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WO2024130065A1 - Substituted dihydropyrrolo[3, 4-d]pyrimidine compounds and their use in treating medical conditions - Google Patents

Substituted dihydropyrrolo[3, 4-d]pyrimidine compounds and their use in treating medical conditions Download PDF

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Publication number
WO2024130065A1
WO2024130065A1 PCT/US2023/084189 US2023084189W WO2024130065A1 WO 2024130065 A1 WO2024130065 A1 WO 2024130065A1 US 2023084189 W US2023084189 W US 2023084189W WO 2024130065 A1 WO2024130065 A1 WO 2024130065A1
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Prior art keywords
compound
certain embodiments
cycloalkyl
alkyl
acetylcholine receptor
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PCT/US2023/084189
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French (fr)
Inventor
Kevin Matthew Gardinier
James Edmund Audia
James Monn
Jason Myers
Nadia M. Ahmad
Emanuela Gancia
Elizabeth Anne Skidmore
Niall WAGSTAFF
David G. Evans
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Karuna Therapeutics Inc
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Karuna Therapeutics Inc
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Priority to KR1020257023756A priority Critical patent/KR20250133677A/en
Priority to EP23904645.1A priority patent/EP4634193A1/en
Priority to CN202380093133.5A priority patent/CN120641420A/en
Publication of WO2024130065A1 publication Critical patent/WO2024130065A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed 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
    • A61K31/495—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • Muscarinic acetylcholine receptor mediated disorders such as major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia are psychiatric disorders that continue to be a significant public health problem.
  • Antidepressant drugs, mood stabilizers, and antipsychotics currently available to patients can alleviate certain symptoms of mood disorders in some patients but are only partially effective for a significant number of patients, with many patients being refractory to treatment using currently available drugs.
  • Patients with major depressive disorder often present with at least two weeks of pervasive low mood, low self- esteem, and loss of interest or pleasure in normally enjoyable activities.
  • Patients with bipolar disorder often present with periods of depression and periods of abnormally elevated mood that last from days to weeks each.
  • muscarinic acetylcholine receptor can be used to treat diseases associated with muscarinic acetylcholine receptor activity, such as major depressive disorder, bipolar disorder, and schizophrenia.
  • the muscarinic acetylcholine receptor is an acetylcholine receptor that forms G protein-coupled receptor complexes in the cell membrane of certain neurons and other cells.
  • U.S. Patent 10,604,519 describes certain compounds as being active towards the M4 muscarinic acetylcholine receptor. However, new compounds
  • one aspect of the invention provides a collection of substituted dihydropyrrolo-pyrimidine compounds, such as a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of substituted dihydropyrrolo- pyrimidine compounds are described in the detailed description.
  • the compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides a method of treating a muscarinic acetylcholine receptor mediated disorder.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat muscarinic acetylcholine receptor mediated disorder, as further described in the detailed description.
  • a compound described herein such as a compound of Formula I
  • Another aspect of the invention provides a method of activating a muscarinic acetylcholine receptor.
  • the method comprises contacting a muscarinic acetylcholine receptor with an effective amount of a compound described herein, such as a compound of Formula I, to activate the muscarinic acetylcholine receptor, as further described in the detailed description.
  • DETAILED DESCRIPTION [0009]
  • the invention provides substituted dihydropyrrolo-pyrimidine compounds, pharmaceutical compositions, and their use in treating muscarinic acetylcholine receptor
  • alkyl applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms.
  • aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some
  • cycloaliphatic refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bicyclic ring or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom.
  • a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally, or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bridged bicyclics include: .
  • the term “lower alkyl” refers to a C 1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • the term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • phenylene refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
  • a heteroaryl group may be mono– or bicyclic.
  • the term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl
  • heteroarylene refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it. For example, “heteroarylene” is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4– dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • oxo-heterocyclyl refers to a heterocyclyl substituted by one or more oxo group.
  • heterocyclylene refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it.
  • oxo-heterocyclylene refers to a multivalent oxo- heterocyclyl group having the appropriate number of open valences to account for groups attached to it.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • the term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Each R ⁇ is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- 6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,
  • R ⁇ is optionally substituted with a monovalent substituent independently selected from halogen, –(CH2)0–2R ⁇ , –(haloR ⁇ ), –(CH2)0–2OH, –(CH2)0–2OR ⁇ , – (CH 2 ) 0–2 CH(OR ⁇ ) 2 ; -O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R ⁇ , –
  • R * is C 1–6 aliphatic
  • R * is optionally substituted with halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or –NO2, wherein each R ⁇ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • each R ⁇ is independently hydrogen, C1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when
  • R ⁇ is C 1–6 aliphatic, R ⁇ is optionally substituted with halogen, –R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , – O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or –NO2, wherein each R ⁇ is independently selected from C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the invention includes compounds that differ only in the presence of one or more isotopically enriched atoms.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C 1 -C 10 alkyl, and C 1 -C 6 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
  • cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C 3 -C 6 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl.
  • cycloalkylene refers to a bivalent cycloalkyl group.
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen.
  • exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like.
  • haloalkylene refers to a bivalent haloalkyl group.
  • hydroxyalkyl refers to an alkyl group that is substituted with at least one hydroxyl.
  • Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • haloalkoxyl refers to an alkoxyl group that is substituted with at least one halogen.
  • Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.
  • a cyclopentane susbstituted with an oxo group is cyclopentanone.
  • the symbol “ ” indicates a point of attachment.
  • any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • Solidvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H 2 O. [0054] As used herein, the terms “subject” and “patient” are used interchangeable and refer to organisms to be treated by the methods of the present invention.
  • Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
  • the term “EC 50 ” is art-recognized and refers to the concentration of a compound that is required to achieve 50% of the maximal response.
  • the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term “treating” includes any effect, e.g., lessening,
  • the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed.
  • Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts.
  • Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • an amount of acid or base such as an equivalent amount
  • a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Substituted dihydropyrrolo-pyrimidine compounds [0063] One aspect of the invention provides substituted dihydropyrrolo-pyrimidine compounds.
  • the compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds.
  • R 1 is C 1-4 alkoxyl, -N(R 4 ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -O-(C 3-6 cycloalkyl), or -(C1-6 alkylene)-(C3-6 cycloalkyl);
  • R 2 is cyano, C1-4 alkyl, C1-4 haloalkyl, or hydrogen;
  • R 3 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or halo;
  • R 4 represents independently for each occurrence hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R 4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing
  • variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0066] In certain embodiments, the compound is a compound of Formula I.
  • R 1 is C1-4 alkoxyl, -N(R 4 )2, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 1 is C1-4 alkoxyl, -N(R 4 )2, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl).
  • R 1 is -N(R 4 )2, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 1 is C 1-4 alkoxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 1 is C1-4 alkoxyl, -N(R 4 )2, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 1 is C 1-4 alkoxyl, -N(R 4 ) 2 , C 1-6 alkyl, C 3-6 cycloalkyl, or -(C 1-6 alkylene)- (C 3-6 cycloalkyl).
  • R 1 is C 1-4 alkoxyl, -N(R 4 ) 2 , C 1-6 alkyl, C 1-6 haloalkyl,or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 1 is C1-4 alkoxyl, - N(R 4 ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In certain embodiments, R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 1 is -N(R 4 )2, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 1 -N(R 4 )2, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 1 is -N(R 4 ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 1 is -N(R 4 ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In certain embodiments, R 1 is C1-4 alkoxyl, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)- (C 3-6 cycloalkyl). In certain embodiments, R 1 is C 1-4 alkoxyl, C 1-6 alkyl, C 3-6 cycloalkyl, or -(C 1- 6 alkylene)-(C 3-6 cycloalkyl).
  • R 1 is C 1-4 alkoxyl, C 1-6 alkyl, C 1-6 haloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 1 is C1-4 alkoxyl, C1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl. In certain embodiments, R 1 is C 1-4 alkoxyl, -N(R 4 ) 2 , C 3- 6 cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 1 is C 1-4 alkoxyl, - N(R 4 )2, C1-6 haloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 1 is C1-4 alkoxyl, -N(R 4 )2, C1-6 haloalkyl, or C3-6 cycloalkyl. In certain embodiments, R 1 is C1-4 alkoxyl, - N(R 4 ) 2 , C 1-6 alkyl, or -(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 1 is C 1-4 alkoxyl, -N(R 4 ) 2 , C 1-6 alkyl, or C 3-6 cycloalkyl. In certain embodiments, R 1 is C 1-4 alkoxyl, - N(R 4 )2, C1-6 alkyl, or C1-6 haloalkyl. In certain embodiments, R 1 is -N(R 4 )2 or -O-(C3-6 cycloalkyl).
  • R 1 is C 1-4 alkoxyl. In certain embodiments, R 1 is C 1-4 alkoxyl. In certain embodiments, R 1 is C1-3 alkoxyl. In certain embodiments, R 1 is C2-4 alkoxyl. In certain embodiments, R 1 is C 3-4 alkoxyl. In certain embodiments, R 1 is -OCH 3 , - OCH 2 CH 3 , -OCH(CH 3 ) 2 , or -OC(CH 3 ) 3 . In certain embodiments, R 1 is -OCH 3 . In certain embodiments, R 1 is -OCH2CH3. In certain embodiments R 1 is -OCH(CH3)2.
  • R 1 is -OC(CH3)3.
  • R 1 is -N(R 4 ) 2 .
  • R 1 is -N(R 4 ) 2 , wherein R 4 represents independently for each occurrence hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R 4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom.
  • R 1 is -N(R 4 ) 2 , wherein R 4 represents independently for each occurrence C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R 4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom.
  • R 1 is -N(R 4 )2, wherein two occurrences of R 4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom.
  • R 1 is -N(R 4 ) 2 , wherein R 4 represents independently for each occurrence hydrogen or C3-6 cycloalkyl.
  • R 1 is - N(R 4 )2, wherein two occurrences of R 4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom.
  • R 1 is -N(R 4 ) 2 , wherein R 4 represents independently for each occurrence hydrogen or C3-6 cycloalkyl.
  • R 1 is C1-6 alkyl. In certain embodiments, R 1 is C1-4 alkyl.
  • R 1 is C1-3 alkyl. In certain embodiments, R 1 is C2-6 alkyl. In certain embodiments, R 1 is C 3-6 alkyl. In certain embodiments, R 1 is methyl, ethyl, or propyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl. [0072] In certain embodiments, R 1 is C1-6 haloalkyl. In certain embodiments, R 1 is C1-4 haloalkyl. In certain embodiments, R 1 is C 1-3 haloalkyl. In certain embodiments, R 1 is C 2-6 haloalkyl. In certain embodiments, R 1 is C 3-6 haloalkyl.
  • R 1 is C 1-6 haloalkyl, wherein the halogen is F. In certain embodiments, R 1 is C1-4 haloalkyl, wherein the halogen is selected F. In certain embodiments, R 1 is C1-3 haloalkyl, wherein the halogen is F.
  • R 1 is C 2-6 haloalkyl, wherein the halogen is F. In certain embodiments, R 1 is C3-6 haloalkyl, wherein the halogen is F. In certain embodiments, R 1 is CF3. In some embodiments, R 1 is CHF 2 . In some embodiments, R 1 is -CH 2 CF 3 . In some embodiments, R 1 is -CH 2 CHF 2 . [0073] In certain embodiments, R 1 is C3-6 cycloalkyl. In certain embodiments, R 1 is C4-6 cycloalkyl. In certain embodiments, R 1 is C5-6 cycloalkyl.
  • R 1 is cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R 1 is cyclopropyl. [0074] In certain embodiments, R 1 is -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 1 is -(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 1 is -(C2-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 1 is -(C 1-4 alkylene)-(C 5-6 cycloalkyl).
  • R 1 is -(C 1-3 alkylene)-(C 4-6 cycloalkyl). In certain embodiments, R 1 is - (C1-2 alkylene)-(C3-5 cycloalkyl). [0075] In certain embodiments, . [0076] In certain embodiments, R 1 is selected from those depicted in Table 1. [0077] As defined generally above, R 2 is cyano, C1-4 alkyl, C1-4 haloalkyl, or hydrogen. In certain embodiments, R 2 is C 1-4 alkyl, C 1-4 haloalkyl, or hydrogen. In certain embodiments, R 2 is cyano, C 1-4 haloalkyl, or hydrogen.
  • R 2 is cyano, C 1-4 alkyl, or hydrogen. In certain embodiments, R 2 is cyano, C1-4 alkyl, or C1-4 haloalkyl. In certain embodiments, R 2 is cyano. [0078] In certain embodiments, R 2 is C 1-4 alkyl. In certain embodiments, R 2 is C 1-3 alkyl. In certain embodiments, R 2 is C2-4 alkyl. In certain embodiments, R 2 is C3-4 alkyl. In certain embodiments, R 2 is methyl, ethyl, or propyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is ethyl.
  • R 2 is C1-4 haloalkyl. In certain embodiments, R 2 is C1-4 haloalkyl. In certain embodiments, R 2 is C1-3 haloalkyl. In certain embodiments, R 2 is C2-4 haloalkyl. In certain embodiments, R 2 is C 3-4 haloalkyl. In certain embodiments, R 2 is C 1-4 haloalkyl, wherein the halogen is F. In certain embodiments, R 2 is C1-4 haloalkyl, wherein the halogen is selected F. In certain embodiments, R 2 is C1-3 haloalkyl, wherein the halogen is F.
