rql and Rri is independently H or (CrCs)aikyi;
each Z2 is Independently (C Q)aikyl, halo, oxo, or -OR"2, wherein any 3-7 membered carbocycie of Z is optionally substituted with I, 2, 3, 4 or 5 (CrQ)alkyl or halo groups, which may be same or different, and wherein any (C;-Q) ik i of Z2 is optionally substituted with 1. 2, 3, 4 or 5 halo groups, which may be same or different;
each R"2 is independently H, (Cj-C¾)alkyL
Figure imgf000003_0004
or (C3-C7)carbocycle; each Z3 is independently (C]-Cs)alk l, halo, -CN, -OR"3, N02s or -C(O)N 3 r3, wherein any (CrCg)alkyl of Z3 is opiionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each R""' is independently H,
Figure imgf000004_0001
each Rq3 and R'3 is independently H or (CrC6)alkyi;
each Z4 is independently {C. -C6)alkyi, (C2-C&)alkenyl, (QrCjs)alkynyl, (CrC^earbocyele, halo, oxo, -CN, -OR"4, ~GC(G)Rp4 } -OC{0)NR 4Rr4, -SRn ? ~S(0)R^, -S(0)2OH, -S(0)2R≠, -SiOJa R^R" , -NRq Rr4, -NR^COR"4, -NR^COa ^, «NR" CO lq4Rr4, «NRn S(0)2R 5 ■ Rr;4S(0) ,OR!;4 ? -NR"4S(0)2 S 4R.r4, N<¾, -C(0)RR\ ~C(0)ORn s or ~C(0) Rq4Rr s wherein any (C3-C7)carbocycle, of Z3 is optionally substituted with 1, 2, 3, 4 or 5 halo groups or (Q- Cg)aikyl, and wherein any (Ci-Cgjalkyl, (CrC6)alkenyl and. (Ca-CV,)alkynyl of Z4 is optionally substituted with L 2, 3? 4 or 5 halo groups, which may be same or different;
each Rn4 is independently H or (C C5)alkyf;
each r" is (Ci-C5)alkyi; and
each Rq4 and Rr4 is independently H or (C C6)alkyl;
or a pharmaceutically acceptable salt thereof,
[0803] In another aspect, the present disclosure provides a compound of Formula (I):
Figure imgf000004_0002
wherein:
ring A, including the two carbon atoms to which it is fused to ring B. is a 5-6 membered monocyclic hetcfoaryl or phenyl, wherein any 5-6 membered heteroar)'! or phenyl of A is optionally substituted with 1, 2, or 3 Zl groups, wherein the Zl groups are the same or different; ring B, including the two carbon atoms to which it is fused to ring A, is a 5-7 membered monocyclic earboeycle, 6-10 membered bicyclic earboeycle, 5-7 membered monocyclic heterocycle, or 6-10 membered bicyclic heterocycle, wherein any 5-7 membered monocyclic carbocycle , 6-10 membered bicyclic carbocycle, 5-7 membered .monocyclic heterocycle, or 6-10 bicyclic heterocycle of B is optionally substituted with 15 2, 3, 4 or 5 Z2 groups, wherein the Z2 groups are the same or different;
X is C or N; or the moiety
Figure imgf000005_0001
wherein B is as defined above;
R is phenyl, 5-6 membered monocyclic h teroary!, 5-6-membered monocyclic heterocycle, 9-10 membered eyefie heterocycle, or 3-7 membered carbocycie, wherein any phenyl, 5-6 membered monocyclic heteroaryi, 5-6-mernbered monocyclic heterocycle, 9-10 membered bicyclic heterocycle, or 3-7 membered carbocycie of R' is optionally substituted with 1, 2, 3, or 5 Z3 groups, wherein the Is groups are the same or different; or R' is
benzothiofuranyh in which any of the rings are optionally substitute with 1, 2, or 3 Z3 groups;
R2 is (CrQ)aikyl or 3-7 membered carbocycie, wherein any (Ct-Cejalkyl of R2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
R3 is phenyl, 9-10 membered bicyclic aryl, 5-7 membered monocyclic heterocycle, or 8~ 10 membered bicyclic heterocycle, wherein any phenyl, 9-10 membered bicyclic aryl, 5-7 membered monocyclic heterocycle, or §-10 membered bicyclic heterocycle of R.3 is optionally substituted with 1, 2, 3, 4 or 5 Z4 groups, wherein the Z4 groups are the same or different;
R4 is H or (Ci-Q)alkyl optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each Z3 is independently (Cj-Cg)aik l, (C¼^)a!kenyl, (CrCs)alkynyl, 3-7 membered carbocycie, halo, -CN, -OR*1, -OC(0)RPI, -OC(0)NRQ ,RFI, -SR*!,
Figure imgf000005_0002
-S{());()I L
-S(0)2Rpi, ~8(ϋ¾ ΛΓ\ -NRQ5RRS, -NR.OLCORPI, -N ^CX ^ -NRALCONRQLRRT,
~NRnSS(0)2Rpi s -N ^ SiO^OR^ ~NR,V:S<0)2NR iRrt, N02s ~C(0)RKi, -C(0)ORb1, or
-C(0)NRqiRr3 s wherein any 3-7 membered carbocycie of Zl is optionally substituted with I, 2, 3, 4 or 5 halo groups or (Ci-Cg)alkyl, which may be same or different, and wherein any (CR
C6)alkyl, (<¼ ¼)alkenyl and (e2-C6)alkynyl of Z5 is optionally substituted with L 2, 3, 4 or 5 halo groups, which may be same or different;
each Rri1 is independently II or (Ci-C6}alkyi;
each R ! is independently (Cj-Ceja!kyi;
each Rql and Rd is independently H or (CrC6)alkyl;
each Z2 is independently (CrQOaikvi, halo, oxo.. or -OR"2, wherein any 3-7 membered carbocycie of Z2 is optionally substituted with 1, 2, 3, 4 or 5 (CrQ)alky1 or halo groups, which may be sanie or different and wherein any (CrQ)alkyl of Z2 is optionally substituted with !, 2, 3S 4 or 5 halo groups, which may be same or different;
each Rri2 is independently H5 (CrC¾alkyL (C; -C;i)haSoaik L or (€rC?}earbo<ycie;
each Z3 is independently (Ci~Q)alkyl, halo, -CN, -ORn3 ? NO¾ or ~C(0) R.q3Rr3, wherein any (CrC^alkyl of Z3 is optionally substituted with 1, 2, 3, 4 or 5 halo groups., which may be same or different;
each R"' is independently H, (Cr 3)alkyl, (Ci-Cyhaloalkyl, or (C3-C7)carboeycle;
each R'i3 and Rr3 is independently H or (CrQ alkyi;
each " is independently (CrC6)alkyi, (C2-Cs)alkenyl, (C Q aikynyi, (Q^carbocycle, halo, oxos -CN, ~OR.a4, -OC{0) ^, -OC(0) R 4Rrf, ~SR34, -S(G)Rp 5 -S(0)2OHs ~S(0)2Kp4 ? -S(0)2NRq4Rr4, ~ Rq Rr4, -NR^COR1*, -NRn C02Rp4, ~ Rn':C()NR'* Rr4, -NRn4S(0)2Rp ,
-NRR4S(0)2ORp4 J -NRn4S(0)2N q Rr4, N02, -C(G)Rn4, ~C(0)ORn4, or ^OJNR^, wherein any (C3 ¼)carboc es of Z5 is optionally substituted with 1, 2, 3, 4 or 5 halo groups or (€'·- C6)alkyi, and wherein any {C C6)alkyL (C2-C6)aikenyl and (CrCsJaikynyl of Z4 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may he same or different;
each RJs4 is independently H or (Ci-Cg)aikyl;
each Rp4 is (C C¾alk l; and
each Rq and Rr* is independently H or (Ci~Cg)alkyl; or a pharmaceutically acceptable salt thereof.
[0004] One embodiment provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
[00Θ5] One embodiment provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof; and an additional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non- n cleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse
transcriptase, an HIY nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXC 4 inhibitor, a gp! 20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIY integrase inhibitor, or combinations thereof.
[ΘΘ06] One embodiment provides a method for treating a Retr viridae viral infection (e.g., an HIV viral infection) in a patient (e.g., a human), comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to the patient. [0007] One embodiment provides a method for treating n HIV infection in a patient (e.g., a human), comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to the patient.
[0008] One embodiment provides a method for treating an HI V infection in a patient (e.g., human), comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an addi tional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HFV nucleoside inhibitor of reverse transcriptase, an HiV nucleotide inhibitor of reverse transcriptase, an HFV integrate inhibitor, a gp41 inhibitor, a CXCR.4 inhibitor, a g l20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrate inhibitor, or combinations thereof,
[0009] One embodiment provides a compound of formula i, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g., for use In treating a Retroviridae viral infection (e.g., an HiV viral infection) or the proliferation of the HIV virus or AIDS in a patient (e.g., a human)).
iOOiOj One embodiment provides a compound of formula 1, or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment of a Eeiroviridae viral infection, an Hi V virus infection, or AIDS.
One embodiment provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use m the manufacture of a medicament for treating a Retroviridae viral infection (e.g., an HIV viral infection) or the proliferation of the HIV virus or AIDS in a patient (e.g., a hmnmi) One embodiment provides a compound of formula I, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrate inhibitor, a gp4! inhibitor, a C.XCR4 inhibitor, a g l:20 inhibitor, a CCR5 inhibitor, a capsid polymerisation inhibitor, or a non-catalytic site HI V integrase inhibitor and combinations thereof, for use in a method for treating an HIV infection in patient (e.g., a human),
[00121 One embodiment provides processes and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof. Another embodiment provides processes and intermediates disclosed herein that are useful for preparing compounds of any one of formul s I, Ias and lb, or salts thereof.
[0013} Other embodiments, objects, features and advantages will be set forth in the detailed description of the embodiments that follows, and in pari will be apparent from the description, or may be learned by practice, of the claimed invention. These objects and advantages wi.i! be realized and attained by the processes and compositions particularly pointed out in the written description and claims hereof. The foregoing Summary has been made with the understanding that it is to be co idered as a brief and general synopsis of some of the embodiments disclosed herein, is provided solely for the benefit and con venience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the appended claims are lawfully entitled,
DETAILED DESCRIPTION
[00141 The present disclosure relates to, inter alia, compounds useful tor treating viral infections, in particular an HIV infection, pharmaceutical compositions thereof, processes for making the compounds, and methods of use thereof in treating viral infections, in particular an HIV (human immunodeficiency virus) infection.
H.H115| The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed su bject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
Terms
(0016] Unless defined otherwise, all technical and scientific terms nsed herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. A dashed line indicates an optional bond. A prefix such as "Cu.v" or (CU~CV) indicates that the following group has from u to v carbon atoms where u and v are each integers. For example, "Ch lk !" indicates that the alky! group has from 1 to 6 carbon atoms. ]Θ 17] "Alkyl" is a linear or branched saturated hydrocarbon. For example, an alky] group can have 1 to 8 carbon atoms (i.e., (CrCs)alkyl) or 1 to 6 carbon atoms (i.e.. (C ·.-€<; alkyl) or ! to 4 carbon atoms (i.e.. (CrC^a!kyl). Examples of suitable alky! groups include, but are not limited to, methyl (Me, -C!¾), ethyl (El ~C¾C¾), ! -propyl («-Pr, κ-propyl, ~CH2CH2C¾), 2- propyl (i-Pr, /-propyl, -CH(CHj)_0, 1 -butyl (n-Bu, n-butyl, -€¾€¾€¾€¾), 2-raeihyI-l- propyl (/-Bu, i-buiyl, ~CH2CiI(CI¾)2), 2-butyi (j-Bu, j-butyl, -CH(C¾)C¾CH3)? 2~methyl~2~ propyl (ί-Bu, f-butyl, -C(CB3)3)S 1-pentyl («-pentyl, ¾CH.2C¾CH2Ci¾)5 2-pemyJ.
(-CH(C¾)CH2CH2CH3)S 3~pentyl (~CH{CH2CH3)?.)5 2-methy!~2-butyi (-C(C¾)2C¾C¾), 3-methyl-2~butyl (-CU(€1 I -)C1 RCH¾ j, 3-roeibyi- ; -butyl (-CH2C¾CH(CF¾)2); 2-methyH- butyl (»CH2CH(CH3)CH2CI¾)! 1-hexyl (-O^CF Cl bC jCHjCH,), 2-hexyl
(-CH(CH3)C¾CH2C¾CH3)S 3-hexyl (-CH(C]¾CH3)(CHaa¾CH3)), 2-raethyl-2-pentyi (-C(CH3)2CFl2CH2CH3)} 3-methyi-2-pentyi ( :!l(CF )Cii(Cli;jC! i:iCIr , 4-methyi-2-peniyi (-CH(C¾)CH2CH(C¾)2)5 3-metl l~3~pero:yl (~eCCFi3)CCH2e¾)2), 2-me%!~3~pe yi (- CH(CFi2CH3)CH(CJ¾)2), 2J -dimemy!-2-butyi (·0(€¾ 2€Η(€Η·=)¾), 3,3-*meihy!-2-buty! (· CH(CH3)C(CH3)3, and oetyl (-(CH2)7CH3)„
ff)8!§] "Aikenyl" Is a linear or branched hydrocarbon with at least one carbon-carbon double bond. For example, an aikenyl group can have 2 to 8 carbon atoms (he,, Cj-Cg aikenyl), or 2 to 6 carbon atoms (i.e.,€2~Ce aikenyl) or 2 to 4 carbon atoms (Le., C2-C4 aikenyl). Examples of suitable aikenyl groups include, but are not limited to, ethylene or vinyl (-CH^CHa), allyl
C~e¾CH=CH2) and 5-hexenyl (~CH2CI¾CH2C¾CH=CH2).
[001.9] "Alkynyl" is a linear or branched hydrocarbon with at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e.,€2-Cg alkyne,) or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl) or 2 to 4 carbon atoms (i.e., C-rQ. alk n l . Examples of suitable alkynyl groups include, but are not limited 10, acstylenyl (-CsCH), propargyl
(-CHjC-CH), and the like.
[0020] The term "halo" or "halogen" as used herein refers to fi oro (~F), chloro (-C1), bromo (-Br) and iodo (~I).
[§§21] The term "haioalkyP as used herein refers to an aikyi as defined herein, wherein one or more hydrogen atoms of the alkyl are each independently replaced by a halo substituent For example, (Cr^Jhaioalkyi is a (Cj- alkyl wherein one or more of the hydrogen atoms of the (Ci-Cejalky! have been replaced by a halo substhuenl Examples of haloalk ls include but are not limited to fiuoromethyl, fluorochloroin ethyl, difluoromethyl, difiuoroc oromeihyl, trifluoromethyl, 1,1,1-trifluoroethyi and pentafluoroethyl,
[0022J The term "heteroalkyi" as used herein refers to an alkyl in which one or more of the carbon atoms are each independently replaced with a heteroatom selected from the group consisting of O, N, S, and Si, A heteroatom may optionally be oxidized or alkylated. A heteroatom may be placed at any interior position of the heteroalkyi group or at a position at which the group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2OCH¾ -CH2CH2NHCH3> -CH2C¾N(CH3) ~C¾ ~CH2SCH2CH3> -S{0)CH¾ -C¾C¾S(0)2CH3, -CHCHOCH3,™Si(CHj}j, -CH2aiNOC¾. -CeCFI (CH3)CH3>- C¾NHGC¾ and -€H2OS(CH3)3.
[0023) The term "aryl" as used herein refers to any group derived from one or more aromatic rings, thai is, a single aromatic ring, a bicyclic or a multicyclic ring system. Aryl groups include, but are not limited to, those groups derived from acenaphmylene, anthracene, azulene, benzene, cbrysene, a cyelopentadienyl anion, naphthalene, fjuoranthene, fiuorene, indane, perylene, phenalene, phenanthrene, pyreoe and the like. Unless otherwise specified, an aryl group has from 6 to about 20 carbon atoms, for example from 6 to 20 carbon atoms, for example from 6 to 14 carbon atoms, for example from 6 to 10 carbon atoms, for example from about 6 to 10 carbon atoms.
The term "hsteroaryi" as used herein refers to an aryl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom, as defined above, Heieroaryl groups include, but are not limited to, groups derived from aeridine, benzoimidazole, benzothiophene, benzoforars. benzoxazoie, benzoihiazoie, carbazole, carboline, cinno!ine, faran, Imidazole, imidazopyridine, kdazofe, indole, indoiirs.e, kdolisdne, isobenzo.&ran, isoehromene, isoindole, isoindoHne, isoqdnoline, isothiazole, isoxazole, naphtliyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazisie, pteridke, purine, pyran, pyrazine, pyrazole, pyridazine. pyridine, pyrimidme, pyrrole, pyrrolidine, quinazollne, quinoiine, quinollzine, quinoxaiine, tetrazole, thiadsa¾ole, thiazole, thiophene, triazole, xanthene, and the like. Unless otherwise specified, a heieroaryl group has from 5 to about 20 annular atoms, for example from 5 to 20 annular atoms, for example from 5 to 14 annular atoms, for example from 5 to 10 annular atoms. Thus, "heteroaryl" includes single aromatic rings of from about 1 to 6 annular carbon atoms and about 1-4 annular heteroaioms selected from the group consisting of oxygen, nitrogen and sulfer. The sulfur md nitrogen atoms may also be present In m oxidized form provided the ring is aromatic,
|002S] The term "heterocyclyi" or "heterocycle" as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring {i.e., at least one annular heteroatom selected from oxygen, nitrogen, and sulfur). Thus, the term inelud.es single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
Heteroeycles include, but are not limited to, groups derived from azetidme, aziridirse, imidazo!idine, morpholine, oxirane (epoxide), ox.etane, piperazirie, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofurao, tetrah.ydrothiophene, dihydropyridme, tetrahydropyridsne, quinudidine, N-bromopyrrolIdine, N-chlorapiperidine, and the like.
\ΰΰ26] The term "carbocycie" or "carbocyciyl" refers to a single saturated or partially unsaturated all carbon ring having 3 to 7 annular carbon atoms (i.e., (C3-C7)c boc cle) . The term "carbocycie" or "carbocyciyl" also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocydio rings). Accordingly, carbocycie Includes nsulticyelic carbocyles such as a bicycllc carbocycles (e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as bieyelo[3 J.Ojhexane and bicycIo[2.1. ijhexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 annular carbon atoms). The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirementsNon-limiiing examples of monocyclic carbocycles irs elude c clopropyl, cyclobutyl, cyelopentyL l~cycS peni-l~enyls 1 ~cyc3opent-2-enyls l-eyclopent-S -euyl, cyclohexyl, I- cyclohcx~l~enyl, l~cyciohex-2~enyl and l -cyclohex-3-enyl.