  • R 2 is C 2-4 haloalkyl, wherein the halogen is F. In certain embodiments, R 2 is C 3-4 haloalkyl, wherein the halogen is F. In certain embodiments, R 2 is CF 3 . In some
  • R 2 is CHF 2 . In some embodiments, R 2 is -CH 2 CF 3 . In some embodiments, R 4 is -CH2CHF2. [0080] In certain embodiments, R 2 is hydrogen. [0081] In certain embodiments, R 2 is selected from those depicted in Table 1. [0082] As defined generally above, R 3 represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, or halo. In certain embodiments, R 3 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 3 represents independently for each occurrence C1-3 alkyl. In certain embodiments, R 3 represents independently for each occurrence C2-4 alkyl.
  • R 3 represents independently for each occurrence C 3-4 alkyl. In certain embodiments, R 3 represents independently for each occurrence methyl, ethyl, or propyl. [0083] In certain embodiments, R 3 represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R 3 represents independently for each occurrence C 1-3 haloalkyl. In certain embodiments, R 3 represents independently for each occurrence C 2-4 haloalkyl. In certain embodiments, R 3 represents independently for each occurrence C3-4 haloalkyl. [0084] In certain embodiments, R 3 represents independently for each occurrence C 1-4 haloalkyl, wherein the halogen represents independently for each occurrence F.
  • R 3 represents independently for each occurrence C1-4 haloalkyl, wherein the halogen represents independently for each occurrence selected F. In certain embodiments, R 3 represents independently for each occurrence C 1-3 haloalkyl, wherein the halogen represents independently for each occurrence F. In certain embodiments, R 3 represents independently for each occurrence C 2-4 haloalkyl, wherein the halogen represents independently for each occurrence F. In certain embodiments, R 3 represents independently for each occurrence C 3-4 haloalkyl, wherein the halogen represents independently for each occurrence F. [0085] In certain embodiments, R 3 represents independently for each occurrence CF 3 . In some embodiments, R 3 represents independently for each occurrence CHF 2 .
  • R 3 represents independently for each occurrence -CH2CF3. In some embodiments, R 3 represents independently for each occurrence -CH2CHF2. [0086] In certain embodiments, R 3 represents independently for each occurrence halo. In certain embodiments, R 3 represents independently for each occurrence F or Cl. [0087] In certain embodiments, R 3 is C1-4 alkyl. In certain embodiments, R 3 is C1-3 alkyl. In certain embodiments, R 3 is C 2-4 alkyl. In certain embodiments, R 3 is C 3-4 alkyl. In certain
  • R 3 is methyl, ethyl, or propyl. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. [0088] In certain embodiments, R 3 is C 1-4 haloalkyl. In certain embodiments, R 3 is C 1-3 haloalkyl. In certain embodiments, R 3 is C 2-4 haloalkyl. In certain embodiments, R 3 is C 3-4 haloalkyl. In certain embodiments, R 3 is C1-4 haloalkyl, wherein the halogen is F. In certain embodiments, R 3 is C1-4 haloalkyl, wherein the halogen is selected F.
  • R 3 is C 1-3 haloalkyl, wherein the halogen is F. In certain embodiments, R 3 is C 2-4 haloalkyl, wherein the halogen is F. In certain embodiments, R 3 is C3-4 haloalkyl, wherein the halogen is F. In certain embodiments, R 3 is CF3. In some embodiments, R 3 is CHF2. In some embodiments, R 4 is -CH 2 CF 3 . In some embodiments, R 4 is -CH 2 CHF 2 . [0089] In certain embodiments, R 3 is halo. In certain embodiments, R 3 is F. In certain embodiments, R 3 is Cl.
  • R 3 is selected from those depicted in Table 1.
  • R 4 represents independently for each occurrence hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R 4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom.
  • R 4 represents independently for each occurrence C1-6 alkyl.
  • R 4 represents independently for each occurrence C1-4 alkyl.
  • R 4 represents independently for each occurrence C 1-3 alkyl.
  • R 4 represents independently for each occurrence C 2-6 alkyl. In certain embodiments, R 4 represents independently for each occurrence C3-6 alkyl. In certain embodiments, R 4 represents independently for each occurrence methyl, ethyl, or propyl. [0092] In certain embodiments, R 4 represents independently for each occurrence C 3-6 cycloalkyl. In certain embodiments, R 4 represents independently for each occurrence C4-6 cycloalkyl. In certain embodiments, R 4 represents independently for each occurrence C 5-6 cycloalkyl. In certain embodiments, R 4 represents independently for each occurrence cyclopropyl or cyclopentyl.
  • R 4 represents independently for each occurrence -(C1-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 4 represents independently for each occurrence -(C 1-4 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 4 represents independently for each occurrence -(C2-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 4 represents independently for each occurrence -(C 1-4 alkylene)-(C 5-6 cycloalkyl). In certain
  • R 4 represents independently for each occurrence -(C 1-3 alkylene)-(C 4-6 cycloalkyl). In certain embodiments, R 4 represents independently for each occurrence -(C1-2 alkylene)-(C 3-5 cycloalkyl). [0094] In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is C 1-6 alkyl. In certain embodiments, R 4 is C1-4 alkyl. In certain embodiments, R 4 is C1-3 alkyl. In certain embodiments, R 4 is C2-6 alkyl. In certain embodiments, R 4 is C3-6 alkyl. In certain embodiments, R 4 is methyl, ethyl, or propyl.
  • R 4 is methyl. In certain embodiments, R 4 is ethyl. [0095] In certain embodiments, R 4 is C3-6 cycloalkyl. In certain embodiments, R 4 is C4-6 cycloalkyl. In certain embodiments, R 4 is C 5-6 cycloalkyl. In certain embodiments, R 4 is C 3 cycloalkyl. In certain embodiments, R 4 is C 4 cycloalkyl. In certain embodiments, R 4 is C 5 cycloalkyl. In certain embodiments, R 4 is C6 cycloalkyl. In certain embodiments, R 4 is cyclopropyl or cyclopentyl. In certain embodiments, R 4 is cyclopropyl.
  • R 4 is cyclopentyl.
  • R 4 is -(C1-6 alkylene)-(C3-6 cycloalkyl).
  • R 4 is -(C 1-4 alkylene)-(C 3-6 cycloalkyl).
  • R 4 is -(C 2-6 alkylene)-(C 3-6 cycloalkyl).
  • R 4 is -(C 1-4 alkylene)-(C 5-6 cycloalkyl).
  • R 4 represents independently for each occurrence -(C1-3 alkylene)-(C4-6 cycloalkyl).
  • R 4 represents independently for each occurrence -(C1-2 alkylene)-(C 3-5 cycloalkyl).
  • two occurrences of R 4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom.
  • two occurrences of R 4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 4-7 membered saturated ring containing 1 nitrogen atom.
  • two occurrences of R 4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-6 membered saturated ring containing 1 nitrogen atom.
  • R 4 is selected from those depicted in Table 1.
  • R 5 represents independently for each occurrence C 1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6
  • R 5 represents independently for each occurrence halo, C1- 6 haloalkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), cyano, hydroxyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3- 6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C1-6 alkyl, C1-6 haloalkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), cyano, hydroxyl, C 1-6 hydroxyalkyl, C 1- 6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), - (C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C 1-6 alkyl, halo, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), cyano, hydroxyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)- (C 3-6 halocycloalkyl), or -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C 1-6 alkyl, halo, C 1-6 haloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), cyano, hydroxyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), -(C 1-6 alkylene)-(C 3-6 halocycloalkyl), or -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C1-6 alkyl, halo, C 1-6 haloalkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), hydroxyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C1-6 alkyl, halo, C 1-6 haloalkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), cyano, C 1-6 hydroxyalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3- 6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C 1-6 alkyl, halo, C 1-6 haloalkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), cyano, hydroxyl, C 1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-
  • R 5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), cyano, hydroxyl, C 1-6 hydroxyalkyl, C 1- 6 haloalkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), -(C 1-6 alkylene)- (C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, - SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), cyano, hydroxyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyl, -(C 1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C 1-6 alkyl, halo, C 1-6 haloalkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), cyano, hydroxyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)- (C 3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C 1- 6 alkyl, halo, C 1-6 haloalkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C 3-6 halocycloalkyl), or -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C 1-6 alkyl, halo, C 1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1- 6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), or - O-(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 5 represents independently for each occurrence C 1-6 alkyl, halo, C 1-6 haloalkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1- 6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), or -(C 1-6 alkylene)-(C 3-6 halocycloalkyl).
  • R 5 represents independently for each occurrence C 1-6 alkyl, halo, C1-6 haloalkyl, cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, or C1-6 haloalkoxyl. In certain embodiments, R 5 represents independently for each occurrence -SO 2 -(C 1-6 haloalkyl) or -SO 2 -(C 1-6 alkyl).
  • R 5 represents independently for each occurrence - (C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl).
  • R 5 represents independently for each occurrence halo, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), -SO 2 -(C 1-6 alkyl), hydroxyl, C 1-6 alkoxyl, or -(C 1-6 alkylene)-(C 1-6 alkoxyl).
  • R 5 represents independently for each occurrence represents independently for each occurrence halo, C 1-6 haloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, -SO 2 -(C 1-6 haloalkyl), or -SO 2 -(C 1-6 alkyl).
  • R 5 represents independently for each occurrence halo, C1-6 haloalkyl, C1-6 alkyl, or C3-6 cycloalkyl.
  • R 5 represents independently for each occurrence halo or C 1-6 haloalkyl. In certain embodiments, R 5 represents independently for each occurrence halo. In certain embodiments, R 5 represents independently for each occurrence F or Cl. [0102] In certain embodiments, R 5 represents independently for each occurrence C 1-6 haloalkyl. In certain embodiments, R 5 represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R 5 represents independently for each occurrence C1-3 haloalkyl. In certain embodiments, R 5 represents independently for each occurrence C 2-6 haloalkyl.
  • R 5 represents independently for each occurrence C3-6 haloalkyl. In certain embodiments, R 5 represents independently for each occurrence C1-6 haloalkyl, wherein the halogen is F. In certain embodiments, R 5 represents independently for each occurrence C 1-4 haloalkyl, wherein the halogen represents independently for each occurrence selected F. In certain embodiments, R 5 represents independently for each occurrence C 1-3 haloalkyl, wherein the halogen is F. In certain embodiments, R 5 represents independently for each occurrence C 2-6 haloalkyl, wherein the halogen is F. In certain embodiments, R 5 represents independently for each occurrence C3-6 haloalkyl, wherein the halogen is F.
  • R 5 represents independently for each occurrence CF 3, CHF 2 , -CH 2 CF 3 , or -CH 2 CHF 2 .
  • R 5 represents independently for each occurrence C1-6 alkyl.
  • R 5 represents independently for each occurrence C1-4 alkyl.
  • R 5 represents independently for each occurrence C 1-3 alkyl.
  • R 5 represents independently for each occurrence C 2-6 alkyl.
  • R 5 represents independently for each occurrence C3-6 alkyl.
  • R 5 represents independently for each occurrence methyl, ethyl, or propyl.
  • R 5 represents independently for each occurrence C 3-6 cycloalkyl. In certain embodiments, R 5 represents independently for each occurrence C4-6 cycloalkyl. In certain embodiments, R 5 represents independently for each occurrence C 5-6 cycloalkyl. In certain embodiments, R 5 represents independently for each occurrence C 3 cycloalkyl. In certain embodiments, R 5 represents independently for each occurrence C4 cycloalkyl. In certain embodiments, R 5 represents independently for each occurrence C5 cycloalkyl. In certain embodiments, R 5 represents independently for each occurrence C 6 cycloalkyl. In certain embodiments, R 5 represents independently for each occurrence cyclopropyl or cyclopentyl. [0105] In certain embodiments, R 5 represents independently for each occurrence -SO 2 -(C 1-6 haloalkyl). In certain embodiments, R 5 represents independently for each occurrence -SO 2 -(C 1-
  • R 5 represents independently for each occurrence -SO2-(C1-4 haloalkyl), wherein the halogen is F. In certain embodiments, R 5 represents independently for each occurrence -SO 2 -(C 1-3 haloalkyl), wherein the halogen is F. In certain embodiments, R 5 represents independently for each occurrence -SO 2 -(C 2-6 haloalkyl), wherein the halogen is F. [0106] In certain embodiments, R 5 represents independently for each occurrence -SO2-(C1-5 haloalkyl).
  • R 5 represents independently for each occurrence -SO 2 -(C 1- 4 haloalkyl). In certain embodiments, R 5 represents independently for each occurrence -SO2- (C1-3 haloalkyl). In certain embodiments, R 5 represents independently for each occurrence - SO 2 -(C 2-6 haloalkyl). In certain embodiments, R 5 represents independently for each occurrence -SO 2 CF 3, -SO 2 CHF 2 , -SO 2 -CH 2 CF 3 , or -SO 2 -CH 2 CHF 2 . [0107] In certain embodiments, R 5 represents independently for each occurrence -SO2-(C1-6 alkyl).