[0027 The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity)- The word "about" may also be represented
symbolically by w~" in the context of a chemical measurement (e.g., ~ 50 mg or pH ~ 7). Thus, it is understood that "about x" includes and describes "x" per se.
|0028 | As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results. For purposes of thi s invention, beneficial or desired results include, but are not limited to, alleviation of a symptom and/or di inishxaent of the extent of a symptom and/or pre venting worsening of a symptom associated with a disease or condition. In one
embodiment "treatment" or "treating" Includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival,
[0029] As used herein, "delaying" development of a disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition, This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled k the art, a sufficient or significant delay can, in effect encompass prevention, in that the individual does not develop the disease or condition. For example, a method that "delays" development of AIDS is a method that reduces the prohabi!ity of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method. Such comparisons may be based on clinical studies, using a statistically significant number of subjects. For example, the development of AIDS can be detected using known methods, such as confirming an individual's HIV* status and assessing the individual's T-cell count or other indication of AIDS
development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits or groin, or presence of an opportunistic condition that is known to be associated with AIDS (e.g., a condition thai is generally not present in individuals with functioning immune systems hut does occur in AIDS patients). Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence and onset,
[8030] As used herein, an "at risk" individual Is an individual who is at risk of developing a condition to be treated, An individual "at risk" may or may not have detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment of methods described herein. "At risk" denotes that an indi vidual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s). For example, individuals at risk for AIDS are those having HIV.
[0031-1 As used herein, the term "effective amount" refers to an amount that is effective to elicit the desired biological or medical response, including the amou t of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease,, and its severity and the age, weight, etc. of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or muidple doses may be required to achieve the desired treatment endpoint An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conj unction with one or more other agents, a desirable or beneficial result may be or is achieved.
Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
0032] The nomenclature used herein to name the subject compounds is illustrated in the
Examples and elsewhere herein. This nomenclature lias generally been derived using die commercially-available naming program, used in ChemDraw Ultra, Version 12.0 (Perkin Elmer,
Waltham MA).
Compounds
[ΘΘ33] The present disclosure provides a compound of Formula (I);
Figure imgf000013_0001
1
wherein:
ring A, including the two carbon atoms to which it is fused to ring B, is a 5-6 membered monocyclic heteroary! or phenyl wherein any 5-6 membered heieroar ) or phenyl of A is optionally substituted with 1, 2, or 3 Zl groups, wherein the Z1 groups are the same or different; in B, including the two carbon atoms to which it is fused to ring A, is a 5-7 membered monocyclic carbocycie, 6-10 membered bicyclic carbocycie, 5-7 membered monocyclic heterocyele, or 6-10 membered bicyclic hetereeycle, wherein any 5-7 membered monocyclic carbocycie , 6-10 membered bicyclic carbocycie, 5-7 membered monocyclic heterocyele, or 6-10 bicyclic heteroeycle of B Is optionally substituted with 1, 2, 3, 4 or 5 Z" groups, wherein the Z2 groups are the same or different;
X is C or N;
R; is phenyl, 5-6 membered monocyclic heieroary!, 5-6-membered monocyclic heteroeycle, 9-10 membered bicyclic heteroeycle, or 3-7 membered carbocycie, wherein any phenyl, 5-6 membered monocyclic heteroar h 5-6-menibered monocyclic heteroeycle. 9-10 memfoered bicyclic heteroeycle, or 3-7 membered carbocycie of R! is optionally substituted with 1, 2, 3, 4 or 5 1 ' groups, wherein the 7f groups are the same or different;
R2 is (CrC6)alk l or 3-7 membered carbocycie, wherein any (Cri¾alkyi of R2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
R3 is phenyl, 9- 10 membered bicyclic aryl, 5-7 membered monocyclic heteroeycle, or 8- 10 membered bicyclic heteroeycle, wherein any phenyl, 9-10 membered bicyclic aryl, 5-7 membered monocyclic heteroeycle, or 8-10 membered bicyclic heteroeycle of 3 is optionally substituted with ls 2, 3, 4 or 5 Z groups, wherem the Z4 groups are the same or different;
R' Is H or (Cr alkyl optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each ?.} is independently (C Q'Jalkyi (C;rC¼)aIkenyi, (Ca-C^aikynyl, 3-7 membered carbocycie, halo, -CN, -ORnS, -OC(0)Rpl, -OC(0)NRqlRri, ~SRn!, -S(0)Rpl, -S{(%GH, -S(0)2Rpl s -S(0}>NRqlRd 5 ~NRqiRi¾, -NRntCORpi, ~NRnlC02Rpi ? ~NRn 1 CO Rq ' Rr 1 ,
-NR"iS(0)2Rpl 5 -MlniS(0)2QRp! s - RelS(0)2NRqiRri, NO¾ -C(0)Ra3, -C(0)ORni 9 or
~C(0)NRq5Rri, wherein any 3-7 membered carbocycie of Z3 is optionally substituted with 1, 2, 3, 4 or 5 halo groups or (CrC6)aikyl, which may be same or different, and wherein any (C;~ C6)alkyl, iCV(¼)a?kenyi and {G^Cya ikynyl of Z} is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each Rni is independently H or {C C6)alkyl;
each Rpi Is independently (C C6)alkyI;
each R l and Rrt is independently H or (C3-C6)alkyl;
each 7 is independently (C; -Chalky i, halo, oxo, or ~ORi , wherein any 3-7 membered carbocycie of Z2 is optionally substituted with 1, 2, 3, 4 or 5 (C Ce k l or halo groups, which may be same or different, and wherein any (Cj-Cejalkyi of Z2 Is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each K.*2 Is independently R (CrC>)aikvi, {C}~C3)haloaikyL or (C3-C?)car ocyde: each Z3 is independently (Cf -¾)alky], halo, -CN, -OR:,3 5 NO¾ or ~C{0)NR 3RF3 5 wherein any (CrCg)aikyi of Z3 is opiionaiiy substituted with 1 , 2. 3, 4 or 5 balo groups, which may be same or different;
each R"3 is independently H, {C C^alk l, (Ci-C3)haloalkyl, or (C3-C7)carbocycle;
each ¾:- and R1'"' is independently H or (CrC6)aikyl;
each Z4 is independently (Ci-C6)alkyl, (C2-C^)&lkmyl, (Q-C^aikynyj, (C3-€7)carboeycfe, halo, oso, -CN, ·0ίΓ\ -OC(0)RP4, -OC(0) S 4Ri4, -SR!!4 5 -S(0)Rp4 s ~S(0)2OH, -8(0)^, -S(0)2M¥s -NR Rr*, -NR^COR^, R'^CO.R^, -NR,l CONR 4Rf4, - RR4S(0)2RP* -NR"4S(0)2OR^5 - ΚΗ48{0)2»¾Γ , NC¾ -C(0)RN4, ~CXG)OR!I4 5 or -C(0)NR RR S wherein any (CrC?)carboeyele, of Z5 is optionally substituted with I , 2, 3, 4 or 5 halo groups or (€·.- €6)alkyl and wherein any (C;-Cs)alkyl; (C2-C6)alkenyl and (QrCgklkynyl of Z4 is optionally substituted with 1» 2, 3, 4 or 5 halo groups, which may be same or different;
each RN4 is independently H or (CrQ-,)aikyl;
each R554 is (C C6)aikyl; and
each RQ4 and RR4 is independently H or (Q-C6)alkyl;
or a pharmaceutically acceptable salt thereof,
[ΘΘ34] The present disclosure also provides a compound of Formula (I):
Figure imgf000015_0001
I
wherein:
ring A, including the two carbon atoms to which it is fused to ring B, is a 5-6 membered monocyclic heteroaryl or phenyl, wherein any 5-6 membered heteroaryl or phenyl of A is optionally substituted with L 2, or 3 Zs groups, wherein the l) groups are the same or different; ring B, including the two carbon atoms to which it is fused to ring A, is a 5-7 membered monocyclic earboeycle, 6-10 membered bicyclic earboeycle, 5-7 membered monocyclic heterocycle, or 6-10 membered bicyclic heterocycle, wherein any 5-7 membered monocyclic earboeycle , 6-10 membered bicyclic earboeycle, 5-7 membered monocyclic heterocycle, or 6-10 bicyclic heterocycle of B is optionally substituted with 1, 2, 3, 4 or 5 7? groups, wherein the Z2 groups are the same or different;
X is C or N; or the moiety
Figure imgf000016_0001
wherein B is as defined above;
R!' is phenyl, 5-6 membered monocyclic heteroaryl, 5~6~membered. monocyclic hcterocy e, 9-10 membered bicyclic heierocycie, or 3-7 membered carbocyele, wherein any phenyl, 5-6 membered monocyclic heteroaryl, 5-6~membered monocyclic heterocycle, 9-10 membered bicyclic hete.rocycle, or 3-7 membered carbocyele of R i is optionally substituted with I, 2, 3, 4 or 5 Z3 groups, wherein the Z3 groups are the same or different; or R5 is
benzoihiofuranyi, is which any of the rings are optionally substituted with 1, 2, or 3 7/ groups;
R ~ ≥ (€rC )&lkyl or 3-7 membered carbocyele, wherein any
Figure imgf000016_0002
of 2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
R3 is phenyl, 9~I0 membered bicyclic aryl, 5-7 membered monocyclic heterocycle, or 8~ 10 membered bicyclic heterocycle, wherein any phenyl 9-10 membered bicyclic aryt 5-7 membered monocyclic heterocycle, or 8-10 membered bicyclic heterocycle of RJ is optionally substituted with I, 2, 3, 4 or 5 Z4 groups, wherein the Z4 groups are the same or different;
R4 is H or (Cj-Cgjalkyi optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each Z1 is independently (Ci «)alkyl, (Cr¾)aiksrtyl, (Cs-C^alkynyl, 3-7 membered carbocyele, halo, -CN, -ORni s -OC(0)Rpl 5 -OC(0)NRqlRrt, ~SRnl, ~S(0)Rpl s -S(0)2OH, -S(0)2Rp, s -S(0}?NRqiRri, ~NRqfRri, -NRalCORpI, -N ^CO^, -NRBlCONRq5Rrf,
-mr-!5(0)2Rp\ «£iiS(0)2OR i, -NRn5S{0)2NRqiRrl, NO¾ ~C(G)Rnl s -C(0)ORn l, or
-C(0)NRc-!Rri s wherein any 3-7 membered carbocyele of Z1 is optionally substituted with I, 2, 3, 4 or 5 halo groups or (Ci-Q)aik l, which may be same or different, and wherein any (C\~ C6)alkyl5 (C2-C6)alkenyl and (C2~C6)alkynyl of Z1 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each R"J is independently H or (CrQ,)alkyl;
each Rp! is independen ly (€r€6)alkyl;
each RQi and R'; is independently H or (C C6)alkyl;
each Z2 is independently (CrCs)alkyl, halo, oxo, or -OR"2, wherein any 3-7 membered carbocyele of Z2 is optionally substituted with 1, 2, 3, 4 or 5 (C Qtelkyl or halo groups, which may be same or different, and wherein any (Ci -Chalky! of Z2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each R"2 is independently H, (C] -C3)aikyi, (Ci-C3)haioalkyl, or (C3~C7)earbocycie;
each Z3 is independently (C C6)alkyl, halo, -CM, -OR"3, NOZ; or -C(0)NRq3Rr3, wherein any (CrC6)alkyl of Z3 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each Ϊ * is independently H, (€ €¾k¾yl
Figure imgf000017_0001
or (€.r€: carhocy e;
each Rq3 and 3 is independently H or (Ci~C6)aikyf
each Z4 is independently {C.-C6)alkyl, (C2-Q)alkenyl5 (CrCgJaikynyi, (CrC^carbocycle, halo, oxo, -CN, -OR"4, -OC(G)Rp4, ~OC(0)N q Rr s
Figure imgf000017_0002
-S(0)2OH, -S(0)2Rp4 s -5(C¾NRq Rr 5 - q Rr4 ? -NR^COR1*, -NR^CQzR1*, -NR^CO ^R1*, - R^S^ ^, » RSi S(0)2OM^s -NR.n4S(G)2NRq4Rr4, NO¾ ~C(0)Rn4, -C(0)GRn s or -C(0)NRq4Rr4, wherein any (Q-C^carbocyci , of Z; is optionally substituted with I, 2, 3, 4 or 5 halo groups or (C\~ C6)alkyi, and wherein any (C;~C6)aikyL (C C6)aikett l and (C2- 6)aik nyl of Z4 is optionally substituted with I, 2, 3, 4 or 5 halo groups, which may be same or different;
each Rn4 is independently H or (Ci~€¾a!kyl;
each is (CrC6)alkyl; and
each R¾ nd Rr is independently H or (Cr i)a!kyi; or a pharmaceutically acceptable salt thereof.
[QQ35] The present disclosure also provides a compound of Formula (la)
Figure imgf000017_0003
(la)
wherein:
ring A, including the two carbon atoms to which it is fused to ring B, is a 5-6 membered monocyclic heteroaryl or phenyl, wherein any 5-6 membered heteroaryl or phenyl of A is optionally substituted with I, 2, or 3 Z! groups, wherein the Z1 groups are the same or different; ring B, including the two carbon atoms to which it Is fused to ring A, is a 5-7 membered monocyclic carbocycle, 6-10 membered bicyclic carbocycle, 5-7 membered monocyclic heterocycie, or 6-10 membered bicyclic heterocycie, wherein any 5-7 membered monocyclic carbocycle , 6-10 membered bicyclic carbocycle, 5-7 membered monocyclic heterocycie, or 6-10 bicydic heterocycle of B is optionally substituted with 1, 2, 3, 4 or 5 Z2 groups, wherein the Z2 groups are the same or different;
X is C or N;
R1 is phenyl, 5-6 membered monocyclic heteroaryl, 5~0-mernbered monocyclic heterocycle, 9-10 membered bicydic heterocycle, or 3-7 membered carbocycle, wherein any phenyl, 5-6 membered monocyclic heteroaryl, 5~6~membered monocyclic heterocycle, 9-10 membered hicyclic heterocycle, or 3-7 membered carbocycle of R! Is optionally substituted with I , 2, 3, 4 or 5 Z3 groups, wherein the ZJ groups are the same or different;
R7' is (Cj-C6)aikyl or 3-7 membered carbocycle, wherein any (Ci-Q)aikyi of R2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
R3 is phenyl, 9-10 membered bicydic aryl, 5-7 membered monocyclic heterocycle, or 8~ 10 membered bicydic heterocycle, wherein any phenyl, 9-10 membered hicyclic aryl 5-7 membered monocyclic heterocycle, or 8-1.0 membered hicyclic heterocycle of RJ is optionally substituted with i 2, 3, 4 or 5 Z4 groups, wherein the Z4 groups are the same or different;
R4 is H or (CrCg)alkyl optionally substituted with 1 , 2, 3, 4 or 5 halo groups, which may foe same or different;
each Z3 is independently (CrCg)alkyi, (C2-C6)alkenyl5 (C2-C6)alkynyl, 3-7 membered carbocycle, halo, -CN, -OR"5, -OC(0)Rpl, -OC(0)NRqlRrl s -SRn l, -S(0)Rp3, -S(0)2OH, •S(Q)2R≠, -S(0)2NRqSRri, -NRq!Rr!, -NRnICORpI, ~ Rn!C02Rpi s - R^CONR^R'1,
- RBlS(0)2Rp5 , ~ RniS(0)2ORpE, -NRn!S(0)2NRqiRd, NOj, »C(0)Rnl, -CCOjOR"1, or
~C(0)NRqiRf\ wherein any 3-7 membered carbocyeie of Z1 is optionally substituted with 1, 2, 3, 4 or 5 halo groups or (Ci-C^alkyl, which may be same or different, and wherein any (Cp Qiaikyl, (OrC^alkenyl and (C2-C3)alkynyl ofZ* is optionally substituted with L 2, 3, 4 or 5 halo groups, which may be same or different;
each Rn! is independently H or {C|~Cg)alkyI;
each R l is independently (C;-Q)aSky|;
each Rql and Rd is independently H or (CrC6)a!kyl;
each Z2 is independently (Cr Oalkyl halo, oxo, or -ORnA. wherein my 3-7 membered carbocycle of Z2 is optionally substituted with 1, 2, 3, 4 or 5 (CrCs)alkyl or halo groups, which, may be same or different, and wherein any iC;~Ci:)sikyl o 2 is optionally substituted with L 2, 3, 4 or 5 alo groups, which may be same or different;
each Rr,2 is independently ¾ (C3~C3)aikyl, (C5-C3)haloalkyl, or (C3-C7)carbocycle; each £ is independently (C C.≤)a1kyl, halo, -CN, -OR*3, N02, or -C(0)NB.q¾r3 s wherein any (Ci-Cg)alkyS of Z3 is optionally substituted with 1 , 2, 3, 4 or 5 halo groups, which may be same or different;
each Rn3 is independently H, (CrC^alkyl, (Ci-C3)haio lk ls or (C3-C7)carbocycle;
each Rq'! and Rr3 is independently H or (CrCfj)alkyl;
each Z4 is indepeadently (CrCs)alkyL {C2-C6}alkenyl5 (C2 ¼)aikynyL {C3-Cr)carbocydft, halo, oxo, -CN, -O * -OC(0)Rp s ~QC(0)NRq Rf4, -SR"\ -S(G)Ri 4 s ~S(0)aO¾ ~S{C3)2Rp4, -S(0)2NR.<i4R.r ,
Figure imgf000019_0001
-NRn (0)2Rp4 3
Figure imgf000019_0002
wherein any (C¾-C7)carbocyele; of 7.} is optionally substituted with 1, % 3, 4 or 5 halo groups or ((."■- Cg)alkyl. and wherein any (Cj -Ch lk !,
Figure imgf000019_0003
and {C?-Q,}a!kynyi of Z4 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which ma be same or different;
each Rn4 is Independently H or (Q -Q;)alkyl:
each is (C C6)alkyI; and
each Rc and R'4 is independently H or (O.-Q)alkyl;
or a pharmaceutically acceptable salt thereo
[Θ936] Specific values listed below are values for compounds of formula I as well as all related formulas (e.g., formulas la and lb). It is to be understood that two or more values may combined. Thus, it is to be understood that any variable for compounds of formula I may be combined with any other variable for compounds of formula 1 the same as if each and every combination of variables were specifically and individually listed, For example, it is understood that any specific value of R1 detailed herein for compounds of formula I may be combined with any other specific value for one or more of the variables A, B, X, RJ, R3, or R4, the same as if each and e en' combination were specifically and individually listed,
[0037) in one variation of Formula (1), the carbon bearing ~€¾R! is In the (S)-eonfiguration. it is understood that compositions detailed herein may comprise a compound of Formula (I) in a racemie or nou-racemic mixture of stereoisomers or may comprise a compound of Formula (I) as a substantially pure isomer (e.g., as the (S)-Isomer at one or more stereoceniers).