  • R 5 represents independently for each occurrence -SO 2 -(C 1-5 alkyl). In certain embodiments, R 5 represents independently for each occurrence -SO 2 -(C 1-4 alkyl). In certain embodiments, R 5 represents independently for each occurrence -SO2-(C1-3 alkyl). In certain embodiments, R 5 represents independently for each occurrence -SO 2 -(C 2-6 alkyl). In certain embodiments, represents independently for each occurrence -SO 2 CH 3 , - SO2CH2CH3, -SO2CH(CH3)2, -SO2CH2CH(CH3)2, -SO2C(CH3)3, or -SO2CH2C(CH3)3.
  • R 5 represents independently for each occurrence C1-6 hydroxyalkyl. In certain embodiments, R 5 represents independently for each occurrence C 1-4 hydroxyalkyl. In certain embodiments, R 5 represents independently for each occurrence C 1-3 hydroxyalkyl. In certain embodiments, R 5 represents independently for each occurrence C2-6 hydroxyalkyl. [0109] In certain embodiments, R 5 represents independently for each occurrence C 1-6 alkoxyl. In certain embodiments, R 5 represents independently for each occurrence C1-3 alkoxyl. In certain embodiments, R 5 represents independently for each occurrence C 2-6 alkoxyl. In certain embodiments, R 5 represents independently for each occurrence C 4-6 alkoxyl.
  • R 5 represents independently for each occurrence -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH2CH2CH2CH3, -O(CH2)4CH3, -OCH(CH3)2, -OCH2CH(CH3)2, - OCH 2 CH 2 CH(CH 3 ) 2 , -O(CH 2 ) 3 CH(CH 3 ) 2 , -OC(CH 3 ) 3 , -OCH 2 C(CH 3 ) 3, or -OCH 2 CH 2 C(CH 3 ) 3 .
  • R 5 represents independently for each occurrence -OCH 3 or - OCH2CH3.
  • R 5 represents independently for each occurrence C 1-6 haloalkoxyl. In certain embodiments, R 5 represents independently for each occurrence C1-3 haloalkoxyl. In certain embodiments, R 5 represents independently for each occurrence C 2-6 haloalkoxyl. In certain embodiments, R 5 represents independently for each occurrence C 4-6 haloalkoxyl. In certain embodiments, R 5 represents independently for each occurrence C1 haloalkoxyl. In certain embodiments, R 5 represents independently for each occurrence C2 haloalkoxyl.
  • R 5 represents independently for each occurrence C1-6 haloalkoxyl, wherein the halogen is F. In certain embodiments, R 5 represents independently for each occurrence C 1-3 haloalkoxyl, wherein the halogen is F. In certain embodiments, R 5 represents independently for each occurrence C 2-6 haloalkoxyl, wherein the halogen is F. In certain embodiments, R 5 represents independently for each occurrence C4-6 haloalkoxyl, wherein the halogen is F. In certain embodiments, R 5 represents independently for each occurrence -(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 5 represents independently for each occurrence -(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -(C 2-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -(C 1-4 alkylene)-(C 5-6 cycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -(C1-3 alkylene)-(C4-6 cycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -(C 1-2 alkylene)-(C 3-5 cycloalkyl).
  • R 5 represents independently for each occurrence -(C 1-6 alkylene)-(C 1-6 alkoxyl). In certain embodiments, R 5 represents independently for each occurrence -(C1-4 alkylene)-(C3-6 alkoxyl). In certain embodiments, R 5 represents independently for each occurrence -(C 2-6 alkylene)-(C 3-6 alkoxyl). In certain embodiments, R 5 represents independently for each occurrence -(C 1-4 alkylene)-(C 5-6 alkoxyl). In certain embodiments, R 5 represents independently for each occurrence -(C1-3 alkylene)-(C 4-6 alkoxyl).
  • R 5 represents independently for each occurrence -(C 1-2 alkylene)-(C 3-5 alkoxyl). [0112] In certain embodiments, R 5 represents independently for each occurrence -(C1-6 alkylene)-(C3-6 halocycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -(C 1-4 alkylene)-(C 3-6 halocycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -(C 2-6 alkylene)-(C 3-6 halocycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -(C1-4 alkylene)-(C5-6 halocycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -
  • R 5 represents independently for each occurrence -(C1-2 alkylene)-(C3-5 halocycloalkyl). [0113] In certain embodiments, R 5 represents independently for each occurrence -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -O-(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -O-(C2-6 alkylene)-(C3-6 cycloalkyl).
  • R 5 represents independently for each occurrence -O-(C 1-4 alkylene)-(C 5-6 cycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -O-(C1-3 alkylene)-(C4-6 cycloalkyl). In certain embodiments, R 5 represents independently for each occurrence -O-(C 1-2 alkylene)-(C 3-5 cycloalkyl).
  • R 5 is C 1-6 alkyl, halo, C 1-6 haloalkyl, C 3-6 cycloalkyl, -SO 2 - (C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C 1-6 alkylene)-(C 1-6 alkoxyl), -(C 1-6 alkylene)-(C 3-6 cycloalkyl), -(C 1-6 alkylene)- (C 3-6 halocycloalkyl), or -O-(C 1-6 alkylene)-(C 3-6 cycloalkyl).
  • R 5 is cyano. In certain embodiments, R 5 is hydroxyl. In certain embodiments, R 5 is halo. In certain embodiments, R 5 is F or Cl. In certain embodiments, R 5 is F. In certain embodiments, R 5 is Cl. [0116] In certain embodiments, R 5 is C1-6 haloalkyl. In certain embodiments, R 5 is C1-4 haloalkyl. In certain embodiments, R 5 is C1-3 haloalkyl. In certain embodiments, R 5 is C2-6 haloalkyl. In certain embodiments, R 5 is C 3-6 haloalkyl. In certain embodiments, R 5 is C 1-6 haloalkyl, wherein the halogen is F.
  • R 5 is C 1-4 haloalkyl, wherein the halogen is selected F. In certain embodiments, R 5 is C1-3 haloalkyl, wherein the halogen is F. In certain embodiments, R 5 is C 2-6 haloalkyl, wherein the halogen is F. In certain embodiments, R 5 is C 3-6 haloalkyl, wherein the halogen is F. In certain embodiments, R 5 is -CF 3, -CHF 2 , - CH2CF3, or -CH2CHF2. In certain embodiments, R 5 is CF3. In some embodiments, R 5 is CHF 2 . In some embodiments, R 5 is -CH 2 CF 3 .
  • R 5 is -CH 2 CHF 2 .
  • R 5 is C 1-6 alkyl. In certain embodiments, R 5 is C 1-4 alkyl. In certain embodiments, R 5 is C1-3 alkyl. In certain embodiments, R 5 is C2-6 alkyl. In certain embodiments, R 5 is C3-6 alkyl. In certain embodiments, R 5 is methyl, ethyl, or propyl. In certain embodiments, R 5 is methyl. In certain embodiments, R 5 is ethyl. [0118] In certain embodiments, R 5 is C 3-6 cycloalkyl. In certain embodiments, R 5 is C 4-6 cycloalkyl. In certain embodiments, R 5 is C5-6 cycloalkyl. In certain embodiments, R 5 is C3 cycloalkyl. In certain embodiments, R 5 is C 4 cycloalkyl. In certain embodiments, R 5 is C 5
  • R 5 is C 6 cycloalkyl. In certain embodiments, R 5 is cyclopropyl or cyclopentyl. In certain embodiments, R 5 is cyclopropyl. [0119] In certain embodiments, R 5 is -SO 2 -(C 1-6 haloalkyl). In certain embodiments, R 5 is - SO 2 -(C 1-5 haloalkyl), wherein the halogen is F. In certain embodiments, R 5 is -SO 2 -(C 1-4 haloalkyl), wherein the halogen is F.
  • R 5 is -SO2-(C1-3 haloalkyl), wherein the halogen is F. In certain embodiments, R 5 is -SO2-(C2-6 haloalkyl), wherein the halogen is F. In certain embodiments, R 5 is -SO 2 -(C 1-5 haloalkyl). In certain embodiments, R 5 is -SO2-(C1-4 haloalkyl). In certain embodiments, R 5 is -SO2-(C1-3 haloalkyl). In certain embodiments, R 5 is -SO2-(C2-6 haloalkyl).
  • R 5 is -SO2CF3, -SO2CHF2, - SO 2 -CH 2 CF 3 , or -SO 2 -CH 2 CHF 2 .
  • R 5 is -SO 2 -(C 1-6 alkyl). In certain embodiments, R 5 is -SO 2 - (C1-5 alkyl). In certain embodiments, R 5 is -SO2-(C1-4 alkyl). In certain embodiments, R 5 is - SO 2 -(C 1-3 alkyl). In certain embodiments, R 5 is -SO 2 -(C 2-6 alkyl).
  • R 5 is -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -SO 2 CH(CH 3 ) 2 , -SO 2 CH 2 CH(CH 3 ) 2 , -SO 2 C(CH 3 ) 3 , or - SO2CH2C(CH3)3.
  • R 5 is C 1-6 hydroxyalkyl. In certain embodiments, R 5 is C 1-3 hydroxyalkyl. In certain embodiments, R 5 is C 2-6 hydroxyalkyl.
  • R 5 is C1-6 alkoxyl. In certain embodiments, R 5 is C1-3 alkoxyl. In certain embodiments, R 5 is C2-6 alkoxyl.
  • R 5 is C4-6 alkoxyl.
  • R 5 is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH 2 CH 2 CH 2 CH 3 , -O(CH2) 4 CH3, -OCH(CH 3 ) 2 , -OCH 2 CH(CH 3 ) 2 , -OCH 2 CH 2 CH(CH 3 ) 2 , - O(CH2)3CH(CH3)2, -OC(CH3)3, -OCH2C(CH3)3, or -OCH2CH2C(CH3)3.
  • R 5 is -OCH 3 or -OCH 2 CH 3.
  • R 5 is C 1-6 haloalkoxyl. In certain embodiments, R 5 is C 1-3 haloalkoxyl. In certain embodiments, R 5 is C2-6 haloalkoxyl. In certain embodiments, R 5 is C1- 4 haloalkoxyl. In certain embodiments, R 5 is C 1-2 haloalkoxyl. In certain embodiments, R 5 is - OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , or -OCF 2 CF 3. [0124] In certain embodiments, R 5 is -(C1-6 alkylene)-(C3-6 cycloalkyl).
  • R 5 is -(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 5 is -(C2-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 5 is -(C 1-4 alkylene)-(C 5-6 cycloalkyl). In certain embodiments, R 5 is -(C 1-3 alkylene)-(C 4-6 cycloalkyl). In certain embodiments, R 5 is -O- (C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 5 is O-(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R 5 is -O-(C 2-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 5 is -O-(C 2-6 alkylene)-(C 3-6 cycloalkyl). In certain embodiments, R 5 is -O-(C 2-6 alkylene
  • R 5 is -O-(C 1-4 alkylene)-(C 5-6 cycloalkyl). In certain embodiments, R 5 is -O-(C 1-3 alkylene)-(C4-6 cycloalkyl). In certain embodiments, R 5 is -O-(C1-2 alkylene)-(C3-5 cycloalkyl). In certain embodiments, R 5 is -(C 1-6 alkylene)-(C 1-6 alkoxyl). In certain embodiments, R 5 is - (C 1-4 alkylene)-(C 3-6 alkoxyl). In certain embodiments, R 5 is -(C 2-6 alkylene)-(C 3-6 alkoxyl).
  • R 5 is -(C1-4 alkylene)-(C5-6 alkoxyl). In certain embodiments, R 5 is -(C1-3 alkylene)-(C4-6 alkoxyl). In certain embodiments, R 5 is -(C1-2 alkylene)-(C3-5 alkoxyl). In certain embodiments, R 5 is -(C 1-6 alkylene)-(C 3-6 halocycloalkyl). In certain embodiments, R 5 is -(C1-4 alkylene)-(C3-6 halocycloalkyl). In certain embodiments, R 5 is -(C2-6 alkylene)-(C3-6 halocycloalkyl).
  • R 5 is -(C1-4 alkylene)-(C5-6 halocycloalkyl). In certain embodiments, R 5 is -(C 1-3 alkylene)-(C 4-6 halocycloalkyl). In certain embodiments, R 5 is -(C 1-2 alkylene)-(C 3-5 halocycloalkyl). [0125] In certain embodiments, R 5 is selected from those depicted in Table 1.
  • a 1 is phenyl or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the phenyl and heteroaryl are substituted with n occurrences of R 5
  • a 1 is phenyl substituted with n occurrences of R 5
  • a 1 is 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl are substituted with n occurrences of R 5 .
  • a 1 is pyridinyl substituted with n occurrences of R 5 .
  • a 1 is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, thiophenyl, or pyridinyl, each of which is substituted with n occurrences of R 5 .
  • a 1 is pyrazolyl, imidazolyl, oxazolyl, or isoxazolyl, each of which is substituted with n occurrences of R 5 .
  • a 1 is pyrazolyl substituted with n occurrences of R 5 . [0129] In certain embodiments, A 1 is selected from those depicted in Table 1.
  • X 1 is -(C 1-4 alkylene)-(C 3-5 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -(C 1-3 alkylene)-(C 3-5 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -(C1-2 alkylene)-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -(C 2-4 alkylene)-(C 3-5 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -(C 3-4 alkylene)-(C 3-5 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -(C1-4 alkylene)-(C3-4 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is
  • X 1 is -(C1-3 alkylene)-(C3-4 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -(C 1-2 alkylene)-(C 3-4 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -CH 2 -(C 3-5 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -CH2CH2-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -CH 2 -(C 3 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -CH2-(C4 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -CH2-(C5 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -CH 2 CH 2 -(C 3 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -CH2CH2-(C4 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is -CH 2 CH 2 -(C 5 cycloalkylene)-***, wherein *** is a point of attachment to A 1 .
  • X 1 is , wherein *** is a point of attachment to A 1 .
  • m is 0, 1, 2, or 3.
  • m is 0, 2, or 3.
  • m is 0, 1, or 3.
  • m is 0, 1, or 2.
  • m is 2 or 3.
  • m is 0 or 1.
  • m is 0 or 3.
  • m is 0 or 2.
  • m is 1 or 2.
  • m is 1 or 3.
  • m is 0.
  • m is 1. In certain embodiments, m is 2.
  • n is 0, 1, or 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is 0 or 2. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. [0135] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments.
  • the compound of Formula I is further defined by Formula Ia or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above: [0137] In certain embodiments, the compound of Formula I is further defined by Formula Ib or Ic or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above: [0138] In certain embodiments, the compound of Formula I is further defined by Formula Id or Ie or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above: Id Ie.
  • the compound of Formula I is further defined by Formula If or Ig, or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above: [0140] In certain embodiments, the compound of Formula I is further defined by Formula Ih or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above: [0141] In certain embodiments, the compound of Formula I is further defined by Formula Ii, Ij, Ik, or Il or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above: Ik Il.
  • the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. TABLE 1. Exemplary Compounds Exam le Structure Stereoisomer 1
  • 6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidine A is coupled to carboxylic acid B using amide-bond forming conditions (e.g., HATU mediated acid amine coupling) to afford dihydropyrrolo- pyrimidines C.
  • amide-bond forming conditions e.g., HATU mediated acid amine coupling
  • the modular synthetic route illustrated in Scheme 1 can also be readily modified by one of skill in the art to provide additional compounds by conducting functional group transformations on the intermediate and final compounds.
  • Such functional group transformations are well known in the art, as described in, for example, “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992).
  • Compounds Useful in Synthetic Procedures [0146] Another aspect of the invention provides compounds that are useful in the synthetic procedures.
  • one aspect of the invention provides a compound of Formula II: (II) or a salt thereof; wherein: R 1A is C1-4 alkoxyl, -N(R 5A )2, -O-(C3-6 cycloalkyl), C1-6 alkyl, or C3-6 cycloalkyl;
  • R 2A is cyano, C 1-4 alkyl, C 1-4 haloalkyl, halogen, or hydrogen;
  • R 3A and R 4A are independently hydrogen or C1-4 alkyl;
  • R 5A represents independently for each occurrence hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 cycloalkyl); or two occurrences of R 5A attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom; and
  • Z 1 is hydrogen or -C(O) 2 (C 1-6 alkyl).
  • variables in Formula II above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula II.
  • R 1A is C1-4 alkoxyl, -N(R 5A )2, -O-(C3-6 cycloalkyl), C1-6 alkyl, or C3-6 cycloalkyl.
  • R 1A is .
  • R 1A is C1-4 alkoxyl.
  • R 1A is -N(R 5A )2.
  • R 1A is -O-(C3-6 cycloalkyl).
  • R 1A is C1-6 alkyl.
  • R 1A is C 3-6 cycloalkyl.
  • R 1A is selected from the groups depicted in the compounds in Table 1-A below.
  • R 2A is cyano, C1-4 alkyl, C1-4 haloalkyl, halogen, or hydrogen.
  • R 2A is methyl, chloro, or cyano.
  • R 2A is methyl.
  • R 2A is chloro.
  • R 2A is cyano.
  • R 2A is C1-4 alkyl.
  • R 2A is C1-4 haloalkyl.
  • R 2A is halogen.
  • R 2A is hydrogen.
  • R 2A is selected from the groups depicted in the compounds in Table 1-A below.
  • R 3A and R 4A are independently hydrogen or C1-4 alkyl. In certain embodiments, R 3A is hydrogen. In certain embodiments, R 3A is C1-4 alkyl. In certain embodiments, R 3A is selected from the groups depicted in the compounds in Table 1-A below. In certain embodiments, R 4A is hydrogen. In certain embodiments, R 4A is C 1-4 alkyl. In certain
  • R 4A is hydrogen or methyl. In certain embodiments, R 4A is methyl. In certain embodiments, R 4A is selected from the groups depicted in the compounds in Table 1-A below. [0152] As defined generally above, R 5A represents independently for each occurrence hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or -(C 1-6 alkylene)-(C 3-6 cycloalkyl); or two occurrences of R 5A attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, R 5A is hydrogen.
  • R 5A is C 1-6 alkyl. In certain embodiments, R 5A is C 3-6 cycloalkyl. In certain embodiments, R 5A is -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, two occurrences of R 5A attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, R 5A is selected from the groups depicted in the compounds in Table 1-A below. [0153] As defined generally above, Z 1 is hydrogen or -C(O)2(C1-6 alkyl). In certain embodiments, Z 1 is hydrogen or tert-butoxycarbonyl.
  • Z 1 is hydrogen. In certain embodiments, Z 1 is tert-butoxycarbonyl. In certain embodiments, Z 1 is -C(O) 2 (C 1-6 alkyl). In certain embodiments, Z 1 is selected from the groups depicted in the compounds in Table 1-A below. [0154] The description above describes multiple embodiments relating to compounds of Formula II. The patent application specifically contemplates all combinations of the embodiments. [0155] Another aspect of the invention provides a compound in Table 1-A below. TABLE 1-A. - cyano met y
  • R 1A is .
  • R 2A is methyl, chloro, or cyano.
  • R is hydrogen.
  • R 4A is hydrogen or methyl.
  • Z 1 is hydrogen or tert-butoxycarbonyl.
  • the particular compound of Formula I is a compound defined by one of the embodiments described in Section I, above.
  • Methods described herein may be further defined according to additional features, such as the identity of the muscarinic acetylcholine receptor mediated disorder and/or the subject.
  • Muscarinic acetylcholine receptor mediated disorders can be treated or prevented by modulating the muscarinic system. Such diseases include those in which direct activation of muscarinic acetylcholine receptors themselves or inhibition of cholinesterase enzymes provides a therapeutic effect.
  • Exemplary muscarinic acetylcholine receptor medicated disorders include schizophrenia, movement disorders, mood disorders, cognitive disorders, attention disorders, addictive disorders, and pain.
  • the muscarinic acetylcholine receptor mediated disorder is selected from schizophrenia, movement disorders, mood disorders, cognitive disorders, attention disorders, addictive disorders, and neurologic disorders. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is a movement disorder, mood disorder, or cognitive disorder. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from attention disorders and addictive disorders. [0160] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is schizophrenia or a related disorder.
  • Disorders related to schizophrenia include schizo-affective disorder, psychosis disorders, psychosis associated with Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, psychosis associated with Parkinson’s disease, psychotic depression,
  • the muscarinic acetylcholine receptor mediated disorder is selected from a schizo-affective disorder, psychosis, delusional disorders, psychosis associated with Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch- Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, cerebral amyloid angiopathy, and Lewy Body dementia.
  • the muscarinic acetylcholine receptor mediated disorder is selected from a schizo-affective disorder, psychosis, psychosis associated with Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, cerebral amyloid angiopathy, and Lewy Body dementia.
  • the muscarinic acetylcholine receptor mediated disorder is a movement disorder.
  • Exemplary movement disorders include Gilles de la Tourette’s syndrome, Friederich’s ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington’s chorea, dyskinesia, restless leg syndrome, and other diseases or disorders whose symptoms include excessive movements, tics, and spasms.
  • the muscarinic acetylcholine receptor mediated disorder is selected from Gilles de la Tourette’s syndrome, Friederich’s ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington’s chorea, dyskinesia, and restless leg syndrome.
  • the muscarinic acetylcholine receptor mediated disorder is a mood disorder.
  • mood disorders include major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, bipolar disorder, mania, and anxiety.
  • the muscarinic acetylcholine receptor mediated disorder is selected from major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, bipolar disorder, mania, and anxiety.
  • the muscarinic acetylcholine receptor mediated disorder is a cognitive disorder.
  • Exemplar cognitive disorders are diseases or disorders marked by a cognitive deficit (e.g., having abnormal working memory, problem-solving abilities, etc.), such as Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, Parkinson’s Disease, Parkinson's Disease-levodopa-induced dyskinesia, cerebral amyloid angiopathy, dementia (e.g., AIDS-
  • the muscarinic acetylcholine receptor mediated disorder is selected from Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, Parkinson’s Disease, Parkinson's Disease-levodopa-induced dyskinesia,cerebral amyloid angiopathy, dementia (e.g., AIDS-related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, and idiopathic dementia), Pick’s disease, tauopathies, synucleinopathies, confusion, mild cognitive impairment, cognitive deficit associated with fatigue, learning disorders, traumatic brain injury, autism, age-related cognitive decline, and Cushing’s Disease.
  • Alzheimer’s disease Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder
  • Parkinson’s Disease Parkinson's
  • the muscarinic acetylcholine receptor mediated disorder is an attention disorder.
  • attention disorders are diseases or conditions marked by having an abnormal or decreased attention span, such as attention deficit and hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down’s Syndrome, growth delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss Syndrome.
  • the muscarinic acetylcholine receptor mediated disorder is selected from hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down’s Syndrome, growth delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss Syndrome [0168]
  • the muscarinic acetylcholine receptor mediated disorder is an addictive disorder.
  • addictive disorders are diseases or conditions marked by addiction or substance dependence as defined by the Diagnostic & Statistical Manual V (DSM- 5). Such disorders are often characterized by physical dependence, withdrawal, and tolerance to a substance.
  • Addictive disorders also encompass behaviors that a patient does compulsively or continually despite clear negative consequences. For instance, ludomania (gambling addiction or compulsive gambling) is recognized by those skilled in the art as being an addictive behavior that often has devastating consequences. In certain embodiments, the addictive behavior may be Internet Gaming Disorder (gaming addiction), as defined in the DSM-5.
  • addictive behavior may be Internet Gaming Disorder (gaming addiction), as defined in the DSM-5.
  • the muscarinic acetylcholine receptor mediated disorder is addiction to one of the following substances: alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, or cannabis; ludomania; and Internet Gaming Disorder.
  • the muscarinic acetylcholine receptor mediated disorder is a neurologic disorder.
  • Exemplary neurologic disorders are pain, physical suffering, or discomfort caused by illness or injury. Pain is a subjective experience, and the perception of pain is performed as part of the central nervous system (CNS).
  • the muscarinic acetylcholine receptor mediated disorder is selected from acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is acute pain.
  • the muscarinic acetylcholine receptor mediated disorder is chronic pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is neuropathic pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is inflammatory pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is nociceptive pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is inflammatory pain or nociceptive pain.
  • the muscarinic acetylcholine receptor mediated disorder is selected from a schizo-affective disorder, psychosis, psychosis associated with Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, psychosis associated with Parkinson’s disease, Parkinson's Disease-levodopa-induced dyskinesia, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, cerebral amyloid angiopathy, Lewy Body dementia, Gilles de la Tourette’s syndrome, Friederich’s ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington’s chorea, dyskinesia, restless leg syndrome, major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, mania, anxiety, Alzheimer’s disease, Her
  • Alzheimer's disease vascular dementia, age-related dementia, dementia associated with Lewy bodies, and idiopathic dementia
  • Pick’s disease tauopathies, synucleinopathies, confusion, mild cognitive impairment, cognitive deficit associated with fatigue, learning disorders, traumatic brain injury, autism, age-related cognitive decline, Cushing’s Disease, hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down’s Syndrome, growth delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss Syndrome, and addiction to one of the following substances: alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, or cannabis, ludomania, Internet Gaming Disorder, acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain.
  • the muscarinic acetylcholine receptor mediated disorder is schizophrenia, psychosis, mild cognitive impairment, Alzheimer's Disease, Parkinson's Disease, Parkinson's Disease-levodopa-induced dyskinesia, Huntington's Disease, dyskinesia, cerebral amyloid angiopathy, dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, a prion disorder, amyotrophic lateral sclerosis, progressive supranuclear palsy, autism, addiction, or a sleep disorder.
  • HHWA-D Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type
  • Creutzfeld-Jakob disease a prion disorder
  • amyotrophic lateral sclerosis progressive supranuclear palsy
  • autism addiction
  • addiction or a sleep disorder.
  • the muscarinic acetylcholine receptor mediated disorder is a schizo-affective disorder, psychosis, a delusional disorder, psychosis associated with Alzheimer’s disease, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, Lewy Body dementia, Gilles de la Tourette’s syndrome, Friederich’s ataxia, Huntington’s chorea, restless leg syndrome, major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, bipolar disorder, mania, anxiety, Alzheimer’s disease, Parkinson’s Disease, dementia, Pick’s disease, tauopathies, synucleinopathies, confusion, cognitive deficit associated with fatigue, a learning disorder, traumatic brain injury, autism, age-related cognitive decline, Cushing’s Disease, attention deficit and hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down’s Syndrome, growth delay due to insulin-like
  • Another aspect of the invention provides a method of activating a muscarinic acetylcholine receptor.