[0038] In certain embodiments of Formula (I) and (la), the 5-6 membered heteroaryl of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms. In certain instances, ring A is a 5-6 membered monocyclic heteroaryl wherein the 5-6 membered heteroaryl of A comprises 1 -2 nitrogen atoms and 3-4 carbon atoms in the ring, and wherein any 5-6 membered heteroaryl of A is optionally substituted with one or two Z groups, in certain instances, ring A, including the two carbon atoms to which it is fused to ring B, Is a 5-6 mernbered monocyclic heteroaryi, wherein the 5-6 membered heteroaryi of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring, and wherein any 5-6 membered heteroaryi of A is optionally substituted with one or two Z1 groups; and X is N.
[0039] In certain embodiments of Formula (I) and (la), the 5-6 membered heteroaryi of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring. In certain instances, the 5-6 membered heteroaryi of A comprises 2 annular nitrogen atoms and 3 annular carbon atoms.
[0040] In certain embodiments of Formula (I) and (la), ring A is a 5-6 membered monocyclic heteroaryi or phenyl, wherein the 5-6 membered heteroaryi of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring, and wherein any 5-6 membered heteroaryi or phenyl of A. is optionally substituted with 1 , 2, or 3Z1 groups, in certain embodiments, ring A Is a 5-6 membered monocyclic heteroaryi or phenyl, wherein the 5-6 membered heteroaryi of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring, and wherein any 5-6 membered heteroaryi or phenyl of A is optionally substituted with 1 or 2 Zl groups.
[0941 ] In certain embodiments of Formula (!) and (la), ring A Is a 5-6 membered monocyclic heteroaryi, wherein the 5-6 membered hsteroaryl of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring, and wherein any 5-6 membered heteroaryi of A is optionally substituted with 1 , 2, or 3 Z1 groups. In one such variation, X is N, In certain embodiments, ring A is a 5-6 membered monocyclic heteroaryi, wherein the 5-6 membered heteroaryi of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms In the ring, and wherein any 5-6 membered heteroaryi of A is optionally substituted with 1 or 2 Zl groups, in one such variation, X is N.
embodiments of Formula (I) and (la), the moiety
Figure imgf000020_0001
Figure imgf000020_0002
. wherein Y is CZ or N; Z is CZlB or N; and each Z is independently H or Z\ In certain embodiments, Y is N. In certain embodiments, Y is CZ , wherein " is H, In certain embodiments, Y is CZia, wherein Z3a is 7; . In certain embodiments, Y is CZl,\ wherein Z5 is I and ; is an optionally substituted (C3-C6)aikyi (e.g., -€H3 and --CF3)5 halo, or -NRqtRrt (e.g., -N¾). In certain embodiments, Z is N. In certain embodiments, Z is CZia, wherein Zia is H, In certain embodiments, Z is CZis, wherein Z is Z¾. In certain embodiments, Z is€Zla, wherein Zi is Z3 amiZ3 is an optionally substituted (€rCf,)alkyl (e.g., -C¾ and -CF;$)> halo, or -NR !Rr; (e.g., ~MH2). It is understood that any Y moiety may be combined with any Z moiety the same as if each and every combination were specifically and individually listed. For example, it is understood that in one embodiment, Y is N and Z is CZls where Z¾a is Z1 (e.g., an optionally substituted <C: -Chalky!}. B i these embodiments may be any 8 moiety as detailed herein.
Figure imgf000021_0001
wherein each Z1a is independently H or z In certain embodiments, each Z5a is H. In certain embodiments, Zla is Z\ In certain embodiments, Zia is Z1 and Z1 is an optionally substituted (C C6)aiky1 (e.g., -C¾ and ~-CF3)» halo, or -NR^R^ (e.g., -N¾). B in these embodiments may be any B moiety as detailed herein.
&&44] in certain embodiments of Formula (I) and (la), ine moiety v ) f is
Figure imgf000022_0001
, wherein Z5a is independently H or Z\ In certain embodiments, Zia is H, certain embodiments, Z1 a is z In certain embodiments, Zia is Zl and Z! Is an optionally substituted (CrC6)aikyl (e.g., -€'¾ md-CFs), haio, or - R¾iRri (e.g., ~NH2). .B in these embodiments may be any B moiety as detailed herein,
(0 51 In certain embodiments of Formula (Γ) and (la), the moiety ( 8 ] ? is
Figure imgf000022_0002
or , B in these embodiments may be any B moiety as detailed herein,
embodiments of Formula (I) and (la), the moiety
Figure imgf000022_0003
is
Figure imgf000022_0004
wherein Z18 is independently H or Zs; and each Zia is independently H or Z2. in certain embodiments, Zu is H and each Z2a is H. in certain embodiments,, ZSs is Z! and Zl is a optionally substituted (Ci-Ce)alky{ (e.g., -€¾ and -CFj), halo, or -NR lRri (e.g., -NH¾). In certain embodiments, ZIa is™CP3, in certain embodiments, at least one Z2& is an optionally substituted (€.rQ)a1kyl (e.g., -C¾ and -CF;?), halo, or oxo. in certain embodiments, at least one Z2a is halo (e.g., fluoro). In certain embodiments, two Z¾ are halo (e.g., fkora) and two Z2s are hydrogen,
[00
Figure imgf000023_0001
[004S] in certain embodiments of Formula (Ϊ) and ( a), R is FJ.
[0049] in certain embodiments, a compound of Formula (I) is a com ound of Formula (lb):
Figure imgf000023_0002
(lb)
wherein Z!a is H or Z!.
Θ05 1 In one aspect, the compounds contain ls 2, 3, 4 or 5 Z3 moiety, in one aspect, the compounds contain 1 or 2 Z1 moiety, in certain embodiments of Formula (I), (la), and (lb), Z1 is independently {'C C¾a]kyl, halo, -OH, or -NR¾ri, wherein any (Q-C^alkyl of 7.} Is optionally substituted with 1, 2, 3, 4 or 5 halo groups. In certain embodiments, Z! is independently (C C6)alkyl, halo, -OH, or ~ Rq'Rr!, wherein any (Cr ^alkyi of Z1 is optionally substituted with L 2, or 3 halo groups. In certain embodiments, Zx is independently an optionally substituted (C;~ C6)alkyl (e.g., -C¾ and ~CF3), halo, or -NR¾l rt (e.g., -N¾),
[ΘΘ5.Ι] In certain embodiments of Formula (I), (la), and (lb), 1; is Independently -CF3, halo, -OH, or -Nil?,
10052} in certain embodiments of Formula (I)5 (la), and (lb), Z1 is H, ~CF¾ or OH. In certain instances, Z1 is ~CI¾.
[0053] In certain embodiments of Formula (I), (la), and (lb), ring B is a 5-7 membered monocyclic carbocycle,. or 6-10 membered hicyciic carbocycle, wherein any 5-7 membered monocyclic carbocycle or 6-10 membered bicyelic carbocycle of B is optioaally substituted with 1, 2, 3, 4 or 5 Z2 groups, in certain embodiments, ting B is a 5-7 membered monocyclic carbocycle, or 6-10 membered bicyclle carbocycle, wherein any 5-7 membered monocyclic carbocycle or 6-10 membered bicyelic carbocycle of B is optionally substituted with 1, 2, or 3 Z2 groups, in certain embodiments, ring B is a 5-7 membered monocyclic carbocycle, or 6-10 membered bicyelic carbocycle, wherein any 5-7 membered monocyclic carbocycle or 6-10 membered bicyelic carbocycle of B is optionally substituted with 1 or 2 Z groups,
[00S4J In certain embodiments of Formula (I), (la), and (lb), ring B is a 6-7 membered monocyclic carbocycle, or 6 membered bicyelic carbocycle, wherein any 6-7 membered monocyclic carbocycle or 6 membered bicycile carbocycle of B is optionally substituted with L 2, 3, 4 or 5 Z2 groups, in certain embodiments, ring B is a 6-7 membered monocyclic carbocycle, or 6 membered bicyelic carbocycle, wherein any 6-7 membered monocyclic carbocycle or 6 membered bicyelic carbocycle of B is optionally substituted with 1. 2, or 3 Z2 groups, in certairs embodiments, ring B is a 6-7 membered monocyclic carbocycle, or 6 membered bicyclle carbocycle, wherein any 6-7 membered monocyclic carbocycle or 6 membered bicyelic carbocycle of B is optionally substituted with I or 2 Z" groups.
0055J I s certain embodiments of Formula (I), (la), and (lb), ring B is a 6-10 membered bicyelic carbocycle, or 6-10 membered bicyelic heteroeycle, wherein any 6-10 membered bicyelic carbocycle or 6-10 bicyclle heteroeycle of B is optionally substituted with 1, 2, 3, 4 or 5 Z2 groups, in certain embodiments, ring B is a 6-10 membered bicyclle carbocycle, or 6-10 membered bicyclle heteroeycle, wherein any 6-10 membered bicyelic carbocycle or 6-10 bicyclic heterocycle of B is optionally substituted with 1, 2, or 3 2/ groups, in certain embodiments, ring B is a 6-10 membered bicyclic carbocycie, or 6-10 membered bicyclic heieroc cle, wherein any 6-10 membered bicyclic carbocycie or 6-10 bicyclic heteroeycle of B is optionally substituted with 1 or 2 Z2 groups.
[0056] In certain embodiments of Formula (I), (la), and (lb), ring B is a 6-10 membered bicyclic carbocycie, whereia any 6-10 membered bicyclic carbocycie of B is optionally substituted with 1, 2, 3, 4 or 5 Z2 groups, in certain embodiments, ring B is a 6-10 membered bicyclic carbocycie, wherein any 6-10 membered bicyclic carbocycie of B is optionally substituted with 1, 2, or 3 Z2 groups, In certain embodiments, ring B is a 6-10 membered bicyclic carbocycie, wherein any 6-10 membered bicyclic carbocycie of B is optionally substituted with 1 or 2 Z2 groups.
(00571 In certain embodiments of Formula (Ϊ), (la), and (lb), ring B is a 6-7 membered bicyclic- carbocycie, wherein any 6-7 membered bicyclic carbocycie is optionally substituted with 1, 2, 3, 4 or 5 Z2 groups, In certain embodiments, ring B is a 6-7 membered bicyclic carbocycie, wherein any 6-7 membered bicyclic carbocycie is optionally substituted with 1, 2, or 3 Z2 groups, in certain embodiments, ring B is a 6-7 membered bicyclic carbocycie, wherein any 6-7 membered bicyclic carbocycie is optionally substituted with 1 or 2 Z2 groups.
i&iSUi In certain embodiments of Formula (J), (la), and (lb), ring B is bicyclop. L0]hex~2~ cue, wherein bieyclo[3,LQJhex-2-ene is optionally substituted with 1, 2, 3, 4 or 5 Z2 groups, in. certain embodiments, ring B is bicyc1o[3-L0]hex-2-ene, wherein bicyclo[3.h0]hex~2~ene is optionally substituted, with 1, 2, or 3 Z2 groups, in certain embodiments, ring B is
bicycio[3,1.0]hex-2~en.e, wherein bicycio[3,L0]hex-2-ene is optionally substituted with 1 or 2 Z2 groups,
[0059] In certain embodiments of Form ula (Ϊ), (la), and (lb), ring B is a 6-7-membered monocyclic carbocycie. In certain embodiments, ring B, including the two carbon atoms to which it is fused to ring A, is a 6-membered bicyclic carbocycie. In. certain embodiments, ring B is a 6-membered monocyclic heteroc cie. In certain embodiments, ring B is a IQ-membered bicyclic heterocycie.
[0060] In certain embodiments of Formula (I), (la), and (lb), ring B is
Figure imgf000026_0001
[©061] In one aspect, the compounds contain at least one 7? moiety, in one aspect, the corn pounds contain 1, 2 or 3 Z2 moiety. In certain embodiments of Formula (I), (la), and (lb), each Z2 is independently (CrQ)alkyl, halo, oxo, or -OR"2, wherein any (CrC=)alkyl of Z2 is optionally substituted witli 1, 2, 3, 4 or 5 halo groups. In certain embodiments, each Z" is independently (€j-Q)alkyL halo, oxo, or -OR ", wherein my (CrQ)alkyl of Z1 is optionally substituted with 1, 2, or 3 halo groups. In certain embodiments, Z2 is an optionally substituted (C C6)alkyl (e.g., -CF¾ and -CF3), balo, or oxo.
10062] in certain embodiments of Formula (I), (la), and (lb), each Z2 is independently methyl, fiuoro, oxo, or OH, In certain embodiments of Formula (I), (la), and (lb), each Z2 is
independently methyl, Quota, or OH,
[0663] in certain embodiments of Formula (I), (la), and (lb), : is phenyl, 9 · ! O-membered bicyclic heterocycle, 5-6 membered monocyclic heteroaryl or 3-7 member carbocycie, wherein any phenyl, 9-l G-membered bicyclic heterocycle, 5-6 membered monocyclic heteroaryl or 3-7 member carbocycie of R5 is optionally substituted with I, 2, 3. 4, or 5 Z3 groups, in certain embodiments of Formisla (I), (la), and fib), R: is phenyl, 9-10-membered bicyclic heterocycle, or 5-6 membered monocyclic heteroaryl, wherein any phenyl, 9-10-membered bicyclic heterocycle, or 5-6 membered monocyclic heteroaryl of R.; Is optionally substituted with h 2, 3, 4, or 5 Z3 groups, in certain embodiments, ! is phenyl or 5-6 membered monocyclic heteroaryl, wherein any phenyl or 5-6 membered monocyclic heteroaryl of R1 is optionally substituted with 1, 2, or 3 Z3 groups. In certain embodiments, Rl is phenyl or 5-6 membered monocyclic heteroaryl, wherein any phenyl or 5-6 membered monocyclic heteroaryl of R1 is optionally substituted with 1 or 2 Z3 groups.
(0064] In certain embodiments of Formula (I), (la), and (lb), R1 is phenyl, wherein the phenyl is optionally substituted with 1, 2, or 3 Z3 groups. In certain embodiments, R1 is phenyl, wherein the phenyl is optionally substituted with 1 or 2 Z3 groups. |1Θ65| in certain embodiments of Formula (I), (la), and (lb), R : is pyridinyL thiofiiranyi, imidazolyl, beszothiof ranyL thiazolyi, or pyrazolyl, In which any of the ring are optionally substitaied with 1, 2, or 3 Z3 groups. In certain embodiments of Formula (Ϊ), (la), and (lb), R : is tetrahydrofuranyl, which is optionally substituted with 1, 2, or 3 Z3 groups, in certain embodiments of Formula (I), (la), and (lb), Rl is cyclobutyi, which is optionally substituted with i, 2, or 3 7 groups,
[0066] In one aspect, the compounds contain at least one Z moiety. In certain embodiments of Formula (I), (la), and (lb), each Z3 is independently (C Q)alkyl, halo, -CM, - N<¾, or
-C(0)NR 3R , wherein any (C C6)aikyl of Z3 is optionally substituted with L 2, 3, 4 or 5 halo groups, In certain embodiments, each Z3 is independently (Cj-Csjaikyl, halo, -CM, - NO¾ or -e(0) Rq3Rr3, wherein any (CrC6)alkyi of Z3 is optionally substituted with 1, 2, or 3 halo groups.
|0 6?j In certain embodiments of Formula (Ϊ), (la), and (ib), each Z3 is independently methyl, fluoro, bfomo, chloro, CN, N<¼, ~C(0)N¾ or -CF3
[0068] In certain embodiments of Formula (I), (la), and (lb), each Z3 is fiuoro.
[0069] In certain embodiments of Formula (Ϊ), ( a), and (Ib), Rl is:
Figure imgf000027_0001
[0070] In certain embodiments of Formula (I), (la), and (lb), R2 is (C Q>)alkyl. | *f i in certain embodiments of Formula (Ϊ), (la), and (lb), R2 is methyl
[§§72] In certain embodiments of Formula (I), (la), and (lb), R2 is optionally substituted with
1 , 2, or 3 halo groups,
[0073] In certain embodiments of Formula (I), (la), and (lb), R3 is phenyl, 9-10 membered bicyc!ic aryl, or 8-10 membered bicyclic heteroeycle, wherein any phenyl, 9- 0 membered bicyclic aryl or §-10 niembered bicyclic heierocycle of R5 is optionally substituted with L 2 or 3 Z4 groups.
(0074] in certain embodiments of Formula (I), (la), and (lb), R3 is phenyl or 9-10 membered bicyclic aryl, wherein any phenyl or 9-10 membered bicyclic aryl of R4 is optionally substituted with I, 2 or 3 Z* groups.
[0075] Irs certain embodiments of Formula (1), (la), and (lh% R3 is phenyl, naphthyl or isoindoJm-I -one, wherein any phenyl, naphthyl, or isoindorin-l-one of R4 is optionally substituted with I, 2 or 3 Z4 groups. In certain embodiments, R3 is phenyl, wherein the phenyl of II4 is optionally substituted with 1, 2 or 3 Z4 groups.