  • the method comprises contacting a muscarinic acetylcholine receptor with an effective amount of a compound described herein, such as a compound of Formula I, to activate the muscarinic acetylcholine receptor, as further described in the detailed description.
  • the muscarinic acetylcholine receptor is muscarinic acetylcholine receptor M4.
  • Subjects [0177] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. Medical Uses [0178] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as a muscarinic acetylcholine receptor mediated disorder.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein, such as a muscarinic acetylcholine receptor mediated disorder.
  • a medical disorder such as a medical disorder described herein, such as a muscarinic acetylcholine receptor mediated disorder.
  • Assay for Evaluating Compound Biological Activity in Rats Compounds may be tested for ability to impact behavior activity of rats according to the following procedures. Animals: Adult male, Sprague Dawley rats (Envigo, Indianapolis, IN, USA) are housed in a colony maintained at 23 °C with 12 h light/dark cycles (lights on at 0600 hours).
  • Risperidone (0.55 mg/kg, 30 minutes, s.c.) may be used as a positive control and is administered to group 5.
  • rats are placed in the open area and allowed to habituate for 30 min before being s.c. dosed with 0.5 mg/kg AMP.
  • Locomotor data (distance traveled) is recorded as 5- minute bins throughout the 90-minute session.
  • the dose of AMP is chosen based on the selective increase in locomotor behavior relative to stereotypes.
  • the dose of risperidone is chosen that produced reliable effects and served as a positive control.
  • Spontaneous locomotion (prior to AMP administration) is calculated as the total distance traveled during the first 30 minutes of the experimental session.
  • AMP-evoked responses are calculated as the total distance traveled during the last 60 minutes of the experimental session which commenced immediately after AMP administration.
  • Locomotor data may be analyzed by a one-way ANOVA. When there is a significant overall ANOVA, post hoc comparisons may be made by Dunnett’s test with statistical significance determined as p ⁇ 0.05.
  • Another aspect of the invention provides for combination therapy.
  • the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co- administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • One or more other therapeutic agent may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen.
  • one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition.
  • one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another.
  • one or more other therapeutic agent and a compound or composition of the invention are administered as a multiple dosage regimen more than 24 hours apart.
  • Various pharmaceutically active agents may be selected for use in conjunction with the compounds of the presentinvention, depending on the disease, disorder, or condition to be treated.
  • compositions of the present invention include, without limitation: [0185] (i) acetylcholinesterase inhibitors, such as donepezil hydrochloride (ARICEPT, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigmine sulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine (MESTINON), ambenonium (MYTELASE), demarcarium, Debio 9902 (also known as ZT-1; Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361, galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX), tolserine, velnacrine maleate, memoquin, huperzine A (HUP- A; NeuroHitech), phenserine, e
  • amyloid-lowering or -inhibiting agents including those that reduce amyloid production, accumulation and fibrillization
  • amyloid-lowering or -inhibiting agents such as dimebon, davunetide, eprodisate, leuprolide, SK-PC-B70M, celecoxib, lovastatin, anapsos, oxiracetam, pramiracetam, varenicline, nicergoline, colostrinin, bisnorcymserine (also known as BNC), NICS-15 (Humanetics), E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2 (Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and its R-enantiomer tarenflurbil 34 (FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), i
  • gingko biloba extract EGb-761 (ROKAN, TEBONIN), tramiprosate (CEREBRIL, ALZHEMED), eprodisate (FIBRILLEX, KIACTA), compound W [3,5-bis(4- nitrophenoxy)benzoic acid], NGX- 96992, neprilysin (also known as neutral endopeptidase (NEP)), scyllo-inositol (also known as scyllitol), atorvastatin (LIPITOR), simvastatin (ZOCOR), KLVFF-(EEX)3, SKF-74652, ibutamoren mesylate, BACE inhibitors such as ASP- 1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609 and TTP
  • BACE inhibitors such as ASP- 1702,
  • alpha-adrenergic receptor agonists such as guanfacine (INTUNIV, TENEX), clonidine (CATAPRES), metaraminol (ARAMINE), methyldopa (ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine (also known as neosynephrine), methoxamine, cirazoline, guanfacine (INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, and armodafinil (NUVIGIL); [0190] (vi) beta-adrenergic receptor blocking agents (beta blockers), such as carteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE), oxpren
  • beta-adrenergic receptor blocking agents beta blockers
  • (ix) antipsychotics such as lurasidone (LATUDA, also known as SM-13496; Dainippon Sumitomo), aripiprazole(ABILIFY), chlorpromazine (THORAZINE), haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate (DEPIXOL, FLUANXOL), reserpine (SERPLAN), pimozide (ORAP), fluphenazine decanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO), asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MOBAN), perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE), ramelteon, clozapine (CLOZARIL), norclo
  • LATUDA also known as SM-13496; Dainippon Sum
  • (xix) immunomodulators such as glatiramer acetate (also known as copolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic protein peptide), dimethyl fumarate, fingolimod (also known as FTY720), roquinimex (LINOMIDE), laquinimod (also known as ABR-215062 and SAIK-MS), ABT-874 (human anti-1L-12 antibody; Abbott), rituximab (RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab (TYSABRI); [0203] (xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX), mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), mycophenolate sodium (MYFORTIC), azathioprine (glatiramer acetate (also known as copo
  • PDE2 inhibitors e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, and those described in U.S. Pat. No.6,174,884
  • PDE3 inhibitors e.g., anagrelide, cilostazol, milrinone, olprinone, parogrelil, and pimobendan
  • PDE4 inhibitors e.g., apremilast, ibudilastroflumilast, rolipram, Ro 20-1724, ibudilast (KETAS), piclamilast (also known as RP73401), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast, oglemilast (also known as GRC 3886), tetomilast (also known as OPC-6535), lirimifast, theophy
  • trophic factors such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin, meteorin, and glial-derived neurotrophic factor (GDNF), and agents that stimulate production of trophic factors, such as propentofylline, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082 (NEOTROFIN); [0222] (xxxix) Glycine transporter-1 inhibitors such as paliflutine, ORG-25935, JNJ- 17305600, and ORG-26041; [0223] (xl) AMPA-type glutamate receptor modulators such as perampanel, mibampator, selurampanel, GSK-729327, N- ⁇ (3 S,4 S)-4 - [4
  • (xli) Janus kinase inhibitors such as, but not limited to, tofacitinib, ruxolitinib, baricitinib, CYT387, GLPG0634, lestaurtinib, pacritinib, and TG101348.
  • (xlii) Interleukin-1 receptor-associated kinase 4 inhibitors (IRAK4) such as, but not limited to, PF-06650833.
  • the additional therapeutic agent is an orthosteric agonist of the muscarinic acetylcholine receptor.
  • methods described herein further comprise administering to the subject in need thereof a therapeutically effective amount of an orthosteric agonist of the muscarinic acetylcholine receptor.
  • the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject concurrently with a substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I.
  • the subject is administered a pharmaceutical composition comprising (i) the orthosteric agonist of the muscarinic acetylcholine receptor and (ii) a substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I.
  • the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject separately from a substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I.
  • the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject via a first pharmaceutical composition, and the substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I, is administered to the subject via a second pharmaceutical composition.
  • another aspect of the invention provides a method for treating a disorder ameliorated by muscarinic receptor activation in a subject in need thereof, wherein the method comprises administering to the subject a substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I, in combination with an orthosteric agonist of the muscarinic acetylcholine receptor (e.g., xanomeline or a salt thereof) wherein the orthosteric agonist of the muscarinic acetylcholine receptor and the substituted dihydropyrrolo-pyrimidine compound operate on the same muscarinic acetylcholine receptor subtype.
  • a substituted dihydropyrrolo-pyrimidine compound described herein such as a compound of Formula I
  • an orthosteric agonist of the muscarinic acetylcholine receptor e.g., xanomeline or a salt thereof
  • the orthosteric agonist of the muscarinic acetylcholine receptor and the substituted dihydropyrrolo-pyrimidine compound operate on the M1 subtype or M4 subtype of the muscarinic acetylcholine receptor.
  • the terms “muscarinic orthosteric agonist,” “orthosteric muscarinic agonist,” and “muscarinic agonist” refers to agents that activate the muscarinic acetylcholine receptor.
  • Orthosteric refers to a site of a receptor in which the endogenous ligand binds to produce its effect.
  • Muscarinic orthosteric agonists bind to the site of the muscarinic acetylcholine receptor in which endogenous muscarinic ligands bind to produce their effects.
  • Muscarinic acetylcholine receptors are G-protein coupled receptors with five different receptor subtypes (M1–M5), each of which is found in the CNS with different tissue distributions.
  • the term “muscarinic acetylcholine receptor” refers to G-protein-linked receptors that bind the neurotransmitter acetylcholine.
  • M1 means subtype one muscarinic acetylcholine receptor .
  • M2 means subtype two muscarinic acetylcholine receptor.
  • M3 means subtype three muscarinic acetylcholine receptor.
  • M4 means subtype four muscarinic acetylcholine receptor.
  • M5 means subtype five muscarinic acetylcholine receptor.
  • An agonist of the muscarinic acetylcholine receptor may be selective or prefer binding to only one muscarinic receptor subtype, partially selective or prefer binding to two to four subtypes, or non-selective, preferring to bind to each of the five subtypes.
  • Agonists of the muscarinic acetylcholine receptor can be parasympathomimetic. Their mechanism of action is different depending on which receptor is activated. For instance, the mood stabilizers lithium and valproic acid, used for treating bipolar depression, may affect the muscarinic system, mainly through the M4 subtype receptor. Genetic evidence directly links the muscarinic system and alcohol addiction.
  • the agonist of the muscarinic acetylcholine receptor is an orthosteric agonist of the muscarinic acetylcholine receptor.
  • the orthosteric agonist of the muscarinic acetylcholine receptor is a compound in the following table or a pharmaceutically acceptable salt thereof: Muscarinic Acet lcholine Rece tor Subt e L 687,306 X
  • the agonist of the muscarinic acetylcholine receptor is an orthosteric agonist of the muscarinic acetylcholine receptor selected from 77-LH-28-1, A 72055, AF 125, AF 150(S), aceclidine, alvameline, arecoline, bethanechol, carbachol, cevimeline, CI 1017, CMI 1145, CMI 936, FPL 14995, furmethide, HTL-0016878, iperoxo, itrameline, KST 5452, L 670,548, L 687,306, L 689,660, L 686,986, methacholine, N- desmethylclozapine, MCD 386, milameline, NC 111585, nebracetam, NGX267, ORG 20091,
  • the agonist of the muscarinic acetylcholine receptor is an orthosteric agonist of the muscarinic acetylcholine receptor selected from xanomeline or a pharmaceutically acceptable salt thereof.
  • Xanomeline has activity towards both the M1 and M4 muscarinic acetylcholine receptors.
  • the agonist of the muscarinic acetylcholine receptor is a M1 orthosteric agonist of the muscarinic acetylcholine receptor selected from 77-LH-28-1, A 72055, AF 125, AF 150(S), alvameline, bethanechol, carbachol, cevimeline, CI 1017, FPL 14995, iperoxo, itrameline, KST 5452, L 687,306, L 689,660, L 686,986, methacholine, N- desmethylclozapine, MCD 386, milameline, NC 111585, nebracetam, NGX267, ORG 20091, oxotremorine, PD 142505, PD 151832, pilocarpine, sabcomeline, SR 46559A, talsaclidine, tazomeline, thiopilocarpine, tremorine
  • methods described herein further comprise administering to the subject in need thereof a therapeutically effective amount of an orthosteric antagonist of the muscarinic acetylcholine receptor.
  • the orthosteric antagonist of the muscarinic acetylcholine receptor is trospium chloride.
  • the doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disorder.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.
  • the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
  • kits comprising a therapeutically effective amount of the compound described herein (such as a compound of Formula I, or other compounds in Section I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.
  • a therapeutically effective amount of the compound described herein such as a compound of Formula I, or other compounds in Section I
  • a pharmaceutically acceptable carrier such as a compound of Formula I, or other compounds in Section I
  • vehicle or diluent optionally at least one additional therapeutic agent listed above.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or
  • the invention provides a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, or other compounds in Section I) and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, or other compounds in Section I) and a pharmaceutically acceptable carrier.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin;
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [0254]
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to
  • 62 30816081 398813-004WO (206432) increase the flux of the compound across the skin.
  • the rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. [0268] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively,
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
  • the effective amount may be less than when the agent is used alone.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • the invention further provides a unit dosage form (such as a tablet or capsule) comprising a compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein.
  • a unit dosage form such as a tablet or capsule
  • Analytical data is included within the procedures below, in the illustrations of the general procedures, or in the tables of examples.