In one aspect, the compounds contain at least one Z4 moiety. In certain embodiments of Formula (I), (la), and (lb), the compounds contain 1 , 2, or 3 Z4 moiety. In certain embodiments of Formula (I), (la), and (lb), the compounds contain 2 Z4 moieties, in certain embodiments of Formula (I), (l ), and (lb), the compounds contain 1 Z4 moiety, in certain embodime ts of Formula (I), (la), and (lb), each Z4 is independently (CrC¾alkyls halo, -CM, -OR"4. ~NR 4Rr4, or oxo, wherein any (Ci-C^afkyl, of Z4 is optionally substituted with 1, 2, 3, 4 or 5 halo groups. In certain embodiments, each Z is independently (C-.-Q>)alkyl, halo, -CN, -OR"4, -NR^R' , or oxo, wherein any (€r€?,)alkyl, of Z4 is optionally substituted with 1.5 2, or 3 halo groups,
[0077] in certain embodiments of Formula (I), (la), and (lb), each 24 is independently (Cj- C6)alkyl, halo, -CN, -0(Ci-C6)a!kyl} -N((CrC6)alk.yl)2, or oxo,
[0078] In certain embodiments of Formula (I), (la), and (lb), each Z4 is independently methyl, -OCH3, fluoro, chloro, - t'CHjJj, or oxo,
[6079] In certain embodiments of Form la (I), (la), and (lb), R3 is:
Figure imgf000028_0001
1O08 In certain embodiments of Formula (I), (la), and (lb), R4 is H. 0081 j It is understood that any variable for ring B of Formula (I) and (la) may be combined with any variable of 4 of Formula (I) and (la) the same as if each and every combination were specifically and individually listed. For example, in one variation of Formula (I) and (la), ring B is an optionally substituted 6-7 member earbocycle and R4 is hydrogen. In another variation, ring B is a 6-7 member earbocycle substituted with ~€'F:, and 4 is hydrogen.
10082] it is understood that any variable for ring B of Formula (I) and (la) may be combined with any variable of R5 of Formula ( ) and (la) the same as if each and even,- combination were specifically and individually listed. For example, in one variation of Formula (Ϊ) and (la), ring B is an optionally substituted 6-7 member earbocycle and R: is optionally substituted and is phenyl pyridinyl, thiofuranyl, imidazoly!, benzothioforanyl, thiazolyl pyrazoJyl,
tetrahydroforanyi, or cyelobutyl. In another variation, ring B is an optionally substituted 6-7 member earbocycle and R! is optionally substituted and is phenyl, in another variation, ring B is a 6-7 member earbocycle substituted with -€F3 and is optionally substituted and is phenyl, pyridmyi, thiofuranyl, imidazolyl, benzotWofuranyl, tbiazolyl, pyrazolyl, tetrahydrofuranyl, or cyelobutyi. In another variation, ring B is a 6-7 membered earbocycle substituted with -€¾ and R: is optionally substituted and is phenyl.
[0083] It is understood that any variable for ring B of Formula (I) and (la) may be combined with any variable of R' of formula (i) and (la) the same as if each and every combination were specifically and individually listed. For example, in one variation of Formula (i) and (la), ring B Is an optionally substituted 6-7 membered earbocycle and is (CrCs)alkyl} such as methyl. In another variation, ring B is a 6-7 membered earbocycle substituted with -CF3 and R2 Is (Cs~ i¾alkyl, such as methyl
[0084] It is understood that any variable for ring B of Formula (I) and (la) may be combined with any variable of RJ of Formula (I) and (la) the same as If each and every combination were specifically and individually listed. For example, in one variation of Formula (Ϊ) and (la), ring B is an optionally substituted 6-7 member earbocycle and RJ is phenyl, naphthyl or isoindoiin-l- one, wherein any phenyl naphthyl, or isoindolin-1-οηε of R4 is optionally substituted with I, 2 or 3 Z4 groups. In another variation, ring B is a 6-7 member earbocycle substituted with -CF3 and R3 Is phenyl, naphthyl or isomdob°n~l~one, wherein any phenyl naphthyl, or isomdolin-i- one of R4 Is optionally substituted with I, 2 or 3 Z4 groups.
[0085] it Is understood that any variable for R2 of Formula (I) and (la) may be combined with any variable of R3 of Formula (I) and (la) the same as if each and every combination were specifically and individually listed. For example, in one variation of Formula (I) and (la), 2 is (CrCg)alkyl, such as m thyl and R3 is phenyl, naphthyl or isoindolin-l-one, wherein, any phenyl, naphthyl, or isoindolm-l -one of R4 is optionally substituted with 1. 2 or 3 Z groups,
[ΘΘ86] in certain embodiments of Formula (Ϊ) and (la), where the moiety
Figure imgf000030_0001
has an A ring as detailed herein, the compounds may have any one or more of the following structural features:
(a) ring B is a 5-7 membered monocyclic carbocycle (e.g., eycloheptane, cyclohexane and cyelopentane) optionally substituted with 1, 2, 3, 4 or 5 Z2 groups (e.g., - CH;¾,-Cl:' i, -OH, halo or oxo), such as uiisubstiMed eyclohexane or a mono-or di- substituted cyelohexane:
(b) R4 is H;
(c) R* is phenyl, 9-10-membered bicyclic heterocycle (e.g., tetrahydrofuranyl), 5-6 membered monocyclic heteroaryl (e.g., pyridinyl, tMoferanyl, iraidazoly!, henzothiofuranyi, thiazolyl, pyrarolyl), or 3-7 member earbocyele (e.g., cyclobutyi), wherein any phenyl, 9-lG-membered bicyclic heterocycle, 5-6 membered monocyclic heteroaryl or 3-7 member carbocycle of R5 is optionally substituted with one or more Z3 groups;
(d) R2 Is (CrC6)alkyl (e.g., methyl); and
(e) R'5 is phenyl or 9-10 membered bicyclic aryl, wherein any phenyl or 9» 10
membered bicyclic aryl of R4 is optionally substituted with I , 2 or 3 Z4 groups (e.g., phenyl, naphthyl, or isomdolin-I -one).
[0087] In one variation, the compounds conform to at least one of features (a)-(e). In another variation, the compounds conform to two or more (and in certain variations, ail) of features (a)~ (e). In a particular variation, the compounds conform to feature (a). In another variation, the compounds confirm to feature (a) and (b). embodiments of Formula (I) and (la), where the moiety
Figure imgf000031_0001
has a B ring as detailed herein, the compounds may have any one or more of the following structural features:
(a) ring A is a 5-6 membered heteroary! ring (e.g., a 5-6 membered heteroaryi ring bearing 1-2 annular nitrogen atoms and 3-4 annular carbon atoms) optionally substituted with 1, 2, or 32/ groups (e.g., ~CI- ,-<¾ halo or -N¾). For example, ring A may be a 5 membered heteroaryi containing 2 annular nitrogen atoms, e.g., pyrazolyl (e.g., -CF; substituted pyrazolyl) arid imidazolyl (e.g., » N¾ substituted imidazoiyl);
(b) R is H;
(c) R1 is phenyl, 9 0-membered bicyclic heterocycle (e.g., teirahydrofuranvl), 5-6 membered monocyclic heteroaryi (e.g., pyridmyl, thiofurasiyl, imidazolyl, benzothiofurarryl, thiazolyl, pyrazolyl), or 3-7 member earbocyeie (e.g., eyclobutyl), wherein any phenyl. 9-1 ~membered bicyclic heterocycle, 5-6 membered monocyclic heteroary! or 3-7 member e rbocyc!e of 5 is optionally substituted with 1, 2, 3, 4. or 5 Z3 groups;
(d) R2 is (CrCfi)alkyl; (e.g., methyl); and
(e) R3 is phenyl or 9-10 membered bicyclic aryl, wherein any phenyl or 9-10
membered bicyclic aryl of R4 is optionally substituted with 1, 2 or 3 Z4 groups (e.g., phenyl, naphthyl, or isoindo!m-l-one).
]¾089] In one variation, the compounds conform to at least one of features (a)-(e). In another variation, the compounds conform to two or more (and in certain variations, all) of features (a)~ (e). in a particular variation, the compounds conform to feature (a). In another variation, the compounds conform to features (a) and (b).
j'ii09(IJ In certain embodiments, the compound of Formula (!}, (la), or (lb), is selected from a compoun of Form ula (II)
Figure imgf000032_0001
(II)
wherein Rl, Zl&, Z2, and Z4are as defined herein.
[0091] In certain embodiments of Formula (ΪΙ), each Z2 is independently (Ci-Cg)alkyl} halo, oxo, or -OR"2, wherein any (Cj-Cejaikyi of Z2 is optionally substituted with 1, 2, 3, 4 or 5 halo groups. In certain embodiments, each Z2 is independently (€i-C6)alkyi, halo, oxo, or -OR"2, wherein any (Cr€&)aikyl of Z2 is optionally substituted with 1, 2, or 3 halo groups. In certain embodiments., 7? is m optionally substituted (Cr-QJalkyl (e.g., -C¾ and -CP.-;), halo, or oxo, [0092] In certain embodiments of Formula (II), each Z2 is independently methyl, fluoro, oxo, or OH. In certain embodiments of Formula {II}, each Z2 is independently methyl, fluoro, or OH,
10093 j ϊη certain embodiments of Formula (II), R! is phenyl, 9-10~memhered bicyciie heterocycle, 5-6 membered monocyclic heteroary! or 3-7 member carbocycie, wherein any phenyl, 9-1 O-membered bieyclic heterocycle, 5-6 membered monocyclic heteroaryl or 3-7 member carbocycie of R1 is optionally substituted with I, 2, 3, 4, or 5 Z3 groups. In certain embodiments of Formula (11), R! is phenyl, 9-10 -membered bieyclic heterocycle, or 5-6 membered monocyclic heteroaryl, wherein any phenyl, 9-10-membered bieyclic heterocycle, or 5-6 membered monocyclic heteroaryl of R3 is optionally substituted with 1, 1, 3S 4, or 5 Z3 groups, in certain embodiments, "iV is phenyl or 5-6 membered monocyclic heteroaryl, wherein any phenyl or 5-6 membered monocyclic heteroaryl of R1 is optionally substituted with 1, 2, or 3 Z3 groups. In certain embodiments, R¾ is phenyl or 5-6 membered monocyclic heteroaryl, wherein any phenyl or 5-6 membered monocyclic heteroaryl of R¾ is optionally substituted with 1 or 2 Z3 groups, fW94J In certain embodiments of Formula (II), R ; Is phenyl, wherein tine henyl is optionally substituted with 1 , 2, or 3 ZJ groups, in certain embodiments, Rl is phenyl wherein the phenyl is optionally substituted with I or 2 Z3 groups,
[0095| Irs certain embodiments of Formula (II), R! is pyridinyl, thiofuranyl, imidazotyi, benzothio&ranyl, thiazolyl, or pyrazoiyl, in which any of the ring are optionally substituted with I , 2, or 3 Z3 groups. In certain embodiments of Formula (11), Rl is tetrahydrofUranyl, which is optionally substituted with 1, 2, or 3 Z3 groups. In certain embodiments of Formula (IF), R! is c ciobutyf, which is optionally substituted with I, 2, or 3 Z3 groups.
[0096] In one aspect, the compounds contain at least one Z3 moiety. In certain embodiments of Formula (II), each Z3 is independently (C;-C6)aikyl halo, -CN, - N02} or -C(0) R 3Ri3 } wherein any (Ci-C«)alkyl of Z3 is optionally substituted with I, 2S 3, 4 or 5 halo groups. In certain embodiments, each Z3 is independently (C OOalk L halo, -CM, - NO¾ or -C{0)NRq Rr3 s wherein any (CrCi )alkyI of Z3 is optionally substituted with 1, 2, or 3 halo groups.
[00971 In certain embodiments of Formula (IS), each Z3 is independently methyl, fluoro, bromo, chloro, CN, N<¾, -C(0)NH2s or ~CF3.
[0098] In certain embodiments of Formula (II), each Z3 is fluoro.
[0099] In certam embodiments of Formula (II), R! is:
Figure imgf000033_0001
[§§100] In certain embodiments of . Formula (II), the compounds contain 2 Z4 moieties, In certain embodiments of Formula (II), the compounds contain 1 Z4 moiety. In certain embodiments of Formula (II), each Z4 is independently (C\~Ce)&lkyi, halo, -CN. -ORi:4,
or oxo, wherein any (€;~(¾3&νΙ, of Z4 is optionally substituted with I, 2, 3, 4 or 5 halo groups, in certain embodiments, each Z4 is independently (Ci~C6)aikyl, halo, -CN, -OR"4, or oxo, wherein an {CrQ)alkyl, of Z4 is optionally substituted with 1 , 2, or 3 halo groups.
f 0101] in certain embodiments of Formula (II), each Z4 is independently (Ci-€<-,)aIkyl3 halo, - CN, -0(C Q)alkyL -N((Ci~C6)aikyl)2s or oxo,
[§§102] in certain embodiments of Formula (If), each Z4 is independently methyl, -()€¾, fluoro, chioro, ~N(CI¾)2, or oxo,
(001031 in certain embodiments of the compound of Formula (II), Zis is H or Z1, wherem each 7 is independently (C C6)alky!, halo, -OH, or ~NKqlR! wherein any (G-C6)alkyi ofZ? Is optionally substituted with 1 , 2, or 3 halo groups. In certain embodiments, each Z1 is independently -CF3, halo, -OH, or -NH2- ¾i certain embodiments, each Z5 is independently -CF¾ or -OR
(00104] The present disclosure provides the following compounds or a pharmaceutically acceptable salt thereof.
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001

Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
The present disclosure provides the following compounds or a pharmaceutically acceptable salt thereof. 40
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
43
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
[00106] One skilled i n fee art will recogni ze that substituents and other moieties of fee compounds of Formula (I), (la), or (lb), such as Compounds I -35 or lz-35z, should foe selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated Into an acceptably stable pharmaceutical composition. Compounds of Formula (Ϊ), (la), or (!b), such as Compounds 1-35 or lz-35z„ which have such stability are contemplated as falling within the scope of the present invention,
{001071 The compounds ofForm.uk (I), (la), or (lb), such as Compounds 1-35 or lz-35z, may be prepared and/or formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable sails Include sulfates, pyrosulfales, bi sulfates, sulfites. bisulfites, phosphates, monohydrogen-phosphates, dihydrogesphosphates, metaphosphates. pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoales, propioiates, oxalates, malorta es, succinates, suberates, sebacates, fumarates, maleates, buiyne- 1 ,4-dioates, hexyne- 1 ,6~dioates, benzoates, c lorobeszoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxyhenmates, phthalates, sulfonates, methylsulfonates,
pro ylsulfonates, besylates, xylencsuifonates, naphthalene- 1 -sulfonates, naphthalene-2- suifonates, phenylacetates, phenylpropionates, phenylbutyrat.es, citrates, lactates, γ- hydroxybutyrates, glycolates, tartrates, and mandeiates. Lists of other suitable pharmaceutically acceptable salts are found in Remington The Science and Practice of Pharmacy.. 21st Edition, lippincott Williams and Wiikins, Philadelphia, Pa., 2006.
[0¾1Q8J Often crystallizations produce a solvate of the compound of the invention. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of fee invention with one or more molecules of solvent The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as a hydrate, including a monohydrate. dihydrate, hemihydrate, sesqulhydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the invention may be true solvates, while in other eases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent,
[00109] it is understood by one skilled in the art that tills invention also includes any compound provided herein that may be enriched at any or ail atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (2H or D),
|ββ1ίβ) The compounds disclosed herein may contain chiral centers, which may be either of the (R) or (3) configuration, or which may comprise a mixture thereof. Accordingly, the present disclosure includes stereoisom ers of the compounds described herein, where applicable, either individually or admixed in any proportions. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemie mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present disclosure,
[00111] The compounds of the present disclosure may be compounds according to Formula (I), (la), or (lb) with one or more chiral centers, which may be either of the (R) or (S) configuration, or which may comprise a mixture thereof The carbon to which R4 and the carbon to which - CHj-R1 are connected may be either of the R or S configurations. When R4 is a substituent other than H, the carbon to which R4 s connected is a chiral center and may be either of the R or S configuration. The carbon to which s connected to is a chiral center and may be either of the R or S configuration . In one variation of Form ula L R4 is H and the chiral center is of the S configuration,
[00112] The present disclosure includes both racemie mixtures of a compound of Formula I and isolated isomers of Formula L Where more than one chiral center is present in a compound of fee present disclosure, some, none, or all of the chiral centers may be eaantiomerically enriched. Thus, mixtures of a compound of Formula I may he racemie with respect to one or more chiral centers and/or enantiomericaiiy enriched with respect to one or more chiral centers. [00113] The compounds disclosed herein are .formulated with, conventional carriers (e.g., inactive ingredient or exeipieni material) which will be selected la accord with ordinary practice. Tablets will contain excipients including glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Ail formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as ED I' A. carbohydrates such as dextrin, hydroxyatkytceirulose, hydroxyaikylfflethytediulose, stearic acid and the like. One embodiment provides the formulation as a solid dosage form including a solid oral dosage form. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
[0011 ] While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations (compositions). Such formulations comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients. The earrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
[00115] The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co,, Easton, PA), Such methods include the step of bringing into association the active ingredient with inactive ingredients (e.g., a carrier, pharmaceutical excipients, etc) which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and Intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
0 08] Formulations described herein that are suitable for oral administration may be presented as discrete units including bisi not limited to capsules, cachets or tablets each containing a predetermined am ount of the active ingredient,
[QlQl] Pharmaceutical formulations disclosed herein comprise one o more compounds disclosed herein together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be In any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersibie powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydraie, croscarraeilose sodium, povidone, calc um or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, rmerocrystal!mc cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearaie, stearic acid or talc.
Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption m the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
(0102 J The amount of active ingredient that Is combined with the inactive ingredients to produce a dosage form will vary depending upon the host treated and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans contains approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material), In some embodiments, a dosage form, (e.g., for oral administration to humans) contains: .from 1.0 mg to 1000 mg or from 50 mg to 1000 mg or from .100 mg to 1000 mg or from 200 mg to .1000 mg or from 300 mg to 1000 mg or from 10 mg to 800 mg or from 10 mg to 600 mg or from 10 mg to 500 mg or from 10 mg to 400 mg or from 10 mg to 300 mg or from 50 mg to 800 mg or from 100 mg to 600 mg or from ISO mg to 500 mg or from 200 mg to 400 mg or from 50 mg to 500 mg or from 10 mg to 300 mg or from 50 mg to 300 mg or from 10 mg to 200 mg or from 50 mg to 200 mg or from 100 mg to 300 mg or from 100 mg to 200 mg or from 200 mg to 300 mg of active material (e.g., a compound of any of Formula (1), (la), or (lb)). In some embodiments, a dosage form tor oral administration to humans contains at least any of 10, 25, 50, 100, ISO, 200, 250 or 300 mg and no more than 500 or 800 or 1000 mg of active material (e.g., from at least 50 mg to no more than 500 mg). In some embodiments, a dosage form for oral administration to humans contains at least any of 10, 23, 50, 100, ISO, 200, 250 or 300 mg or no more than 500 or 800 or 1000 mg of active material In some embodiments, a dosage form for oral administration to humans contains any of 10, 25, 50, 100, ISO, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of active material, it is understood that a dosage form in an amount provided herein may be administered to a patient (e.g., a human in need thereof? in accordance with a dosing regimen provided herein, such as once, twice or thrice daily dosing. m one aspect, a dosing regimen provides for administratio of at least 10 mg and no more than 1,000 mg of active material (e.g., a compound of any of Formula (I), (la), or (lb)) daily, and it is understood that the amount may he provided in any suitable dosage form and amount (e.g., 500 mg twice daily or 1,000 mg once daily would provide the same amount of 1,000 mg/day dosing). The invention embraces once daily dosing to an individual (e.g,, a human in need thereof) of a dosage form of compound (e.g., a compound of any of Formula (I), (la), or (lb)) containing at least 50 mg and not more than 300 mg of compound. In certain embodiments, the carrier material varies from about 5 to about 95% of the total compositions (weightrwdght).