  • Some examples that are not limiting include flash chromatography performed on the COMBIFLASH® Companion purification system or the Biotage SP1 purification system, products were purified using an Isolute® SPE Si II cartridge, (‘Isolute SPE Si cartridge’ refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles with average size of 50 ⁇ m and nominal 60 ⁇ porosity), and a solvent or combination of solvents (heptane, EtOAc, DCM, MeOH, MeCN, water, etc.) that elutes the desired compounds; RP-HPLC purification performed on Waters Mass Directed FractionLynx systems (2767 autosampler, System Fluidics Organiser, 2998 Photodiode array, 2545 pump, 3x515 pump, QDa mass spectrometer), Gilson system (GX281 autosampler, 322 pump, 155 UV/vis detector), Interchim PuriFlash 4125 coupled to a UV DAD (see Table 2
  • Pellets were then washed twice by centrifugation in 30 mL of 20mM HEPES, pH 7.4, and stored at -80 o C until the day of the assay. On the day of the assay, pellets were thawed on ice and resuspended in 1 mL of 20 mM HEPES, pH 7.4, 10 mM MgCl2, 100 mM NaCl using dounce homogenization.
  • Membrane protein concentration is determined by BCA protein assay (Promega, Madison, WI) according to Promega guidelines.
  • test PAM compounds were brought up in assay buffer (20 mM HEPES, 10 mM MgCl 2 , 100 mM NaCl) at 4X final assay concentration. 25 ml/well of membrane homogenates (containing 5 mg of membrane protein) were prepared
  • Results are presented below in Table 9. Compounds having an activity designated as "A” had an EC50 ⁇ 100 nM; compounds having an activity designated as “B” had an EC50 in the range of 100 nM to 500 nM; compounds having an activity designated as "C” had an EC50 of from greater than 500 nM to 2000 nM; and compounds having an activity designated as "D” had an EC 50 >2000 nM. N/A indicates that no data was available. Table 9. I-12 A B A

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Abstract

The invention provides substituted dihydropyrrolo-pyrimidine compounds, pharmaceutical compositions, and their use in treating muscarinic acetylcholine receptor mediated disorders.

Description

SUBSTITUTED DIHYDROPYRROLO[3,4-D]PYRIMIDINE COMPOUNDS AND THEIR USE IN TREATING MEDICAL CONDITIONS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63/433,238, filed December 16, 2022, the contents of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION [0002] The invention provides substituted dihydropyrrolo-pyrimidine compounds, pharmaceutical compositions, and their use in treating muscarinic acetylcholine receptor mediated disorders. BACKGROUND [0003] Muscarinic acetylcholine receptor mediated disorders such as major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia are psychiatric disorders that continue to be a significant public health problem. Antidepressant drugs, mood stabilizers, and antipsychotics currently available to patients can alleviate certain symptoms of mood disorders in some patients but are only partially effective for a significant number of patients, with many patients being refractory to treatment using currently available drugs. Patients with major depressive disorder often present with at least two weeks of pervasive low mood, low self- esteem, and loss of interest or pleasure in normally enjoyable activities. Patients with bipolar disorder often present with periods of depression and periods of abnormally elevated mood that last from days to weeks each. Patients with schizophrenia often present with active social avoidance, passive social withdrawal, emotional withdrawal, and anxiety. Supportive therapies are used in some contexts to help alleviate the symptoms of muscarinic acetylcholine receptor mediated disorders; however, supportive therapies do not directly treat the disorder and are not a good long-term solution to the patients’ medical needs. [0004] Compounds that modulate the muscarinic acetylcholine receptor can be used to treat diseases associated with muscarinic acetylcholine receptor activity, such as major depressive disorder, bipolar disorder, and schizophrenia. The muscarinic acetylcholine receptor is an acetylcholine receptor that forms G protein-coupled receptor complexes in the cell membrane of certain neurons and other cells. U.S. Patent 10,604,519 describes certain compounds as being active towards the M4 muscarinic acetylcholine receptor. However, new compounds
1 30816081 398813-004WO (206432) with good drug-like properties are needed to treat muscarinic acetylcholine receptor mediated disorders. [0005] Accordingly, the need exists for new therapeutic methods and compounds for treating muscarinic acetylcholine receptor mediated disorders. The present invention addresses the foregoing needs and provides other related advantages. SUMMARY [0006] The invention provides substituted dihydropyrrolo-pyrimidine compounds, pharmaceutical compositions, and their use in treating muscarinic acetylcholine receptor mediated disorders. In particular, one aspect of the invention provides a collection of substituted dihydropyrrolo-pyrimidine compounds, such as a compound represented by Formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of substituted dihydropyrrolo- pyrimidine compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. [0007] Another aspect of the invention provides a method of treating a muscarinic acetylcholine receptor mediated disorder. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat muscarinic acetylcholine receptor mediated disorder, as further described in the detailed description. [0008] Another aspect of the invention provides a method of activating a muscarinic acetylcholine receptor. The method comprises contacting a muscarinic acetylcholine receptor with an effective amount of a compound described herein, such as a compound of Formula I, to activate the muscarinic acetylcholine receptor, as further described in the detailed description. DETAILED DESCRIPTION [0009] The invention provides substituted dihydropyrrolo-pyrimidine compounds, pharmaceutical compositions, and their use in treating muscarinic acetylcholine receptor
2 30816081 398813-004WO (206432) mediated disorders. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology” (F.M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety. [0010] Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls. Definitions [0011] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. [0012] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some
3 30816081 398813-004WO (206432) embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0013] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally, or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
Figure imgf000005_0001
4 30816081 398813-004WO (206432) [0014] Exemplary bridged bicyclics include:
Figure imgf000006_0001
. [0015] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0016] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0017] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)). [0018] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0019] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [0020] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
5 30816081 398813-004WO (206432) [0021] The term “-(C0 alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3 alkylene)-” encompasses a bond (i.e., C0) and a -(C1-3 alkylene)- group. [0022] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. [0023] The term “halogen” means F, Cl, Br, or I. [0024] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “phenylene” refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. [0025] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl
6 30816081 398813-004WO (206432) group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [0026] The term “heteroarylene” refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it. For example, “heteroarylene” is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it. [0027] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4– dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N–substituted pyrrolidinyl). [0028] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “oxo-heterocyclyl” refers to a heterocyclyl substituted by one or more oxo group. The term “heterocyclylene” refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it. The term “oxo-heterocyclylene” refers to a multivalent oxo- heterocyclyl group having the appropriate number of open valences to account for groups attached to it.
7 30816081 398813-004WO (206432) [0029] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [0030] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0031] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; –(CH2)0–4R ^; –(CH2)0–4OR ^; -O(CH2)0-4Ro, –O–(CH2)0– 4C(O)OR°; –(CH2)0–4CH(OR ^)2; –(CH2)0–4SR ^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; – CN; –N3; -(CH2)0–4N(R ^)2; –(CH2)0–4N(R ^)C(O)R ^; –N(R ^)C(S)R ^; –(CH2)0–4N(R ^)C(O)NR ^2; -N(R ^)C(S)NR ^2; –(CH2)0–4N(R ^)C(O)OR ^; –N(R ^)N(R ^)C(O)R ^; -N(R ^)N(R ^)C(O)NR ^2; -N(R ^)N(R ^)C(O)OR ^; –(CH2)0–4C(O)R ^; –C(S)R ^; –(CH2)0–4C(O)OR ^; –(CH2)0–4C(O)SR ^; -(CH2)0–4C(O)OSiR ^3; –(CH2)0–4OC(O)R ^; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0– 4SC(O)R ^; –(CH2)0–4C(O)NR ^2; –C(S)NR ^2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR ^2; -C(O)N(OR ^)R ^; –C(O)C(O)R ^; –C(O)CH2C(O)R ^; –C(NOR ^)R ^; -(CH2)0–4SSR ^; –(CH2)0– 4S(O)2R ^; –(CH2)0–4S(O)2OR ^; –(CH2)0–4OS(O)2R ^; –S(O)2NR ^2; –S(O)(NR ^)R ^; – S(O)2N=C(NR ^2)2; -(CH2)0–4S(O)R ^; -N(R ^)S(O)2NR ^2; –N(R ^)S(O)2R ^; –N(OR ^)R ^; – C(NH)NR ^2; –P(O)2R ^; -P(O)R ^2; -OP(O)R ^2; –OP(O)(OR ^)2; SiR ^3; –(C1–4 straight or branched alkylene)O–N(R ^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R ^)2. [0032] Each R ^ is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5- 6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,
8 30816081 398813-004WO (206432) notwithstanding the definition above, two independent occurrences of R ^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R ^ selected from =O and =S; or each R ^ is optionally substituted with a monovalent substituent independently selected from halogen, –(CH2)0–2R ^, –(haloR ^), –(CH2)0–2OH, –(CH2)0–2OR ^, – (CH2)0–2CH(OR ^)2; -O(haloR ^), –CN, –N3, –(CH2)0–2C(O)R ^, –(CH2)0–2C(O)OH, –(CH2)0– 2C(O)OR ^, –(CH2)0–2SR ^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR ^, –(CH2)0–2NR ^2, – NO2, –SiR ^3, –OSiR ^3, -C(O)SR ^, –(C1–4 straight or branched alkylene)C(O)OR ^, or –SSR ^. [0033] Each R ^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^ is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –
Figure imgf000010_0001
or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is –O(CR* 2)2–3O–, wherein each independent occurrence of R* is selected from hydrogen, C1–6 aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [0034] When R* is C1–6 aliphatic, R* is optionally substituted with halogen, – R ^, -(haloR ^), -OH, –OR ^, –O(haloR ^), –CN, –C(O)OH, –C(O)OR ^, –NH2, –NHR ^, –NR ^2, or –NO2, wherein each R ^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^ is unsubstituted or where preceded by halo is substituted only with one or more halogens. –
Figure imgf000010_0002
C - - – C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R† is independently hydrogen, C1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when
9 30816081 398813-004WO (206432) R† is C1–6 aliphatic, R† is optionally substituted with halogen, –R ^, -(haloR ^), -OH, –OR ^, – O(haloR ^), –CN, –C(O)OH, –C(O)OR ^, –NH2, –NHR ^, –NR ^2, or –NO2, wherein each R ^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^ is unsubstituted or where preceded by halo is substituted only with one or more halogens. [0036] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3– phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [0037] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.
10 30816081 398813-004WO (206432) [0038] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [0039] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. [0040] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. [0041] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further,
11 30816081 398813-004WO (206432) to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention. [0042] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. [0043] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. [0044] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10 alkyl, and C1-C6 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. [0045] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group. [0046] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “haloalkylene” refers to a bivalent haloalkyl group. [0047] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like. [0048] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
12 30816081 398813-004WO (206432) [0049] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like. [0050] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane susbstituted with an oxo group is cyclopentanone. [0051] The symbol “ ” indicates a point of attachment. [0052] When any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated. [0053] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O. [0054] As used herein, the terms “subject” and “patient” are used interchangeable and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans. [0055] The term “EC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% of the maximal response. [0056] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening,
13 30816081 398813-004WO (206432) reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. [0057] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. [0058] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975]. [0059] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. [0060] In addition, when a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. [0061] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps. [0062] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.
14 30816081 398813-004WO (206432) I. Substituted dihydropyrrolo-pyrimidine compounds [0063] One aspect of the invention provides substituted dihydropyrrolo-pyrimidine compounds. The compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds. [0064] One aspect of the invention provides a compound represented by Formula I:
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof; wherein: R1 is C1-4 alkoxyl, -N(R4)2, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O-(C3-6 cycloalkyl), or -(C1-6 alkylene)-(C3-6 cycloalkyl); R2 is cyano, C1-4 alkyl, C1-4 haloalkyl, or hydrogen; R3 represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, or halo; R4 represents independently for each occurrence hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom; R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), - (C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl); A1 is phenyl or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the phenyl and heteroaryl are substituted with n occurrences of R5; X1 is -(C1-4 alkylene)-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A1; m is 0, 1, 2, or 3; and n is 0, 1, or 2. [0065] The definitions of variables in Formula I above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a
15 30816081 398813-004WO (206432) variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0066] In certain embodiments, the compound is a compound of Formula I. [0067] As defined generally above, R1 is C1-4 alkoxyl, -N(R4)2, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O-(C3-6 cycloalkyl), or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, -N(R4)2, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is -N(R4)2, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, -N(R4)2, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, -N(R4)2, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)- (C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, -N(R4)2, C1-6 alkyl, C1-6 haloalkyl,or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, - N(R4)2, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl. In certain embodiments, R1 is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is -N(R4)2, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 -N(R4)2, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is -N(R4)2, C1-6 alkyl, C1-6 haloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is -N(R4)2, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl. In certain embodiments, R1 is C1-4 alkoxyl, C1-6 haloalkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)- (C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, C1-6 alkyl, C3-6 cycloalkyl, or -(C1- 6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl. In certain embodiments, R1 is C1-4 alkoxyl, -N(R4)2, C3- 6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, - N(R4)2, C1-6 haloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, -N(R4)2, C1-6 haloalkyl, or C3-6 cycloalkyl. In certain embodiments, R1 is C1-4 alkoxyl, - N(R4)2, C1-6 alkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is C1-4 alkoxyl, -N(R4)2, C1-6 alkyl, or C3-6 cycloalkyl. In certain embodiments, R1 is C1-4 alkoxyl, - N(R4)2, C1-6 alkyl, or C1-6 haloalkyl. In certain embodiments, R1 is -N(R4)2 or -O-(C3-6 cycloalkyl).