[0103] It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
[0104] In certain embodiments, a formulation comprising an active ingredient provided herein (a compound of any one of Formul (I), (la), or (lb), such as any one of Compounds 1-35 or J.z- 35z or a pharmaceutical salt thereof) in one variation does not contain an agent that affects the rate at which the active ingredient is metabolized, Thus, it is understood that compositions comprising a compound of any one of Formula (I), (la), or (Ufa) in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of any one of Formula (Ϊ), (la), or (lb) or any other active ingredient administered separately, sequentially or simultaneously with a compound of any one of formula (Ϊ), (la), or (lb). It is also understood that any of the methods, kits, articles of manufacture and the like detailed herein in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of any one of Formula (Ϊ), (ia), or (lb) or any other active ingredient administered separately, sequentially or simultaneously wife a compound of any one of Formula (I), (la), or (lb),
!©1Q5] In certain embodiments, a compound of any one of Formula (I), (la), or (lb), such as any one of Compounds 1-35 or lz~35z, is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HiV, In certain instances, the tablet can contain another active ingredient for treating HiV, such as an HIV protease inhibiting compound, an HIV non-nucleoslde inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HiV integrase inhibitor, a gp 1 inhibitor, a CXCR.4 inhibitor, a gpi20 inhibitor, a CCR5 inhibitor, a capsid polymerizatio inhibitor, or a non-catalytic site HIV integrase inhibitor, and combinations thereof In one variation, such tablets are suitable for once daily dosing.
[01(16] Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylacticaily (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinicia using conventional dose escalation studies.
Methods of Use
(Θ1Θ7] Provided herein is a method of inhibiting the proliferation of the HIV virus in an individual in need thereof, comprising administering a compound of any of Formula (I), (la), (lb) or (II), or a pharmaceutically acceptable salt thereof, to the individual. Also provided herein is a compound of any of Formula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof, for use in such a method, In one aspect, the individual In need thereof is a human who has been infected with HIV. In one variation, the indi vidual in need thereof Is a human who has been infected with HIV but who has not developed AIDS. In one variation, the individual in need thereof is an individual at risk for developing AI DS, In another variation, the individual in need thereof is a human who has been infected with HIV and who has developed AIDS, In one aspect of the methods provided herein, a compound of any of Formula (I), (la), (lb), or (ΪΙ), or a pharmaceutically acceptable salt thereof, is administered to the individual separately, sequentially or simultaneously with another active ingredient for treating HiV, such as an HIV protease inhibiting compound, an HIV non-nucleoside Inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 Inhibitor, a gp!20 inhibitor, a CC S Inhibitor, a capsid polymerization inhibitor, or a noin -catalytic site HIV integrate inhibitor and combinations thereof,
0108! One embodiment provides a method for treating a Reiroviridae viral infection (e.g., an HIV viral infection) in an individual (e.g. , a human), comprising administering a compound of any of Form ula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof, to the individual,
[0109] One embodiment provides a method tor inhibiting the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS in an individual (e.g., a human), comprising adm inistering a compound of any of Formula Formula (Ϊ), (la), (lb), or (II), or a
harmaceutically acceptable salt thereof, to the individual,
f 01 til J One embodiment provides a method for treating an HIV infection k an individual (e.g., a human), comprising administering a compound of any of Formula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof, to the individual
[0111] One embodiment provides a method for treating an HIV infection in an individual (e.g., a human), comprising administering to the individual In need thereof a therapeutically effective amount of a compound of any of Formula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of an additional therapeutic agent, wherein the therapeutic agent is an HIV protease inhibiting compound, an HIV non-nueleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV iotegra.se inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp!20 inhibitor, a CCR5 Inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HI integrase inhibitor and combinations thereof Also provided herein is a compound of my of Formula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof, for use in such a method,
( lll j One embodiment provides a compound of any of Formula (I), (la), (lb), or (II), or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g., for use in treating a Reiroviridae viral infection (e.g., an HIV viral infection) or the proliferation of the HIV virus or AIDS or delaying the onset of AIDS irs an individual (e.g., a human)).
[0113] One embodiment provides a compound of any of Formula (1), (la), (lb), or (ΙΪ), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a Reiroviridae viral infection (e.g., an HIV viral infection) or the proliferation of the HIV virus or AIDS or delaying the onset of AIDS in an individual (e.g., a human). One embodiment provides a compound of any of Formula (I), (la), (ib), or (II), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of the proliferation of a Reiroviridae virus, an HIV virus or AIDS or for use in the therapeutic treatment of delaying the onset of AIDS.
[01.14] One embodiment provides the use of a compound of any of Formula (I). (la), (Ib), or (II), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for a Reiroviridae virus Infection (e.g., an HIV virus infection) in an individual (e.g., a human). One embodiment provides a compound of any of Formula (I), (la), (Ib), or (II), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of a Reir oviridae virus infection (e.g., an H virus infection).
[8115] In some embodiments, In the methods of use, the administration is to an Individual (e.g., a human) In need of the treatment. In some embodiments, in the methods of use, the administration Is to an individual (e.g., a human) who is at risk of developing AIDS,
Routes of Admini tration
[8116] One or more compounds disclosed, herein (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like, It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds disclosed herein is that, they are orally bloavailabie and can be dosed orally.
Dosing Regimen
[8117] The compound, such as a compound of any of Formula (I), (la), (ib), or (H), may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the individual's Site,
[0118] The dosage or dosing frequenc of a compound of any of Formula (I), (la), (Ib), or (II) may be adjusted over the course of the treatment e.g., based on the judgment of the
administering physician, [0J 91 The compound may be administered to at; individual in an effective amount. in one aspect the compound is administered once daily. In one aspect, the compound is administered twice a day. In one aspect, the compound Is administered three times daily, it is understood that the compound, may be administered in any dosage amount provided herein, such as a dosage amount that would provide at least 10 mg day dosing and no more than 15000 mg/day dosing. Once daily oral dosing is embraced, such as by administering a dosage form containing from 50 mg to 300 mg of compound.
Combination Therapy
[01201 In one embodiment, the invention provides a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection. Also provided herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in such a method.
[01211 A compound as disclosed herein (e.g., a compound of any of Formula (I), (la), (Ib)5 or (II) or a pharmaceutically acceptable salt thereof) may be combined with one or more additional therapeutic agents in any dosage amount of the compound (e.g., from 50 mg to 300 mg of compound).
[0122] In one embodiment, a method for treating or preventing an HIV infection in a human having or at risk of having the infection Is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents. Also provided herein is a compound disclosed hereto, or a pharmaceutically acceptable salt thereof, for use in such a method.
[0123] In one embodiment, the invention provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, In combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier. For example, the therapeutic agent used in combination with the compound disclosed herein can be any and- HIV agent,
[0124] In one embodiments combination pharmaceutical agents comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents are provided. [1)125] One embodiment provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent, and a phanBaeeutieafly acceptable carrier, in one embodiment the additional therapeutic agent may be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds (HIV protease inhibitors), HIV non -nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide Inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or ailosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp4I inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp!20 inhibitors, G6PD and NADH-oxtdase inhibitors, capsid polymerization inhibitors or capsld disrupting compounds such as those disclosed In US 2013/0165489 (University of Pennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drug for treating HIV, and combinations thereof.
|()i26] One embodiment provides a pharmaceutical composition comprising a compound disclosed herein; and an additional therapeutic agent wherein the additional therapeutic agent is an HI protease inhibiting compound, an HIV non-nuc!eoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HI V nucleotide inhibitor of reverse transcriptase, an HIV integrase Inhibitor, a gp41 inhibitor, a CXC 4 inhibitor, a p!20 inhibitor, a CC 5 inhibitor, a capsld polymerization inhibitor, or a non-catalytic site HIV Integrase Inhibitor and combinations thereof.
0127} n further embodiments, the additional therapeutic agent is selected from one or more of:
(1) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mossenavir (DMP-450), JE-214? (AG1776), L-756423, RO0334649, ΚΝΪ-272, DPC-681, DPC-684, GW64Q385X, DG17, PPL-100, DG35, and AG
1859;
(2) HIV non-nucteoside or non-nucieotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DFC-083. DFC-961, DPC-963, MIV-150, TMC-120, rilpivirene, B1LR 355 BS, VRX 840773, lersivirine (UK- 53061), DEA806, M023 and - 1439;
(3) HIV nucleoside inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosme, sta udirse, zaleitabine, lamivudine, ahacav!r, amdoxovir, elvueitabine, alovudine, MiV-210, ±-FT€, D~d4FC, emtricitabine, phosphatide, fozivudine tidoxil, apricitibme (AVX754), amdoxovir, KP-1 61, GS-9131 (Gilead Sciences) and fosalvudirie tidoxil (formerly HDP 99.0003);
(4) H1Y nucleotide inhibitors of reverse transcriptase selected from the group consisting of tenofovir, tenofovir disoproxii fumarate, tenofovir disoproxii hemifo arate, tenofovir disoproxii, tenofovir atafen amide fumarate, tenofovir alafenanride hemifumarate, tenofovir aiafenamide, GS-7340 (Gilead Sciences). GS- 148 (Gilead Sciences), adefovir, adefovir dipivoxii, CMX-001 (C merix) and CMX-157 (Chinierix);
(5) f is integrase Inhibitors selected from the group consisting of curcumin, derivatives ofeure min, chicoric acid, derivatives of chicoric acid, , 5 -dicaf&oy Iqu ins c acid, derivatives of 3,5-dieaffeoylquinIc acid, aurintriearboxyiic acid, derivatives of aurintri arboxyiic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, iyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-I360, AR-177. L-870812, and L-870810, raitegravir, BMS-538158, GS 364735C, BMS-707035, MK-2048. BA 011, eivitegravir, dolutegravir and GSK-744;
(6) HIV non-catalytic site, or allosteric, ktegrase inhibitors (NCINl) including, but not limited to, BI-224436, CX05 I 6, CX0S045, CXI.4442, compounds disclosed in WO
2009/062285 (Boehringer Xnge!heim), WO 2010/130034 (Boehringer Ingel eim), WO
2013/159064 (GMead Sciences), WO 201.2/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 201.2/003498 (Gilead Sciences) each of which is incorporated by reference in its entirety herein;
(7) gp41 inhibitors selected from the group consisting of en&vir ide, sifuvirtide, aibuvirtide, FB006M, and TRi-1 .144;
(8) the CXCR4 inhibitor AMD-070;
(9) the entry inhibitor SP01A;
(10) the gp!20 inhibitor BMS-488043;
(11) the G6PD and NADH~oxida.se inhibitor immunitm; (12) CC 5 inhibitors selected from the group consisting of aplaviroe, vkriviroc, maraviroc, cenicriviroc, PRO- 140, INCB15050, PF-232798 (Pfizer), and CCRSmAbOOA;
(13) CD4 attachment inhibitors selected from the group consisting of ibalizumah (T B- 355) and BMS-068 (B S-663068);
(14) pharmacokinetic enhancers selected from the group consisting of cobieistat, ritonavir, and SPI-452; and
(15) other drugs for treating H!V selected from the group consisting of B AS- 100, SP1- 452, REP 9, 5Ρ-0ΙΆ, TNX-3S5, DES6, ODN-93, ODN-1 12, VGV-1, PA- 57 (tevirirnat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-22I HIV, DEBIO-025, BAY 50-4798, MDX01G (ipilimumab), PBS 119, AI.G 889, and PA-1050040 (PA-040),
[0128] in certain embodiments, a compound disclosed herein, or a pharmaceuticall acceptable salt thereof, is combined with two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with, two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The two, three four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can he selected from different classes of therapeutic agents. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase and an HIV non~ nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a further embodiment a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an RW nucleotide inhibitor of reverse transcriptase, an HIV non-nueleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound, In an additional embodiment a compound disclosed herein, or a pharmaceutically acceptable salt thereof, s combined with an HIV nucleotide inhibitor of reverse transcriptase, an HIV non -nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer,
[0129] In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil furnarate, tenofovir disoproxil. hemifumarate, ienofovir disoproxil, ienofovir alafena ide fum&raie, ienofovir alafenamide hemifumarate, or ienofovir aiafenanwde. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with ienofovir disoproxil fumarate, ienofovir disoproxil hemifumarate, or ienofovir a!afenamide. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with emtricitabine, abacavir or lamivudine.
(01301 In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one of: tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil henufumarate, tenofovir disoproxil, ienofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir aiafenamlde and one of: emtricitabine, abacavir or lamivudine. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one of: tenofovir disoproxil fumarate, tenofovir disoproxil Iienii&marate, ienofovir alafenamide fumarate, or ienofovir aiafenamlde and one of: emtricitabine or abacavir,
[0131] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-30 mg tenofovir aiafenamlde fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. in some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5- 10; 545; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. Is some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of any of Formula (I), (la), (lb), or (ΪΪ) or a pharmaceutically acceptable salt thereof) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from SO mg to 300 mg of compound) the same as if each combination of dosages were specifically and individually listed.
[0132] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200- 250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil arid 200 mg emtricitabine. In some embodiments, a compound disclosed herei , or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemi fumarate, or tenofovir disoproxil and 200 mg cmtricitabine. A compound as disclosed herein (e.g., a compound of any of Formula (I), (la), (Ih), or (II) or a pharmaceutically acceptable salt thereof) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 300 mg of compound) the same as if each combination of dosages were specifically and individually listed.
[0133] In some embodiments, one or more of the compounds disclosed herein are combined with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. In certain embodiments, a pharmaceutical composition including one or more of the compounds disclosed herein combined with one or more other active therapeutic agents is provided. In certain embodiments, the compounds disclosed herein are combined with one or more ot er active therapeutic agents in a solid dosage form. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administsriid m two or more admhvsinnkws. [§134] In some embodiments, one or more of the compounds disclosed herein are coadministered with one or more other active therapeutic agents. Co-administration of a compound disclosed herein with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more other active therapeutic agents, such that therapeutically effective amounts of disclosed herein and one or more other active therapeutic agents are both present in the body of the patient,
[0135] In yet another embodiment, the present application provides a method for treating an H V infectio comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents such as those disclosed above. Also provided is a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents such as those disclosed above, for use in treating an HIV Infection. The invention also provides a product comprising a compound disclosed, herein, or a pharmaceutically acceptable salt or co-crystal thereof, and an additional therapeutic agent such as those disclosed above as a combined preparation for simultaneous, separate or sequential use in therapy (e.g., in treating an HIV infection).
Kits and Articles of Manufacture
[0136] The present disclosure provides a kit comprising a compound of arty of Formula (I), (la), (lb), or (II), or a pharmaceuticall acceptable salt thereof, The kit may further comprise instructions for use, e.g., for use In Inhibiting an HIV protease, such as for use k treating an HIV infection or AIDS. The instructions for use are generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable.
[6137] The present disclosure also provides a pharmaceutical kit comprising one or more containers comprising a compound of any of Formula (I), (la), (ib), or (0), or a pharmaceutically acceptable salt thereof. Optionally associated with such contamer(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice reflects approval by the agency for the manufacture, use or sale for human administration, Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross- reactivity and shelf life permit. The kits may be in unit dosage forms, bulk packages (e.g., rauiti-dose packages) or sub-unit doses. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies),
[0138] Also provided are articles of manufacture comprising a unit dosage of a compound of any of Formula (I), (la), (ib), or (II), or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed.
General Synthetic Procedures
[0139] The embodiments are also directed to processes and intermediates useful .for preparing the subject compounds or pharmaceutically acceptable salts thereof,
[1)1 0) Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry; Reactions, Mechanisms, and Structure, 7th edition, Wiley -Interseience, 2013.)
[01411 Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modem Liquid Chromatography, 2nd ed,, ed. L, R. Snyder and J. I, Kirkiand. John Wiley and Sons, 1979; and. Thin Layer
Chromatography, E. StaM (ed,), Springer- Verlag, New York, 1969.
[0142] Although some schemes below may illustrate a certain stereochemistry, it is understood that the schemes and methods are applicable to compounds of the general structure provided, and are not limited to the compounds with the stereochemistry as shown.
[0143] During any of the processes for preparation of the subjec t compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 4th ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
[0144] Exemplary chemical entities useful In methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials ma be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substiraent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the ait will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes is preferably run at a temperature from about 0 °C to the reflux, temperature of the organic solvent used. Unless otherwise specified, the variables are as defined above in reference to Formula (Ϊ), (la), (lb), or (II), .{0145] Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow.
[0146] Scheme 1 shows a representative synthesis of the compounds of the embodiments.
§g¾eg¾e 1
1) Deprolection
Figure imgf000063_0001
[01.47J iR Scheme 1, ring A, ring B, X,
Figure imgf000063_0002
R2, K3, and R4 ate as defined herein. As discussed below, PG3 is an amino protecting group. Starting materials may be obtained from commercial sources or via well-established synthetic procedures,
[Θ148] With continued reference to Scheme 19 the carboxyl group of Compound 1~A can react with the amino group of Compound 1-B through standard coupling conditions to produce Compound 1-C. In certain instances, the carboxyl group of Compound 1-A can be activated to facilitate reaction with an amine, Activating agents for carboxyl groups include, but are not limited to, various phosphorus compounds, carbodiimides, and c oroformates. in certain instances, an activating agent for a carboxyl group is isobutyl chlorofomiate,
[01 9] Compound 1-C is then deproteeted to remove the amino protecting group PG1. in some instances, the protecting group PG; is a Boc-group, which cars be removed with TFA, Other examples of suitable protecting groups for amino groups and the procedure for removal of the protecting group can be found in T, W. Greene and P. G, M. Wats, "Protective Groups in Organic Synthesis," 4* ed,5 Wiley, New York 2006.
fSlSO] Upon removal of the protecting group, the amino group of Compound 1-C can react with the carboxyl group of Compound 1-C through standard peptide coupling conditions to produce a compound of Formula (I). Reagents such as EDCi/HOBt, HOBt, PyBOP, HATU, or BEM (Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397. Carplno, L. A.; EhFaham, A, I Am. Chem. Soc. 1995, 1 17, 5401. Li, P.; Xu, J, C, I Pept. Res. 2001, 58, 129.) in the presence of a base such as DIEA or other bases familiar to one skilled in the art and n an appropriate solvent can. be used. {0151] Accordingly, and as described in more detail herein, the present disclosure provides a process of preparing a compound of the present disclosure, the process involving:
reacting a compound of formula:
Figure imgf000064_0001
(1-C) with compound of formula:
Figure imgf000064_0002
thereby producing a compound of Formula (I), wherein ring A, ring B, X, R\ R2, R:\ and R4 are described herein,
[0152] In certain instances, the above processes farther involve the step of forming a salt of a compound of the present disclosure. Embodiments are directed to the other processes described herein; and to the product prepared by any of the processes described herein.