16 30816081 398813-004WO (206432) [0068] In certain embodiments, R1 is C1-4 alkoxyl. In certain embodiments, R1 is C1-4 alkoxyl. In certain embodiments, R1 is C1-3 alkoxyl. In certain embodiments, R1 is C2-4 alkoxyl. In certain embodiments, R1 is C3-4 alkoxyl. In certain embodiments, R1 is -OCH3, - OCH2CH3, -OCH(CH3)2, or -OC(CH3)3. In certain embodiments, R1 is -OCH3. In certain embodiments, R1 is -OCH2CH3. In certain embodiments R1 is -OCH(CH3)2. In certain embodiments, R1 is -OC(CH3)3. [0069] In certain embodiments, R1 is -N(R4)2. In certain embodiments, R1 is -N(R4)2, wherein R4 represents independently for each occurrence hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, R1 is -N(R4)2, wherein R4 represents independently for each occurrence C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, R1 is -N(R4)2, wherein two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, R1 is -N(R4)2, wherein R4 represents independently for each occurrence hydrogen or C3-6 cycloalkyl. In certain embodiments, R1 is - N(R4)2, wherein two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, R1 is -N(R4)2, wherein R4 represents independently for each occurrence hydrogen or C3-6 cycloalkyl.
Figure imgf000018_0001
[0070] In certain embodiments, . [0071] In certain embodiments, R1 is C1-6 alkyl. In certain embodiments, R1 is C1-4 alkyl. In certain embodiments, R1 is C1-3 alkyl. In certain embodiments, R1 is C2-6 alkyl. In certain embodiments, R1 is C3-6 alkyl. In certain embodiments, R1 is methyl, ethyl, or propyl. In certain embodiments, R1 is methyl. In certain embodiments, R1 is ethyl. [0072] In certain embodiments, R1 is C1-6 haloalkyl. In certain embodiments, R1 is C1-4 haloalkyl. In certain embodiments, R1 is C1-3 haloalkyl. In certain embodiments, R1 is C2-6 haloalkyl. In certain embodiments, R1 is C3-6 haloalkyl. In certain embodiments, R1 is C1-6 haloalkyl, wherein the halogen is F. In certain embodiments, R1 is C1-4 haloalkyl, wherein the halogen is selected F. In certain embodiments, R1 is C1-3 haloalkyl, wherein the halogen is F.
17 30816081 398813-004WO (206432) In certain embodiments, R1 is C2-6 haloalkyl, wherein the halogen is F. In certain embodiments, R1 is C3-6 haloalkyl, wherein the halogen is F. In certain embodiments, R1 is CF3. In some embodiments, R1 is CHF2. In some embodiments, R1 is -CH2CF3. In some embodiments, R1 is -CH2CHF2. [0073] In certain embodiments, R1 is C3-6 cycloalkyl. In certain embodiments, R1 is C4-6 cycloalkyl. In certain embodiments, R1 is C5-6 cycloalkyl. In certain embodiments, R1 is cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R1 is cyclopropyl. [0074] In certain embodiments, R1 is -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is -(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is -(C2-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R1 is -(C1-4 alkylene)-(C5-6 cycloalkyl). In certain embodiments, R1 is -(C1-3 alkylene)-(C4-6 cycloalkyl). In certain embodiments, R1 is - (C1-2 alkylene)-(C3-5 cycloalkyl). [0075] In certain embodiments,
Figure imgf000019_0001
. [0076] In certain embodiments, R1 is selected from those depicted in Table 1. [0077] As defined generally above, R2 is cyano, C1-4 alkyl, C1-4 haloalkyl, or hydrogen. In certain embodiments, R2 is C1-4 alkyl, C1-4 haloalkyl, or hydrogen. In certain embodiments, R2 is cyano, C1-4 haloalkyl, or hydrogen. In certain embodiments, R2 is cyano, C1-4 alkyl, or hydrogen. In certain embodiments, R2 is cyano, C1-4 alkyl, or C1-4 haloalkyl. In certain embodiments, R2 is cyano. [0078] In certain embodiments, R2 is C1-4 alkyl. In certain embodiments, R2 is C1-3 alkyl. In certain embodiments, R2 is C2-4 alkyl. In certain embodiments, R2 is C3-4 alkyl. In certain embodiments, R2 is methyl, ethyl, or propyl. In certain embodiments, R2 is methyl. In certain embodiments, R2 is ethyl. [0079] In certain embodiments, R2 is C1-4 haloalkyl. In certain embodiments, R2 is C1-4 haloalkyl. In certain embodiments, R2 is C1-3 haloalkyl. In certain embodiments, R2 is C2-4 haloalkyl. In certain embodiments, R2 is C3-4 haloalkyl. In certain embodiments, R2 is C1-4 haloalkyl, wherein the halogen is F. In certain embodiments, R2 is C1-4 haloalkyl, wherein the halogen is selected F. In certain embodiments, R2 is C1-3 haloalkyl, wherein the halogen is F. In certain embodiments, R2 is C2-4 haloalkyl, wherein the halogen is F. In certain embodiments, R2 is C3-4 haloalkyl, wherein the halogen is F. In certain embodiments, R2 is CF3. In some
18 30816081 398813-004WO (206432) embodiments, R2 is CHF2. In some embodiments, R2 is -CH2CF3. In some embodiments, R4 is -CH2CHF2. [0080] In certain embodiments, R2 is hydrogen. [0081] In certain embodiments, R2 is selected from those depicted in Table 1. [0082] As defined generally above, R3 represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, or halo. In certain embodiments, R3 represents independently for each occurrence C1-4 alkyl. In certain embodiments, R3 represents independently for each occurrence C1-3 alkyl. In certain embodiments, R3 represents independently for each occurrence C2-4 alkyl. In certain embodiments, R3 represents independently for each occurrence C3-4 alkyl. In certain embodiments, R3 represents independently for each occurrence methyl, ethyl, or propyl. [0083] In certain embodiments, R3 represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R3 represents independently for each occurrence C1-3 haloalkyl. In certain embodiments, R3 represents independently for each occurrence C2-4 haloalkyl. In certain embodiments, R3 represents independently for each occurrence C3-4 haloalkyl. [0084] In certain embodiments, R3 represents independently for each occurrence C1-4 haloalkyl, wherein the halogen represents independently for each occurrence F. In certain embodiments, R3 represents independently for each occurrence C1-4 haloalkyl, wherein the halogen represents independently for each occurrence selected F. In certain embodiments, R3 represents independently for each occurrence C1-3 haloalkyl, wherein the halogen represents independently for each occurrence F. In certain embodiments, R3 represents independently for each occurrence C2-4 haloalkyl, wherein the halogen represents independently for each occurrence F. In certain embodiments, R3 represents independently for each occurrence C3-4 haloalkyl, wherein the halogen represents independently for each occurrence F. [0085] In certain embodiments, R3 represents independently for each occurrence CF3. In some embodiments, R3 represents independently for each occurrence CHF2. In some embodiments, R3 represents independently for each occurrence -CH2CF3. In some embodiments, R3 represents independently for each occurrence -CH2CHF2. [0086] In certain embodiments, R3 represents independently for each occurrence halo. In certain embodiments, R3 represents independently for each occurrence F or Cl. [0087] In certain embodiments, R3 is C1-4 alkyl. In certain embodiments, R3 is C1-3 alkyl. In certain embodiments, R3 is C2-4 alkyl. In certain embodiments, R3 is C3-4 alkyl. In certain
19 30816081 398813-004WO (206432) embodiments, R3 is methyl, ethyl, or propyl. In certain embodiments, R3 is methyl. In certain embodiments, R3 is ethyl. [0088] In certain embodiments, R3 is C1-4 haloalkyl. In certain embodiments, R3 is C1-3 haloalkyl. In certain embodiments, R3 is C2-4 haloalkyl. In certain embodiments, R3 is C3-4 haloalkyl. In certain embodiments, R3 is C1-4 haloalkyl, wherein the halogen is F. In certain embodiments, R3 is C1-4 haloalkyl, wherein the halogen is selected F. In certain embodiments, R3 is C1-3 haloalkyl, wherein the halogen is F. In certain embodiments, R3 is C2-4 haloalkyl, wherein the halogen is F. In certain embodiments, R3 is C3-4 haloalkyl, wherein the halogen is F. In certain embodiments, R3 is CF3. In some embodiments, R3 is CHF2. In some embodiments, R4 is -CH2CF3. In some embodiments, R4 is -CH2CHF2. [0089] In certain embodiments, R3 is halo. In certain embodiments, R3 is F. In certain embodiments, R3 is Cl. [0090] In certain embodiments, R3 is selected from those depicted in Table 1. [0091] As defined generally above, R4 represents independently for each occurrence hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, R4 represents independently for each occurrence C1-6 alkyl. In certain embodiments, R4 represents independently for each occurrence C1-4 alkyl. In certain embodiments, R4 represents independently for each occurrence C1-3 alkyl. In certain embodiments, R4 represents independently for each occurrence C2-6 alkyl. In certain embodiments, R4 represents independently for each occurrence C3-6 alkyl. In certain embodiments, R4 represents independently for each occurrence methyl, ethyl, or propyl. [0092] In certain embodiments, R4 represents independently for each occurrence C3-6 cycloalkyl. In certain embodiments, R4 represents independently for each occurrence C4-6 cycloalkyl. In certain embodiments, R4 represents independently for each occurrence C5-6 cycloalkyl. In certain embodiments, R4 represents independently for each occurrence cyclopropyl or cyclopentyl. [0093] In certain embodiments, R4 represents independently for each occurrence -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R4 represents independently for each occurrence -(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R4 represents independently for each occurrence -(C2-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R4 represents independently for each occurrence -(C1-4 alkylene)-(C5-6 cycloalkyl). In certain
20 30816081 398813-004WO (206432) embodiments, R4 represents independently for each occurrence -(C1-3 alkylene)-(C4-6 cycloalkyl). In certain embodiments, R4 represents independently for each occurrence -(C1-2 alkylene)-(C3-5 cycloalkyl). [0094] In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is C1-6 alkyl. In certain embodiments, R4 is C1-4 alkyl. In certain embodiments, R4 is C1-3 alkyl. In certain embodiments, R4 is C2-6 alkyl. In certain embodiments, R4 is C3-6 alkyl. In certain embodiments, R4 is methyl, ethyl, or propyl. In certain embodiments, R4 is methyl. In certain embodiments, R4 is ethyl. [0095] In certain embodiments, R4 is C3-6 cycloalkyl. In certain embodiments, R4 is C4-6 cycloalkyl. In certain embodiments, R4 is C5-6 cycloalkyl. In certain embodiments, R4 is C3 cycloalkyl. In certain embodiments, R4 is C4 cycloalkyl. In certain embodiments, R4 is C5 cycloalkyl. In certain embodiments, R4 is C6 cycloalkyl. In certain embodiments, R4 is cyclopropyl or cyclopentyl. In certain embodiments, R4 is cyclopropyl. In certain embodiments, R4 is cyclopentyl. [0096] In certain embodiments, R4 is -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R4 is -(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R4 is -(C2-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R4 is -(C1-4 alkylene)-(C5-6 cycloalkyl). In certain embodiments, R4 represents independently for each occurrence -(C1-3 alkylene)-(C4-6 cycloalkyl). In certain embodiments, R4 represents independently for each occurrence -(C1-2 alkylene)-(C3-5 cycloalkyl). [0097] In certain embodiments, two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 4-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-6 membered saturated ring containing 1 nitrogen atom. In certain embodiments, two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-5 membered saturated ring containing 1 nitrogen atom. [0098] In certain embodiments, R4 is selected from those depicted in Table 1. [0099] As defined generally above, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6
21 30816081 398813-004WO (206432) alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence halo, C1- 6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3- 6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1- 6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), - (C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)- (C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3- 6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-
22 30816081 398813-004WO (206432) 6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1- 6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)- (C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, - SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)- (C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1- 6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1- 6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), or - O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1- 6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), or -(C1-6 alkylene)-(C3-6 halocycloalkyl). [0100] In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, or C1-6 haloalkoxyl. In certain embodiments, R5 represents independently for each occurrence -SO2-(C1-6 haloalkyl) or -SO2-(C1-6 alkyl). In certain embodiments, R5 represents independently for each occurrence - (C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence halo, C1-6 haloalkyl, C1-6 alkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), hydroxyl, C1-6 alkoxyl, or -(C1-6 alkylene)-(C1-6 alkoxyl). In certain embodiments, R5 represents independently for each occurrence represents independently for each occurrence halo, C1-6 haloalkyl, C1-6 alkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), or -SO2-(C1-6 alkyl). In certain embodiments, R5 represents independently for each occurrence halo, C1-6 haloalkyl, C1-6 alkyl, or C3-6 cycloalkyl.