[0153] The present disclosure provides for intermediates used to make a compound of the Formula (I), (la). (lb), or (II), The intermediates are contemplated as failing within the scope of the present invention.
[0154] Except as otherwise noted, the methods and techniques of the prese t embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, edition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th editioa, Wiley-Merscience, 2013.
E am ie
jiUSSf The following examples are offered to illustrate but not to limit the invention.
Although the examples herein may show certain stereoisomers, a skilled artisan can adapt the disclosed methods to prepare racemic mixtures and other stereoisomers.
[0156} The following abbreviations may be used throughout the specification, and have the following meanings:
°C - degrees Celsius
A = Angstrom
Ac = acetyl AcOH = acetic acid
aq - aqueous
A? = argon
atm ::: atmosphere
BEP ::: 2-bromo -ethyl pyridinium teirailuoroborate
Bn = benzyl
Boc = ieri-butoxy carbosyl
B0C2O
Figure imgf000065_0001
dicarbonaie
bp :;: boiling point
8 s = 4~bromopheny!sulfonyl
Bu = butyl
ca!cd = calculated
CBS - Corey-Bakshi-Shibata
GDI ::: Ι , -carbonyldi Imidazole
COMU' = (l~cya¾o-2-etlioxy-2-oxoethylidenaminooxy)dImethylamino-mo^holirio- carbenium hexafluorophosphate
DABCO - 1 ,4-diazabicyclo[2.2.2]octane
DBU ·:: 1 ,8-dlazabic clotmdec-7»eos
DCE = Is2»dicblofoetha∞
DCM - dichloromethane
DiA.D :::: diisopropyl azodicarboxy!ate
dioxane ~ 1 ,4-dioxane
Figure imgf000065_0002
DMF = NjW-diraethylformamide
DMAP = 4-dimethylamkopyridiae
DMPU = 1 ~dImeihyl^3,4,5,6 etrahydro«2{lH)"pyrim5dkone
DMSO = dimethyl sulfoxide
dppf - 1, 1 '-bis(diphenylpliosp ifio)ferrocene
DSC = M,N'~disuccinimidyl carbonate
EC;¾> = half maximal effective concentration
EDC = 1 -ethyl~3-(3-dimethylamlnopropyl) carbodiimlde
Et = ethyl EtzG = diethyl ether
EtOAc = ethyl acetate
EtOH = ethajnol
eqidv = equivalent
F-NM ~ fluorine nuclear magnetic resonance spectroscopy
g = gram
h = hour
Figure imgf000066_0001
HCV = hepatitis C virus
Hex ::; hex = hexanes
HMDS = hexameihy!disila2ari.e(azide)
B PA = hexamethyiphcsphoraiBide
'H-NM - proton nuclear magnetic resonance spectroscopy
HOAc = acetic acid
HFLC - high pressure liquid chromatography
L = liter
L€MS-ES ~ liquid chromatography mass spectrometer (elecirospray ionization)
M molar concentration (mol/L)
Me = methyl
MeCN - acetenitri!e
MeOM ::1 methanol
MeTHF - 2-methylteirahydrofuran
mg ~ milligram
MI-Iz = mega He tz
mi, ::: milliliter
mmol millimole
min = minute
MTBB == methyl tet-butyl ether
Ms ::: methanesuifonyi
MsCI ::: methanesuifonyi chloride
MS =;: molecular sieves
n = normal N = normal concentration
NMO™ .Y-methylmorphoHne^V-oxide
NMP :::: N-meihyipyn-oiidmone
o/n = overnight
Pf = 9-pheny!-9H-iluoren«9-yl
PPh-, :::: phcnylphosphine
PE = petroleum ether
Ph ~: phenyl
PhMe ~ toluene
pM = picomoSar
rt = room temperature
sal ::: sat, = saturated
see -····· secondary
SNI = nucleophilic substitution unimolecu!ar
&vfi = nucleophilic substitution bimokcular
S^Ar ~ nucleop ilic substitution aromatic
t = tert ~ tertiary
TBAF = terra-^buty!ammonium fluoride
TBTU = 0-(benzotriazol - 1 ~yl)-N,N, ' jN'-tetrameth I uronixim tetrafluoroborate TEA = triethylamkie
temp - temperature
Tf = trifluoromethanesulfonyl
TFA - trifliioroaceiic acid
THF = tetrahydroforan
TLC = thin layer chromatography
TMS = trimethylsilyl
TMSOTf = trimethylsilyl trifluororaethanesulfonate
TPAP ::: ietraprop I amnion i u m perruihcnate
Tr = triphenylmethyl
Ts para-to 1 u enesu If ony I
w/w = wei giit weight ratio
ExampleJ
Figure imgf000068_0001
Synthesis of (SHert-butyi ( 1 -{methyK phen yl am ino 1 -oxo-3 -phenylpropan-2 -ypearbamate am
[MSI] To a solution of (S)-2-((iert~buioxycarbonyl)ammo)-3-phenylpropanoic acid (1 g. 3,58 mmol) a 4-methyimorpholine (0,43 mL, 3.5S mmol) in DME (L5 mL) at 0 °C5 isobutyi chlorofonnaie (0,49 mL, 3.58 mmol) was added to the solution slowly. After 30 minutes, N- methylaniline (422 mg, 3,94 mmol) was added to the mixture. The reaction mixture was stirred for 2 hours. The reaction mixture was diluted with EiOAe (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was separated and was concentrated to dryness in vacuo. The residue was purified by flash column chromatography (Rf; 03, 20%
EtOAe/Hexanes) to afford LI g of title compound. MS (m/z) 355 [M+H]+.
Synthesis of rS)-N-methvi~ 3-diphesivi~2 2 3 trifjuoromethyi -4 .6j4etrahvdro H- inda2ol ryl)acefeim¾do)propanam e (1):
|0158] To a solution of IB (36 mg, 0.1 mmol) in TFA (1 mL). was stirred for 1 how. The solvent: was removed and concentrated to dryness in vacuo.. To a solution of 2-(3- (trifhioromeihyi)-4, 5,6,7-ietrahydro- 1 H-indazoi - 1 -yl)aeetie acid (50 mg, 0.2 mmol), dilsopropylethylamine (0.05 mL, 0.5 mmol) and HATU (82 mg, 2 mmol) in DMF (1 mL), the TFA salt of prod uct from previous step was added to the solution alter 10 minutes. The reaction mixture was stirred at room temperature for 1 hour. Purified reaction mixture on prep reverse phase HPLC using 20~80%B over 20 rain. (A=0.1 %TF A/H2O;B=0.1 %TF A/ Acetonitrl 1 e). Combined purs fractions as determined by LC/MS and iyopM!ized to provide 26 mg of desired compound. MS (m/z) 485
Figure imgf000069_0001
Example 2
Figure imgf000069_0002
Synthesis of (S)-N-(4-methoxyphenyi)-N-^
tetrahydro-l H-indazol- 1 "yl)acetamido)propanam e (2):
[Θ159] Compound 2 was prepared according to the method presented for the synthesis of Example 1 utilizing 1A and substituting 4-methoxy-N~niethyianiiine for N-methyiamline to provide 14 mg of title compound. MS (m/z) 515 [M+iff .
Figure imgf000069_0003
Synthesis of (SVN-methyl-N-Cnaphthd^
tetrai.ydfo-lH-indazol--l yl)acetamido)propariamide (3):
[0160] Compound 3 was prepared according to the method presented for the synthesis of Example 1 utilizing 1A and substituting N-methylnapfithaien-2~amhie for N-meihylamiine to provide 9 mg of title compound. MS (m/z) 535 M+H]+,
E ampie 4
Figure imgf000070_0001
Synthesis of fSV3-f3 -difluorophenyl)^
{†r|fj¾orome^
[0161| Compound 4 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)-2-((iert~butoxycarbonyi)amino)~3~(3J5-dir orophenyl)propariolc acid for IA and substituting 4~raeihoxy-N-methylanilsfie for N- ethyhmlme to provide 7 mg of title compound, MS (m z) 551 [ΜΉ-l .
Example 5
Figure imgf000070_0002
Swtfaesis of(SVN-methyl-^
tetrahydro- 1 H-mri zol - 1 ~yl)acetgmido)propanamidej 5) :
(0162] Compound 5 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)~2~((l£rt^uto ycar^^ acid for 1A to provide 34 mg of title compound. MS (m/z) 486 [M+H]+,
Figure imgf000071_0001
Synthesis of fS N-methvi-N^^^
tetr¾liydi-o-lH-indag)i-¾ -yl)acetamido)propanamide (€):
P163] Compound was prepared according to the method presented for the synthesis of Example 1. utilizing (S)~2~((tert-buto ycarbonyl)ammo)-3-(pyndin-3-yi)propaiioic acid for 1A to provide 34 mg of t tle compound. MS (m/z) 486 [M-f-H]*
Example 7
Figure imgf000071_0002
tetrahydro-lH-i¾dazoI-i-y1)acetamido propanamide (7):
[0164] Compound 7 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)-2-((tert-bi3toxycarbonyl)amino)-3~(p Tidin~2-yl)propanok acid for IA to provide 31 mg of title compound. MS (m/z) 486 [M+H]1" .
Figure imgf000071_0003
Synthesis of (S)-N-methy1-N-phenyl-3^^
tetrahydro- 1. H-indazoi- 1 "Yl¼eetamldo)propan¾mide {§).:
fS16§] Compound 8 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)~2~((tert-buto¾yvarboHyl)amino)-3-(thiopiien~2~yl)propaiioic acid for 1A to provide 23 mg of title compound. MS (pi/z) 491 [M+HJf'.
Figure imgf000072_0001
4J.6 "tetrahYdro-lH-¾nda¾ol-l -y¾)acetamido)propaBarnide (9);
[0166] Compound 9 was prepared according io the method presented for t e synthesis of Example 1 utilizing (S)-2-((tert~butoxycarbonyI)arnino)-3-(l-methyi~lH~imida¾oI--S- yl)propanoic acid for 1 A to provide 9 mg of title compound. MS (m/z) 489 [M+H]+,
Example 1.0
Figure imgf000072_0002
Synthesis of (S)-3-(ben£o[bjtMophen-3-yl)^
4.5,6 j etrahydro- 1 H-indazol- 1 ~yl)aeetam i do)propaaamide (I CI) :
(Q167\ Compouiid t .0 was prepared according to the method presented for the synthesis of Example ! utilizing (S)-3-(bcnzo[b]thiophen-3~yl)-2-((tert-biitoxycarbonyl)ammo)propanoic acid for A to provide 36 nig of title compound. MS (m ) 541 [M+H]+.
BxaiTiBl?.il
Figure imgf000073_0001
Synthesis of (SVN-methyl-N-phe^
te-trahydro- IH-lndazoI- 1 -yS)aeetam ido)propanamidc (11):
[ΘΪ68] Compound 11 was prepared according to the method presented for the synthesis of Example I utilizing (S)-2-((tert-b toxycarbonyl)ammo)-3-(ihiazoi-4-yl)propanoic add for 1A to provide 23 mg of title compound, MS { /z) 492 Μ+Η]+,
Figure imgf000073_0002
Synthesis of (S )-N-metfay¾-N-phenyS-3 -{ 1 H-pyrazol- 1 - i)-2-{2-{ 3 -( triiluof omethyl)-4, 5.6, 7- tetraj ydrO"lH-½dazol-l-yl)acetamidQ)propanamide (12):
[0169] Compound 12 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)~2~((teri-butoxycarbonyl)amkto)-3-(liI-pyrazol-l-yI)propanoic acid for 1A to provide 20 mg of title compound, MS {m/z) 475 [M+H]+,
Example .13
Figure imgf000073_0003
Synthesis of {S)- -methy¾-NJ-dipheayl-2-f2-(3-f fluoromethy¾)-5,.6.7,S- tetrahydrocyclohepta c pyrazoi- 1 (4ff l-y1)acetamido)prop¾narnide (13):
0171 1 Compound 13 was prepared according to the method presented for the synthesis of Example 1 utilizing 1A and substituting 2~(3-(trifluoromethyi)-5,6s7,8- tetrahydrocye!Ghepta[c]pyra¾ol~i (4H)-yl)ace†ie acid for 2~(3~(trif uoromethyl)-4)5,6s7- tetrahydro H-indazol-l-yl)acetie acid to provide 20 mg of title compound. MS (m/z) 499 pie
Figure imgf000074_0001
Synthesis of CS)-3^yelobuty1~N~raet l-N^
1 H-iadazoi- 1 ~yl)acetamido)propanarnide (14):
[Mil] Compound 14 was prepared according to the method presented tbr the synthesis of Example 1 utilizing {S)-2-((tert~butoxycarbonyl)amino)~3"Cyclob tylpropanoic acid for 1A to provide 20 rag of title compound, MS (m/z) 463 [M+H]+. lK NMR (400 MHz, DMSG~<¾ δ §.47 (d, 1H), 7,52 - 7.25 (m, 4H), 4.74 (ss 2H), 4,22 (id, 4,2 Hz, IB), 3.13 (d, 3H), 2.53 ·■■· 2.41 (m, 6H), 2.04 (p, 1H), 1.86 - 1,74 (m, \ E% 1.71 - 1,45 (m, 7H), 1.44 - 1.28 (m, IB), 0.76 (q, 1H). Example 15
/
Figure imgf000074_0002
[0ί72] Compound IS was prepared according to the method, presented for the synthesis of Example 1 utilizing (S)-2-((ieri-biitoxycarbonyI)mmo)-3-{3-cyanopheiiyI)propartoic acid tor 1A to provide 7 mg of title compou d, MS ( z) 510 [M+H . Ή NMR (400 MHz, DMSO-<&) δ 8,73 (d, lH)t 7,62 (ds 1H), 7.53 - 7.31 (m, 4H), 730 ~ 7,13 (m, 3H}5 7.08 (d, IB), 4.75 - 4.61 (m. 2H), 2.91 (d, 1H)S 2.72 (4 1H), 2,37 (4 3H), 2,12 (d, 1H), 1.60 (m, 4H).
Figure imgf000075_0001
Synthesis of fS)-3-f3-chloroDhenvl)-N-ffiethvl-N-ph^
tetralivdro II"indazol-l~v¾)acetamidoteropaiia.niide (16):
[§173] Compound 16 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)~2- (tert-butoxycarbonyi)amino)-3"(3-chlorophenyl)propanoic acid for 1A to provide 8 mg of title compound. MS (rn/z) 519 [M+H . "Ή NMR (400 MHz, DMSO- ) δ 8.74 (<L IMh 7- 0 (dd, 3H), 7, 19 (dt, 4H), 6.84 - 6,65 (m, 2H)9 4.77 - 4,61 (m, 2H)S 4.45 (m, IH), 2.88 - 2.8 ! (m, IH), 2.64 (dd IH), 2.33 (m, 3H), 2, 15 (m, IH), 1.60 (m, 411).
Example 17
Figure imgf000075_0002
Synthesis of (S)-N-met¾vl-343-ni^
tetehydr - 1 H-indazol- 1 - l)acetamido)propana.m Ide (17) :
[ 1741 Compound 17 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)-2-((iert-butoxycarbonyl)amino)"3--(3~nitropheriyl}propanoie acid for .1 A to provide 7 mg of title compound. MS {m/z) 530 [M-i-B]+. !H NMR (400 MHz, DMSQ-£¼) δ 8,79 (d5 III), 8.01 (d, 1H), 7.64 (s, IH), 7.54 - 7.31 (m, 4H)S 7.23 (d, 3H)S 4.76 ·- 4.61 (m, 2.99 (s, IH), 2.87 - 2.73 (m, IH), 2.42 (d5 2H), 2.29 (ss IH), 2.14 (s, IH), 1.58 (m, 4H).
Figure imgf000076_0001
l.TI-Mdazol-l-vI)acetamido)propyl beiizamide (18):
[0175] Compoimd 18 was prepared accordmg io the meihod presented for the synthesis of Example 1 utilizing (S)-2-((teit-b«toxycarboiiyi)ammo)-3-{3-carbamoylphenyl)propanoic acid for ί A to provide I 1 mg of title compound. MS (m/s) S2B [M Hf . lU NMR (400 MHz, DMSO- >) 8 B.70 (4 IH), 7.78 (s, IH), 7.68 - 7.58 (m, IH% 7.47 - 7.17 (m, 6H), 7.1 1 (d, 2H), 6.87 {d, 1H)5 4.79 - 4,63 (m, 2H)S 2.96 - 2.87 (m, IH), 2.71 - 2.64 (m, IH), 2.42 (s, 2H), 2.32 (d, IH), 2.14 (4 IH), 1.60 (m, 4H).
Example 19
Figure imgf000076_0002
Synthesis of (S)~3~(3-faomophenyl)-N-fflgth^
tetrahydro- 1 H-lndazoS- 1 -yl)acetam ido)propa¾amidc (1 ) :
[0176] Compound 19 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)-3-(3-bromophenyl)~2~((iert-buioxycarbonyl)amHio)propanoic acid, for 1A to provide 5 nig of title compound. MS {nv'z) 563 [M+H , XU NMR (400 MHz, DMSO-ifc) δ 8.74 (d, IE), 7.50 - 7.29 (m, 4H), 7.21 (d, 2H), 7.11 (t, IH), 6.91 (s, IH), 6.78 (s, IH), 4,76 - 4.60 (m, 2H), 4.44 (s, I H), 2,85 (d, IH), 2.42 (¾ 3H), 2,16 (s, IH), 1.61 (m, Example 20
Figure imgf000077_0001
Synthesis of (S)~N-me†hyl-N-phenyl"3-(teto^
4¾5Jj etrahydro-lH ndazol"i-yl)acetariiid.o)propa?¾amide (20):
(0177] Compound 20 was prepared according to the method presented for die synthesis of Example 1 utilizing (S)-2"((tsrt"butoxycarbonyl)amtao)-3~{tetrahydro-2H~p>,ra.n-4-yl)propaiioic acid tor 1A to provide 30 mg of title compound, MS { z) 493 [M+Hf , {H NMR (400 MHz, DMSO- 0 S 8.54 (d, IH), 7.39 (dd, 4H), 4.76 (s5 2H), 4,49 - 4.37 (ra, 1H), 3.74 - 3,58 (m, IH), 3.53 (dd, I H), 3,12 (s, 3H), 2.95 (t, IH), 2,51 (t, 2H), 1.78 - L55 (m, 4I¾ 1.4S - 1.14 (m, 4H), 0.96 (d†5 2H), 0.41 (dd, IH).
Example 21
Figure imgf000077_0002
yl)acet¾mido -3-{3-{triiI oromethyI)p¾enyl propaii¾j¾ide (21):
[S178] Compound 21 was prepared according to the method presented for the synthesis of Example 1 utilizing (2S)-2-[{tert-butoxycarbony!)afnifio]-3-[3-
(trifluoroniethyl)phenyl]propanoic acid for 1A to provide 12 mg of title compound, MS (m/z)
553 [M+B]
Ex m ^!¾
Figure imgf000078_0001
tetrahydro- i fl-indazol- 1 -yl)acetamido)propan¾tnide (22) :
[M79] Compound 22 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)-2-{(ieri~bntoxycarhonyI)amino)-3-(thiopheu~3~yi)proparioic acid for 1A to provide 5 mg of title compound. MS 4 1 [M÷Ii Jf'<
Example 23
Figure imgf000078_0002
4,S,6J-tetra¾ydro- j H-indazol- 1 "yl)acetamido)propariamide..{23);
[§18θ] Compound 23 was prepared according to the method presented for the synthesis of Example I utilizing lA and substituting NI, l,N4-u-imethyibenzene-li4-diamine fo N- methylaniHr!e to provide 58 mg oftiilc compound. MS (m/z) 528 [M-Hf-lf . ¾H NMR (400 MHz, DMSG- .) δ §.72 - S.54 (m, 1H), 7,14 (d, 3H)S 6.96 (d, 2H , 6.82 (d, 2H), 6.69 (d, 2H)S 4.77 - 4.58 (m, 2H), 3.06 (s, 3H), 2.88 (s, 6H), 2,65 - 2.58 (m, 1H), 2.41 (d, 1H), 2.33 (d, 1H), 2.16 (s, IK), 1.73 - 1.55 (m, 5H).
Example 24
Figure imgf000079_0001
Synthesis of (S)-3-(3,5-difiaoropher3yl)-N-^
41S.6.? iTa¾.vdiO- 1 H-mda¾:o¾- 1 -yl)acctemido)propa amide (2§) :
0181] Compound 28 was prepared according to the method presented for the synthesis of Example 1 utilizing (S)-2-((tert-buioxycarbony!)amino)-3-(3,5-difliioropheriyi)propaiioie acid for 1A and substituting 4-fluorO"N~meihyIaniiirie for N-methylamline to pro vide 17 mg of title compound. MS (m/z) 551 [M+H]÷.
Figure imgf000080_0001
Figure imgf000080_0002
Figure imgf000080_0003
Synthesis of (S)-tert-buty¾ 3~(3,5~difluoraphcnyjj ~^
axgpropan-2-y iearbam ate (25B) :
[0182] The title compound was prepared according to the method presented for the synthesis of IB in Example 1 utilizing (S)-2-(ter -biitoxycarbonylammo)-3-(3i5-diiloorophenyl)propaiioic acid and 4-meihoxy-N-methyianIlme to provide title compound.
Synthesis of {S)-2-amino~3 3 "dii½orophenyjV^
(2SC):
[01.83] To a solution of 25E in DCM, TFA was added stirred for i ho . The solvent as removed and concentrated to dryness in vacuo. The material was used directly without further purification, MS ( /z) 321.0 [M+Hf. Synthesis of methyl 2~C0~methyl°3-C ¾orometh^
[£f 1S4] The title compound was prepared according to the method presented for the synthesis of31C in Example 31. utilizing 6-meihyi-3~(tTitluoromethyl)~4?5,6s7 ctrahydro~n-i--indazole (obiained via the method described in WG2G08/148832, which Is incorporated by reference) to provide title compound.
Synthesis of 2-{6-methyi-3-(tf ¾fluoromethyl)-4,5 J,?-tetrahydro- 1 H-indazol- 1 -yijacstio add (25F):
The title compound was prepared from 25E according to the method presented for the synthesis of 3!D in Example 31 to provide title compound.
Syndesis of (2S)-3-f3.5~difluorophew
(triffluoromethyl)- , 5 ,6,_7~tetra¾vdrO" 1 H-iadazpl- 1 - l)ace tanvido propanamid.e (25) :
[0186] The title compound was prepared according to the method presented for the synthesis of IC in Example 1 utilizing 2SC and 25F to provide title compound (87 mg), MS {>«/::} 565.2
[M+H]\
E yj5] 26
Figure imgf000081_0001
Synthesis of methyl 2~(7~methyi~3-CtrifiuQrofflgi^ [9187] The title compound was prepared according to the method presented for the synthesis of 31 C in Example 31 utilizing 7-methyl-3-(trifluoromeihyl)-4,556j etrahydro-l!i~inda2oie (obtained via the method described in. WO20G8/148832, which is mcorporated by reference) to provide title compound.
Synthesis of 2^7-metfavl-3-(triflu^^
(26C):
OiSS] The title compound was prepared from 26B according to the method presented for the synthesis of 3 ID in Example 31 to provide tide compound.
Synthesis of (2Sy3-(33"difluorppheny!)~N-^
Figure imgf000082_0001
[§1§9| The title compound was prepared according to the method presented for the synthesis of IC in Example I utilizing 2SC and 2 C to provide title compound (40 mg), MS (m/s) 565,2
Figure imgf000082_0002
r(4!H)-vI)¾eetate (27B):
[ 1 Θ] The title compound was prepared according to the method presented for the synthesis of 31C in Example 31 utilizing 3,~(iriiluoromethyl)-] , s4,,6's7, etrahydrospiro[[1.33diox.olane- 2}5'-iridazole] (obtained via the method described in WO200S/148832, which is incorporated by reference) to provide title compound, vDaeetic acid (27€):
[0191] The title compound was prepared from 27B according to the method presented for the synthesis of 311? i Example 31 to provide title compound.
Figure imgf000083_0001
firifluoramethyl)-4t5A7 etra^^
[01 2] The title compound was prepared according to the method presented for the synthesis of IC in Example 1 utilizing 2SC and 27C to provide title compound (12 mg). MS (m/¾) 608.7 [M+H]+.
Figure imgf000083_0002
SSSyyynnnttthhheeesssiiisss ooofff (((SSS)))---333---(((333,,,,,,555---dddfflfflffl ooorrroooppphhheeeaaayyyini)^-^N-{^
Figure imgf000083_0003
[[[000111999333]]] CCCooommmpppooouuunnnddd 222777DDD (((444000 mmmggg))) wwwaaasss dddiiissssssooolllvvveeeddd iiinnn 333 mmmLLL ooofff 555000%%% TTTFFFAAA /// CCC¾¾¾CCC111¾¾¾ tttooo iiittt wwwaaasss aaaddddddeeeddd 333000 uuuLLL ooofff wwwaaattteeerrr... AAAftftfteeerrr ssstttiiirrrrrriiinnnggg aaattt aaammmbbbiiieeennnttt ttteeemmmpppeeerrraaatttuuurrreee fffooorrr 333000 mmmiiinnnuuuttteeesss,,, iiittt wwwaaasss qqquuueeennnccchhheeeddd wwwiiittthhh sssaaatttuuurrraaattteeeddd aaaqqquuueeeooouuusss sssooodddiiiuuummm bbbiiicccaaarrrbbbooonnnaaattteee aaannnddd eeexxxtttrrraaacccttteeeddd wwwiiittthhh CCCHHH222CCCIII222--- TTThhheee ooorrrgggaaannniiiccc lllaaayyyeeerrr wwwaaasss ssseeepppaaarrraaattteeeddd,,, dddrrriiieeeddd ooovvveeerrr sssooodddiiiuuummm sssuuulllfffaaattteee aaannnddd cccooonnnccceeennntttrrraaattteeeddd... TTThhheee rrreeesssiiiddduuueee wwwaaasss pppuuurrriiifffiiieeeddd bbbyyy rrreeevvveeerrrssseee ppphhhaaassseee HHHPPPLLLCCC eeekklutttttmminggg wwwiiittt aaaccceeetttooonnniiitttrrrllleee /// wwwaaattteeerrr (((wwwiiittthhh 000...111%%% TTTFFFAAA))) tttooo aaaffffffooorrrddd 111555 mmmggg ooofff ttthhheee tttiiitttllleee cccooommmpppooouuunnnddd,,, MMMSSS (((mmm///zzz))) 555666555,,,000 [[[MMM+++HHH]]]+++,,,
Figure imgf000084_0001
tetrahydro- ί H-mdazol- 1 -yl)acet^Mo)-N 4-methoxypheayl)-N~meth (29) :
| 194| Compound 2§ (38 mg, 0.067 mmol) was dissolved In 0.5 ml, of TI 1F and cooled down to 0 °C, To It was added MeMgBr (3N in diethylether, 22 ί, 0.066 mmol) and stirred at 0 nC for two hours. MeMgBr (3N in diethylether, 22 ϊ ., 0.066 mmol) was added and the reaction mixture was allowed to stir at ambient temperature for overnight. More MeMgBr (3N in diethylether, 22 L, 0.066 mmol) was added mid stirred at ambient temperature for two hours. It was quenched with water at 0 °C and extracted with EtOAc. The organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified by reverse phase 1 FPLC ©luting with acetonitrile / water (with 0,1% TFA) to afford 13 rag of fee title compound. MS
Figure imgf000084_0002
Example 30
Figure imgf000085_0001
Figure imgf000085_0002
Synthesis of S'i-tgn-butvl 1 "{(4-ch.lorophenyl)(methy1)amtno)-3 -(3,5 -difluorophen vD- 1 - QXOpropan"2-yfc¾rfaama†e (30 ):
[01 51 The title compound was prepared according to the method presented for the synthesis of IB in Example 1 utilizing {S)-2-(tert-butoxycarboi¾ylamino)-3-(3 ~difluorophenyi)propaiioic acid and 4-chloro-N-methyiaaiiise io provide title compound.
Synthesis of (S)-2-amingj K4"Chto
[01961 The title compound was prepared from SOB according to the method presented for the synthesis of 2SC in Example 25 to provide title compound. MS (m/z) 325, 1 [M+H]+.
Figure imgf000085_0003
hexahydro- 1 H-indazol- 1 -yl)acetamido jpropanamide (3( ).:
[0197] The title compound was prepared according to the method presented for the synthesis of IC in Example .1 utilizing 30C and 2-(3-oxo-2,3,4>5,657~hexahydro-lH-indazol- yl)acetic acid (30D) to provide title compound (25 mg). MS (m/z) 503.4 [M+H]+,
Example 31 UOH, THF EGH/H20
Figure imgf000086_0001
31A 318
Figure imgf000086_0002
31 D
31
[0198J To a solution of 4,5,6,7-tetrahydro- i H~mdazo)e (488 mg, 4.0 mmol) in DMF (5 mL) was slowly added potassium carbonate (1.1 g, 8,0 mmol) and methyl 2-bromoacetate (765 mg, 5,0 mmol) at room temperature. The reaction mixture was stirred at room temperature for i h and was then poured into ethyl acetate (150 mL) and washed with 5% LiCl solution. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title product (800 mg crude, used in the next ste without further purification). MS (m/z): 195.0 [M+If ';
HPLC retention time 2.69 min (2-98% aeetonitrile: water with 0,05% trifluoroacetic acid).
Synthesis of 4-bromo-5-gthyS-3-(trifluoromej¾vl)-lii-pyrazole (3.1D):
|0199] To a solution of methyl 2-{4,5?6J7~tetrahydro-lH-indazol-l"yl)acetate (31C) (800 nig crude, 4.0 mmol) in a mixture of THF (10 mL), MeOH (1 mL) and I¾0 (1 mL) was added lithium chloride monohydrate (840 mg, 20 mmol). The reaction mixture was stirred at room temperature for 5 min and was then poured into ethyl acetate and washed with saturated NH4CI solution and brine. The organi layer was dried over sodium sulfate, filtered and concentrated. The crude product was used in the next step without further purification, MS (m/z): 181.3
[M-rl-i '; HPLC retention time 2.16 min (2-98% aeetonitrile: water with 0,05% trifluoroacetic acid).
£vnt ej^^^
tetrahydf o- 1 H-indazpl - 1 ~yl)acetanr ido)propanamide (31): Θ200] The title compound was prepared according to the method presented for the synthesis of Example! utilizing 31B and (S)-2-amino-3-(3i5^ifi oropheiiyl)-N-(4~meihoxypheayi)~N- metfoylpropanamide to provide (S)-3-(3,5-ditluoropheEyi)-N-(4-inetlioxypher!yl)-N-meihyl"2- (2-(4!5s6 etTahydro-lH~indazoi-l-yi)acetamido)propanamide: MS (m/z): 483.0 [M+H ; HPLC retention time 2.15 min (2-98% acetonitrile: water with 0,05% iritluoroacetic acid). !H NMR (400 MHz, cd3cS) δ 7.69 (d J - 8.0 Hz, 1H), 7.30 (s, 1H), 6.89 (s, 4H), 6,64 (t, J = 8.8 Hz, IH), 6,37 (d5 J - 6.4 Hz, 2H), 4,96 (s, 2H), 4.74 (q, J - 7.6 Hz, 1H), 3.83 (s, 3H)S 3.21 (s, 1H), 2.89 - 2.84 (m, 1 H), 2.76 - 2.69 (m5 3H), 2,56 - 2.53 (m, 2Ή), L86 - 1.76 (m, 4H).
Example 32
Figure imgf000087_0001
Synthesis ot7S)-2"{2~CS~ammo-3-methyl-2.6 iiQXO^
N~{4 hIorophenyj)~3-C3,5"difl TO^ (32):
[0201] The title compound was prepared according to the method presented for the synthesis of IC in Example 1 utilizing 30C and 2~(8-amko-3-meifayl~2s6-dioxo-2s3-dihydro-l H-puriii- 7(6H)-yl)acetie acid to provide title compound (1.2 mg). MS (?«/z) 545.9 [M+H]+.
Example 33
Figure imgf000087_0002
Synthesis of iS ;-N-f -chiofpphenyu~3-(3.3~d!f! oroph^
benzo d] 13]digxi^ [0202] The title compound was prepared according to the method presented for the synthesis of 1C in Example 1 utilizing 3¾ C and
Figure imgf000088_0001
acid to provide title compound (5 rag). MS (m/z) 518.8 M+H]÷.
Figure imgf000088_0002
Figure imgf000088_0003
3 0 34£
Synthesis of 6-(i¾eth km no)iso¾ndolk" ¾ -one .(34B):
[02Θ3] 6-bromoisoindolin~ 1 -one (1050 mg, 5.0 rnmol), copper powder (32 mg, 0,5 mmol) and methylarnme (40% in ¾0, 2.7 mL) were placed in a pressure vessel and the sealed reaction was heated at 105 °C overnight. The reaction mixture was poured into ethyl acetate (150 mL) and washed with saturated NH CI solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The volatile was removed in vacuo and the residue was then purified by silica gel chromatography elating with MeOH and dichloromethane (Rf ~ 0,2, 5% MeOI ! in DCM) to afford 300 rag of the title compound. MS (m z); 163.13 [M+H]+; HPLC retention time 0,1? mm (2-98% acetonitri!e: water with 0.05% trifluoroacetic acid). lli NMR (400 MHz, dmso) δ 8.28 (ss I B), 7.20 (d, J~ 8.2 Hz, IH% 6.75 (dd, J~ 8.2, 2.2 Hz, 1H)5 6,68 (d, J= 2.1 Hz, 1H), 5.83 (d, J- 5.0 H¾ 1H), 4.15 (s, 211% 2,66 (d, J~ 5,1 H¾ 3H). Synthesis of (S)-tert-butyi (3-f 3 J-difl uor ophenyi)- 1 · (methyl/ 1 "0¾ soffidolm~5~yl¼mino ° 1 - oxopropa¾-2~vr¾carbamate (34C):
[0204] The title compound was prepared according to the method presented for the synthesis of IB in Example 1 utilizing 34 and (S)~2~(Ctert-butoxycarbony ammo)~3~(3sS- difiuorophenyl)propanoic acid to provide (S)-tert-butyl (3-(3,S~difSuorophenyl)~l-(methyi(l- oxoisoindolin~5-y1)amino)-l-oxopropan--2~yl)carbamate: MS (m/z): 445,99 [M+H]+; HPLC retention time 1.17 min (2-98% acetonitnie: water with. 0.05% tflffuoroacetie acid).
Synthesis of (2S)-2-(2-{5,5-dii1uoro~3-{trifluoromethyg)~3b«4,4a^-teirahydfQ--lI-I- cyeiopropa[3 ,4 jeyclopentaj' 1 ,2-c] pyrazoj - 1 ~yl¼cetamido)-3 -(3 , 5-difluorophenyl)-N-methy 1-N- (1 -oxoisomdolin-S-yDpropanamide (34D):
[0205J To (S)-tert-butyl (3 ~(3 ,5 -di fluorophenyl)- 1 -(methy 1( 1 -oxoi soindolin-S -yl)amino)- 1 - oxoprGpan-2-yl)carbatnate in DCM was added 4N HQ in dioxanes. The reaction was stirred at ambient temperature until full conversion was observed by LCMS. Removal of solvents provided the title product which was used without further purification; MS (m/z): 346.32
Synthesis of (2S)-2-(2-{5 -difluoro-3-{ fl ^^
cyclopropa[3,4|cyoiopea i,2^jpyraz:o{-l-yl)aceiam
fl-oxoisoindoh°n~5-yl)propanamide (34):
[0206] The title compound was prepared according to the method presented for the synthesis of Example 1 utilizing 34B and 2-(555~difiuoro-3-(trifliioromethy1)~3b54f4a,5 etrahydro-lFi- eyclopropa[3,4]cyelopenta[L2-c]pyrazol-l-yl)aeetie acid to provide (2S)-2-(2-(5.S-difluoro-3- (trifi oromethy -Sb^^ajS-ieirahydro- 1 H-cyclopropa[3,4]cyelopenta[ 1 s2-c]pyrazoi- 1 - yl)aceiamido}-3-i3,5-difluorophenyl)~M^ as a mixture of diastereomers; MS (m/z): 610.31 [M+H]+: HPLC retention time 1,30 min (2-98% acetonitrile: water with 0.05% trifluoroaceiie acid).
Example 35
Test A: Antiviral assay in MT4 Cells
[0207] For the antiviral assay, 40 ΐ, of a concentration required to achieve a final effective I test concentration of 3 -fold serially diluted compound in culture medium with 10% FBS was added to each well of a 384~well plate (10 concentrations) i quadruplicate, MT~4 cells were next mixed with HIV-IIIb at an m.o.i of 0.003 for 1 hour, after which time 35 nL of virus/cell mixture (2000 cells) was Immediately added to each well containing 40 Τ of diluted compound. The plates were then incubated at 37CC for 5 days. After 5 days of incubation, 25 μί of 2X concentrated CellTiter-Glo Reagent (catalog # G7571, Promega Biosciences, fee,, Madison, WI) was added to each well containing MT~4 cells. Cell lysis was carried out by incubating at room temperature for 10 mm and then chemilummescence was read. EC 50 valises were c lculated as the compound concentration that caused a 50% decrease in luminescence signal, a meas re of HXV-1 replication. Percent inhibition of virus-induced cell killing calculated from the dose response curve at 2 μΜ drug concentration is shown in the table below,
Test B: Cytotoxicity assay
(Q2QS] Compound cytotoxicity and the corresponding CC50 values was determined using the same protocol as described in the antiviral assay (Test A.) except that uninfected cells were used. [Θ269) Compounds of the present invention demonstrate antiviral activity (Test A) as depicted in the table below. Shown below are the corresponding values for CCS0 and percent inhibition of vims-induced cell killing fa the presence of 2 μΜ drag concentration. In the table, percent inhibition values have been normalized to 100% where the calculation of percent inhibition would have resulted in a value greater iban 100,
Figure imgf000090_0001
ϋ 21 >530O0
12 10 >53000
13 87 22205.4
14 16 28975.4
15 26 26322.9
16 58 16730.7
17 0 19170.1
18 0 >53000
19 27 17287
20 0 >53000
21 0 11317 tf 94 25007,9
23 100 19226.1
24 93 12172.3
25 100 11124.3
26 100 9823.1
27 32 19929.9
28 76 37230.5
29 82 32072.2
30 100 22247.5
31 78 >53000
32 39 >53000
33 34 18390.2
34 97 >53000 [CI210] In one embodiment the compounds demonstrate >10% inhibition at 2 μΜ. In one embodiment, the compounds demonstrate >30% inhibition at 2 μΜ, In one embodiment, the compounds demonstrate >50% inhibition at 2 μΜ In one embodiment, the compoimds demonstrate >70% inhibition at 2 μΜ, In one embodiment, the compounds demonstrate >75% inhibition at 2 μΜ, In one embodiment, the compounds demonstrate >S0% inhibi tion at 2 μΜ. In one embodiment, the compounds demonstrate >85% inhibition at 2 μΜ. ϊη one embodiment, the compounds demonstrate >90% inhibition at 2 μΜ. In one embodiment, the compounds demonstrate >95% inhibition at 2 uM. It is to be understood that the compounds disclosed herein cars be grouped according to their % inhibition as described above,
[0211] In one variation, a compound is of any formulae provided herein, wherein the compound exhibits from 85%~IGQ% inhibition of virus-induced cell killing at 2 μΜ. In other embodiments, a compound is of any formulae provided herein wherein the compound exhibits from 50-100, 60-100, 70-100, 80-100, or 90-100% inhibition of virus-induced cell killing at 2 μΜ.
[0212] It Is understood that % Inhibition may be evaluated by techniques known in the art. In a particular variation, a compound is of any formulae provided herein wherein the compound exhibits from 85%~iO0% Inhibition of virus-induced cell killing at 2 μΜ as measured by the method provided in the Test A and Test B sections discussed above.
[0213] The specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present
pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present invention.
[02141 T¾e Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It Is to be understood that Individual steps described herein may be combined. It is also to be understood tbat separate hatches of a compound may be combined and then carried forth in the next synthetic step,
[0215] All references, Including publications., patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques.
However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

I , A compound of Formula I:
Figure imgf000093_0001
I
wherein:
ring A, including the two carbon atoms to which it is fused to ring B, Is a 5-6 membered monocyclic heteroaryi or phenyl, wherein any 5-6 membered hetetoaryl or phenyl of A is optionally substituted with 1, 2, or 3 Z3 groups, wherein the 7.) groups are the s me or different; ring B, including the two carbon atoms to which it is fused to ring A, is a 5-7 membered monocyclic carbocycie, 6-10 membered bicyclic carbocycie, 5-7 membered monocyclic heteroeycle, or 6- 10 membered bicyclic heteroeycle, wherein any 5-7 membered monocyclic carbocycie , 6-10 membered bicyclic carbocycie, 5-7 membered monocyclic heteroeycle, or 6-10 bicyclic heteroeycle of B is optionally substituted with 1, 2, 3, 4 or 5 Z2 groups, wherein the Z2 groups are the same or different;
X ts C or 'N;
or the moiety
Figure imgf000093_0002
wherein B is as defined above;
R is phenyl, 5-6 membered monocyclic heteroaryi 5-6-membered monocyclic heteroeycle, 9-10 membered bicyclic heteroeycle, or 3-7 membered carbocycie, wherein any phenyl, 5-6 membered monocyclic heteroaryi, 5-6-membered monocyclic heteroeycle, 9-10 membered bicyclic heteroeycle, or 3-7 membered carbocycie of R5 is optionally substituted with 1, 2, 3S 4 or 5 Z3 groups, wherein the Z3 groups are the same or different; or R1 is
benzothiofiiranyl, in which any of the rings are optionally substituted with 1, 2, or 3 Z3 groups;
R2 is (€r€s)alkyl or 3-7 membered carbocycie, wherein aay (Cj-Cejalkyl of R2 is optionally substituted with 1, 2, 3S 4 or 5 halo groups, which may be same or different; R" is phenyl, 9-10 membered bicycilc aryl, 5-7 membered monocyclic heterocycle, or 8- 1 0 membered bicydic heterocyde, wherein any phenyl, 9-10 membered bicycilc aryl, 5-7 membered monocyclic heterocycle, or 8-10 membered bicycilc heterocycle of R3 is optionally subst ituted with 1, 2, 3, 4 or 5 Z4 groups, wherein the Z4 groups are the same or different;
R4 Is H or (CrCs)alkyl optionally substituted with 1 , 2, 3, 4 or 5 halo groups, which may be same or different;
each Z1 Is independently (Cj-C¾aikyl, (C2-C6)alkenyl, (C2-Q)alkynyl, 3-7 membered carbocycie, halo, -CN, -OR"', -OC(0)Rp5, -OC(0)NRq,Rrl, -SRn!, ~S(0)Rp\ -S(0)2OH5 ~S(0)2RPI, -S(0)2m.qlR! -NRq3Rrl, - RniCORpi, -MlKIC<¾RP!, -NRalCONR,tRri,
Figure imgf000094_0001
-C(0)()R"', or
-C(0) R5¾D S wherein my 3-7 membered carbocycie of Z1 is optionally substitated with 1, 2, 3, 4 or 5 halo groups or (Cj-C<s)alky1, which may be same or different and wherein any (Cr C6)alkyl, (C6-C6)aikenyl and (C2-C6)a!kynyi of Z3 is optionally substitated with L 2, 3, 4 or 5 halo groups, which may be same or different;
each Rni is independently H or {C C6)alkyl;
each RP ! is independently (Ci-Cg)alkyl;
each R'1' and Rri is independently H or (Ci-C6)alkyl;
each Z2 is independently (C CgJalk l halo, oxo, or »ORn2 s wherein any 3-7 membered carbocycie of Z2 is optionally substituted with 1, 2, 3, 4 or 5 {C'rCg)alkyl or halo groups, which may be same or different, and wherein any (CrCg)alkyl of Z2 is optionally substituted with 1, 2, 3, 4 or 5 halo grotsps, which may be same or different;
each Ril2 is independently H, iC Qa!kyl (C C3)haloaikyt or (C3-C7)carbocycle;
each 7? is Independently (Ci-C^lk l, halo, -CN, -OR"3, Νί¾, or -C(0)NRq3Rr J wherein any (CrCg)alkyl of Z3 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each R"3 is independently B, (C C3)alkyI, (Cs~C3)ha1oa!ky!, or {C3~€¾)eathocycle;
each R 3 and R'5 is independently H or (Ci-C6)alkyl;
each Z* is independently (CrC6)alk 'ls
Figure imgf000094_0002
{C2-C6)alkynyl, {C.rC7)carbocyclei halo, oxo, -CN, -ORk4,
Figure imgf000094_0003
-SR"4, -SCGJR*4, ~S(0)2OH, -S(0)2Rp4 s -S(0)> Rq4Rr 5
Figure imgf000094_0004
-NR"4S(0)2RI>4,
Figure imgf000094_0005
NO& ~C(0)Rfl 5 ·€(0)ΟΚΓ·Λ, or ~C(0)NRq4Kr4, wherein any (CrC^tearbocycte, of Z; is optionally substitated with 1, 2, 3, 4 or 5 halo groups or (Cr Cft)a!Ky and wherein any (Ci -Ce m!k l, {€rCs)alkenyi and (€r€.'.ja!kyo>1 of Z4 is optionally substituted with 1, 2, 3, 4 or 5 halo groups, which may be same or different;
each Rn'" is Independently H or (Ci-C^'dlkyl;
each R≠ is (C €s)alkyl; and
each Rq4 and Rr4 is independently H or (C;~Cf>)alkyi;
or a pharmaceutically acceptable salt thereof.
2, The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is H,
3. The compound of claim ! or 2, or a pharmaceutically acceptable salt, thereof, wherein the compound of Formula I is a compound of Formula la:
Figure imgf000095_0001
la
4, The compound of any one of claims I~3S or a pharmaceutically acceptable salt thereof, wherein the 5-6 membered heteroaryl of A comprises 1-2 annular nitrogen atoms and 3- 4 annular carbon atoms,
5, The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered heteroaryl of A comprises 1-2 n itrogen atoms and 3-4 carbon atoms in the ring, and wherein any 5-6 membered heteroaryl of A is optionally substituted with lor 2 Zl groups.
6, The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring A, including the two carbon atoms to which it is fused to ring B, is a 5-6 membered monocyclic heteroaryl, wherein the 5-6 membered heteroaryl of A comprises 1-2 annular nitrogen atoms and 3-4 annular carbon atoms in the ring, and wherein any 5-6 membered heteroaryl of A is optionally substituted with I or 2 Z3 groups; and
X is N, The compound of any one of claims 1-3, or a pharmaceutically acceptable
thereof, wh
Figure imgf000096_0001
wherek:
Y is CZ'Or N;
Z is CZle or N; ;
each Zis is independently H or Z5.
8. The compound of any one of claims 1-3, or a pharmaceuticall acceptable
thereof, wh
Figure imgf000096_0002
wherein each Z;a is independently H or l} .
9, The compound of any one of claims 1 -3, or a pharmaceutically acceptable salt
thereof, wherein the
Figure imgf000096_0003
,
wherein each Z1a is independently H or Z\
10. The compound of claim 1, or a phammceuticaliy acceptable saii thereof, wherein the compound of Formula I is a compound of Formula lb:
Figure imgf000097_0001
lb
wherein Zia is H or Z¾„
11 , The compound of any one of claims .1 -10, or a pharmaceutically acceptable salt thereof! wherein each ?} is independently (Ci-C^alkyl, halo, -OH, or -NRqlRrl } wherein any (C\~ Ce)alkyl of Z1 Is optionally substituted with I, 2, or 3 halo groups.
1.2. The compound of any one of claims ! -10, or a pharmaceutically acceptable salt thereof, wherem each Z1 is independently -CF3, halo, -OH, or -Nl¾.
13. The compound of any one of claims 1 -11, or a pharmaceutically acceptable salt thereof, wherein 7/ is H, CF¾ or OH,
14. The ceptable salt
thereof wherein th
Figure imgf000097_0002
15. The compound of any one of claims .1-14, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-7 membered monocyclic carbocycle, or 6-10 membered bicyciic carbocycle, wherein any 5-7 membered monocyclic carbocycle or 6-10 membered bicyciic carbocycle of B is optionally substituted with 1, 2, or 3 Z2 groups.
16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherem ring B is a 6-7 membered monocyclic carbocycle, or 6 membered bicyciic carbocycle, wherem any 6-7 membered monocyclic carbocycle or 6 membered bicyciic carbocycle of B is optionally substituted with 1 , 2, or 3 Z2 groups,
17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6-1.0 membered bicyciic carbocycle, or 6-10 membered bicyciic heteroeycle, wherein any 6-10 membered bicyciic carbocycle or 6-10 bicyciic heterocycle of B is optionally substituted with 1, 2, or 3 Z2 groups.
1.8. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherem ring B is a 6-10 membered fokyclic carbocyele, wherein any 6-10 membere MeycMc carbocyde of B is optionally substituted with 1, 2, or 3 Z2 groups.
19. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein ring B is a 6-7 membered bkyeile carbocyele, wherein any 6-7 membered bicyclic earhocycie is optionally substituted with 1 or 2 Z2 groups.
20. The compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein ring B is bicyclo[3.1 ,0]hex~2-ene, wherein bicyclo[3, 1.0]hex-2~ene is optionally substituted with .1 , 2 or 3 Z2 groups.
21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein each Z2 is independently (CrCs)alkyl, halo, or -OR^, wherein any (CVQjaik l of Z2 Is optionally substituted with 1, 2, or 3 halo groups.
22. The compound of any one of claims 1 -20, or a pharmaceutically acceptable salt thereof wherein each Z2 is independently methyl, fluoro, oxo, or OH.
23. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein each Z2 is independently methyl, fluoro, or OI L
24. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt
thereof, wherein th
Figure imgf000098_0001
wherein Z5a is independently H or Z1; and each Z2a is Independently H or Z2.
25. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt
thereof, wherein the
Figure imgf000098_0002
IS
Figure imgf000099_0001
26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R! is phenyl or 5-6 membered monocyclic heteroaryi, wherein any phenyl or 5~ 6 membered monocyclic heteroaryi of R1 Is optionally substituted with 1 or 2 / ' ? groups.
27. The compound of any one of claims 1-25, or a pharmaceutical ly acceptable salt thereof, wherein RE is phenyl, wherein the phenyl is optionally substituted with I or 2 7? groups.
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein each Z3 is independemly (CrQ)alkyL halo, ~CN, - NO¾ or -C(0) Rq3Rr3, wherein any (CrQ,)alkyl of Z3 is optionally substituted with 1, 2, or 3 halo groups.
29. The compound of any one of claims 1 -27, or a pharmaceutically acceptable salt thereof! wherein each Z3 is independently methyl, iluoro, bronio, chloro, CN, N€½, ~C(0)N¾, or -CP;.
30. The compound of any one of claims 1 -27, or a pharmaceutically acceptable salt thereof, wherein each 2'' is iluoro,
31. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein ' is:
Figure imgf000100_0001
32. The compound of any ne of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R~ is (d-CgJalkyl.
33 , The compound of any one of claim s 1 -31, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl.
34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl, 9-10 membered hlcyclic aryl, or 8-10 membered bicyclic heterocyeie, wherein any phenyl, 9-10 membered bicyclic aryl or 8-10 membered bicyclic heterocyeie of RJ is optionally substituted with 1 Z4 group.
35. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof wherein K ' is phenyl or 9-10 membered bicyclic aryl, wherein any phenyl or 9-10 membered bicyclic aryl of XT is optionally substituted with 1 Z4 group.
36. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R.J is phenyl, naphthyl or isoindolin-I-one, wherein any phenyl, naphthyl,, or isoindoiin-l-one of R4 is optionally substituted with 1 Z4 group.
37. The compound of any one of claims 1 -36, or a pharmaceutically acceptable salt thereof, wherein each Z4 is independently (CrQ alkyl, halo, ~CN, -ORr, 5 -NR 4Rrt, or oxo, wherein any (C 3 -Chalk ! of 24 is optionally substituted with 1, 2, or 3 halo groups.
38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein each Z4 is independently {CrQs)alkyls halo, -C . -0(CrQ)alkyl, -N((C-S- Cejalkyl)^, or oxo,
39. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein each Z4 is independently methyl, -OC¾ iluoro, chloro, -NCCH;?)?, or oxo.
40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherei 5 is:
Figure imgf000101_0001
41. . The compound of claim ls or a pharmaceutically acceptable sail thereof, which is
Figure imgf000101_0002
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
104
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
42, The compound of claim I, or a pharmaceutically acceptable salt thereof, which is;
Figure imgf000107_0002
Figure imgf000108_0001
Figure imgf000109_0001
110
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
43. A pharmaceutical composition comprising a compound of Formula I of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising a compound as described in any one of claims 1-42, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non- nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse
transcriptase, an HiV nucleotide inhibitor of reverse transcriptase, m HIV integrase inhibitor, a gp41 Inhibitor, a CXCR4 inhibitor, a gp!20 inhibitor, a CCRS inhibitor, a capsid polymerization inhibitor, or a non-catalytic site site HIV integrase inhibitor and combinations thereof.
45. A method for treating an HIV infection in a patient in need thereof comprising administering a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, to the patient.
46. A method for treating an HiV infection in a patient in need thereof comprising administering to the patient in need thereof a therapeutical ly effective amount of a compound of Formula Ϊ of any one of claim s 1 -42, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an additional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucieoside Inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp 1 inhibitor, a CXCR4 inhibitor, a gp!20 inhibitor, a CCRS inhibitor, a capsid polymerization Inhibitor, or a non-catalytic site HIV Integrase site inhibitor and combinations thereof.
47. A compound of Formula [ of any of claims 1 -42, or a pharmaceutically acceptable salt thereof, for use in medical therapy,
48. A compound of Formula I of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for the therapeutic treatment of an HIV infection,
49. T he use of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HIV virus infection in a patient.
50. A compound or method as described herein,
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