23 30816081 398813-004WO (206432) [0101] In certain embodiments, R5 represents independently for each occurrence halo or C1-6 haloalkyl. In certain embodiments, R5 represents independently for each occurrence halo. In certain embodiments, R5 represents independently for each occurrence F or Cl. [0102] In certain embodiments, R5 represents independently for each occurrence C1-6 haloalkyl. In certain embodiments, R5 represents independently for each occurrence C1-4 haloalkyl. In certain embodiments, R5 represents independently for each occurrence C1-3 haloalkyl. In certain embodiments, R5 represents independently for each occurrence C2-6 haloalkyl. In certain embodiments, R5 represents independently for each occurrence C3-6 haloalkyl. In certain embodiments, R5 represents independently for each occurrence C1-6 haloalkyl, wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence C1-4 haloalkyl, wherein the halogen represents independently for each occurrence selected F. In certain embodiments, R5 represents independently for each occurrence C1-3 haloalkyl, wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence C2-6 haloalkyl, wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence C3-6 haloalkyl, wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence CF3, CHF2, -CH2CF3, or -CH2CHF2. [0103] In certain embodiments, R5 represents independently for each occurrence C1-6 alkyl. In certain embodiments, R5 represents independently for each occurrence C1-4 alkyl. In certain embodiments, R5 represents independently for each occurrence C1-3 alkyl. In certain embodiments, R5 represents independently for each occurrence C2-6 alkyl. In certain embodiments, R5 represents independently for each occurrence C3-6 alkyl. In certain embodiments, R5 represents independently for each occurrence methyl, ethyl, or propyl. [0104] In certain embodiments, R5 represents independently for each occurrence C3-6 cycloalkyl. In certain embodiments, R5 represents independently for each occurrence C4-6 cycloalkyl. In certain embodiments, R5 represents independently for each occurrence C5-6 cycloalkyl. In certain embodiments, R5 represents independently for each occurrence C3 cycloalkyl. In certain embodiments, R5 represents independently for each occurrence C4 cycloalkyl. In certain embodiments, R5 represents independently for each occurrence C5 cycloalkyl. In certain embodiments, R5 represents independently for each occurrence C6 cycloalkyl. In certain embodiments, R5 represents independently for each occurrence cyclopropyl or cyclopentyl. [0105] In certain embodiments, R5 represents independently for each occurrence -SO2-(C1-6 haloalkyl). In certain embodiments, R5 represents independently for each occurrence -SO2-(C1-
24 30816081 398813-004WO (206432) 5 haloalkyl), wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence -SO2-(C1-4 haloalkyl), wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence -SO2-(C1-3 haloalkyl), wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence -SO2-(C2-6 haloalkyl), wherein the halogen is F. [0106] In certain embodiments, R5 represents independently for each occurrence -SO2-(C1-5 haloalkyl). In certain embodiments, R5 represents independently for each occurrence -SO2-(C1- 4 haloalkyl). In certain embodiments, R5 represents independently for each occurrence -SO2- (C1-3 haloalkyl). In certain embodiments, R5 represents independently for each occurrence - SO2-(C2-6 haloalkyl). In certain embodiments, R5 represents independently for each occurrence -SO2CF3, -SO2CHF2, -SO2-CH2CF3, or -SO2-CH2CHF2. [0107] In certain embodiments, R5 represents independently for each occurrence -SO2-(C1-6 alkyl). In certain embodiments, R5 represents independently for each occurrence -SO2-(C1-5 alkyl). In certain embodiments, R5 represents independently for each occurrence -SO2-(C1-4 alkyl). In certain embodiments, R5 represents independently for each occurrence -SO2-(C1-3 alkyl). In certain embodiments, R5 represents independently for each occurrence -SO2-(C2-6 alkyl). In certain embodiments, represents independently for each occurrence -SO2CH3, - SO2CH2CH3, -SO2CH(CH3)2, -SO2CH2CH(CH3)2, -SO2C(CH3)3, or -SO2CH2C(CH3)3. [0108] In certain embodiments, R5 represents independently for each occurrence C1-6 hydroxyalkyl. In certain embodiments, R5 represents independently for each occurrence C1-4 hydroxyalkyl. In certain embodiments, R5 represents independently for each occurrence C1-3 hydroxyalkyl. In certain embodiments, R5 represents independently for each occurrence C2-6 hydroxyalkyl. [0109] In certain embodiments, R5 represents independently for each occurrence C1-6 alkoxyl. In certain embodiments, R5 represents independently for each occurrence C1-3 alkoxyl. In certain embodiments, R5 represents independently for each occurrence C2-6 alkoxyl. In certain embodiments, R5 represents independently for each occurrence C4-6 alkoxyl. In certain embodiments, R5 represents independently for each occurrence -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH2CH2CH2CH3, -O(CH2)4CH3, -OCH(CH3)2, -OCH2CH(CH3)2, - OCH2CH2CH(CH3)2, -O(CH2)3CH(CH3)2, -OC(CH3)3, -OCH2C(CH3)3, or -OCH2CH2C(CH3)3. In certain embodiments, R5 represents independently for each occurrence -OCH3 or - OCH2CH3.
25 30816081 398813-004WO (206432) [0110] In certain embodiments, R5 represents independently for each occurrence C1-6 haloalkoxyl. In certain embodiments, R5 represents independently for each occurrence C1-3 haloalkoxyl. In certain embodiments, R5 represents independently for each occurrence C2-6 haloalkoxyl. In certain embodiments, R5 represents independently for each occurrence C4-6 haloalkoxyl. In certain embodiments, R5 represents independently for each occurrence C1 haloalkoxyl. In certain embodiments, R5 represents independently for each occurrence C2 haloalkoxyl. [0111] In certain embodiments, R5 represents independently for each occurrence C1-6 haloalkoxyl, wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence C1-3 haloalkoxyl, wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence C2-6 haloalkoxyl, wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence C4-6 haloalkoxyl, wherein the halogen is F. In certain embodiments, R5 represents independently for each occurrence -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -(C2-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -(C1-4 alkylene)-(C5-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -(C1-3 alkylene)-(C4-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -(C1-2 alkylene)-(C3-5 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -(C1-6 alkylene)-(C1-6 alkoxyl). In certain embodiments, R5 represents independently for each occurrence -(C1-4 alkylene)-(C3-6 alkoxyl). In certain embodiments, R5 represents independently for each occurrence -(C2-6 alkylene)-(C3-6 alkoxyl). In certain embodiments, R5 represents independently for each occurrence -(C1-4 alkylene)-(C5-6 alkoxyl). In certain embodiments, R5 represents independently for each occurrence -(C1-3 alkylene)-(C4-6 alkoxyl). In certain embodiments, R5 represents independently for each occurrence -(C1-2 alkylene)-(C3-5 alkoxyl). [0112] In certain embodiments, R5 represents independently for each occurrence -(C1-6 alkylene)-(C3-6 halocycloalkyl). In certain embodiments, R5 represents independently for each occurrence -(C1-4 alkylene)-(C3-6 halocycloalkyl). In certain embodiments, R5 represents independently for each occurrence -(C2-6 alkylene)-(C3-6 halocycloalkyl). In certain embodiments, R5 represents independently for each occurrence -(C1-4 alkylene)-(C5-6 halocycloalkyl). In certain embodiments, R5 represents independently for each occurrence -
26 30816081 398813-004WO (206432) (C1-3 alkylene)-(C4-6 halocycloalkyl). In certain embodiments, R5 represents independently for each occurrence -(C1-2 alkylene)-(C3-5 halocycloalkyl). [0113] In certain embodiments, R5 represents independently for each occurrence -O-(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -O-(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -O-(C2-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -O-(C1-4 alkylene)-(C5-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -O-(C1-3 alkylene)-(C4-6 cycloalkyl). In certain embodiments, R5 represents independently for each occurrence -O-(C1-2 alkylene)-(C3-5 cycloalkyl). [0114] In certain embodiments, R5 is C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2- (C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), -(C1-6 alkylene)- (C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl). [0115] In certain embodiments, R5 is cyano. In certain embodiments, R5 is hydroxyl. In certain embodiments, R5 is halo. In certain embodiments, R5 is F or Cl. In certain embodiments, R5 is F. In certain embodiments, R5 is Cl. [0116] In certain embodiments, R5 is C1-6 haloalkyl. In certain embodiments, R5 is C1-4 haloalkyl. In certain embodiments, R5 is C1-3 haloalkyl. In certain embodiments, R5 is C2-6 haloalkyl. In certain embodiments, R5 is C3-6 haloalkyl. In certain embodiments, R5 is C1-6 haloalkyl, wherein the halogen is F. In certain embodiments, R5 is C1-4 haloalkyl, wherein the halogen is selected F. In certain embodiments, R5 is C1-3 haloalkyl, wherein the halogen is F. In certain embodiments, R5 is C2-6 haloalkyl, wherein the halogen is F. In certain embodiments, R5 is C3-6 haloalkyl, wherein the halogen is F. In certain embodiments, R5 is -CF3, -CHF2, - CH2CF3, or -CH2CHF2. In certain embodiments, R5 is CF3. In some embodiments, R5 is CHF2. In some embodiments, R5 is -CH2CF3. In some embodiments, R5 is -CH2CHF2. [0117] In certain embodiments, R5 is C1-6 alkyl. In certain embodiments, R5 is C1-4 alkyl. In certain embodiments, R5 is C1-3 alkyl. In certain embodiments, R5 is C2-6 alkyl. In certain embodiments, R5 is C3-6 alkyl. In certain embodiments, R5 is methyl, ethyl, or propyl. In certain embodiments, R5 is methyl. In certain embodiments, R5 is ethyl. [0118] In certain embodiments, R5 is C3-6 cycloalkyl. In certain embodiments, R5 is C4-6 cycloalkyl. In certain embodiments, R5 is C5-6 cycloalkyl. In certain embodiments, R5 is C3 cycloalkyl. In certain embodiments, R5 is C4 cycloalkyl. In certain embodiments, R5 is C5
27 30816081 398813-004WO (206432) cycloalkyl. In certain embodiments, R5 is C6 cycloalkyl. In certain embodiments, R5 is cyclopropyl or cyclopentyl. In certain embodiments, R5 is cyclopropyl. [0119] In certain embodiments, R5 is -SO2-(C1-6 haloalkyl). In certain embodiments, R5 is - SO2-(C1-5 haloalkyl), wherein the halogen is F. In certain embodiments, R5 is -SO2-(C1-4 haloalkyl), wherein the halogen is F. In certain embodiments, R5 is -SO2-(C1-3 haloalkyl), wherein the halogen is F. In certain embodiments, R5 is -SO2-(C2-6 haloalkyl), wherein the halogen is F. In certain embodiments, R5 is -SO2-(C1-5 haloalkyl). In certain embodiments, R5 is -SO2-(C1-4 haloalkyl). In certain embodiments, R5 is -SO2-(C1-3 haloalkyl). In certain embodiments, R5 is -SO2-(C2-6 haloalkyl). In certain embodiments, R5 is -SO2CF3, -SO2CHF2, - SO2-CH2CF3, or -SO2-CH2CHF2. [0120] In certain embodiments, R5 is -SO2-(C1-6 alkyl). In certain embodiments, R5 is -SO2- (C1-5 alkyl). In certain embodiments, R5 is -SO2-(C1-4 alkyl). In certain embodiments, R5 is - SO2-(C1-3 alkyl). In certain embodiments, R5 is -SO2-(C2-6 alkyl). In certain embodiments, is R5 is -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -SO2CH2CH(CH3)2, -SO2C(CH3)3, or - SO2CH2C(CH3)3. [0121] In certain embodiments, R5 is C1-6 hydroxyalkyl. In certain embodiments, R5 is C1-3 hydroxyalkyl. In certain embodiments, R5 is C2-6 hydroxyalkyl. [0122] In certain embodiments, R5 is C1-6 alkoxyl. In certain embodiments, R5 is C1-3 alkoxyl. In certain embodiments, R5 is C2-6 alkoxyl. In certain embodiments, R5 is C4-6 alkoxyl. In certain embodiments, R5 is -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH2CH2CH2CH3, -O(CH2)4CH3, -OCH(CH3)2, -OCH2CH(CH3)2, -OCH2CH2CH(CH3)2, - O(CH2)3CH(CH3)2, -OC(CH3)3, -OCH2C(CH3)3, or -OCH2CH2C(CH3)3. In certain embodiments, R5 is -OCH3 or -OCH2CH3. [0123] In certain embodiments, R5 is C1-6 haloalkoxyl. In certain embodiments, R5 is C1-3 haloalkoxyl. In certain embodiments, R5 is C2-6 haloalkoxyl. In certain embodiments, R5 is C1- 4 haloalkoxyl. In certain embodiments, R5 is C1-2 haloalkoxyl. In certain embodiments, R5 is - OCH2F, -OCHF2, -OCF3, -OCH2CF3, or -OCF2CF3. [0124] In certain embodiments, R5 is -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 is -(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 is -(C2-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 is -(C1-4 alkylene)-(C5-6 cycloalkyl). In certain embodiments, R5 is -(C1-3 alkylene)-(C4-6 cycloalkyl). In certain embodiments, R5 is -O- (C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 is O-(C1-4 alkylene)-(C3-6 cycloalkyl). In certain embodiments, R5 is -O-(C2-6 alkylene)-(C3-6 cycloalkyl). In certain
28 30816081 398813-004WO (206432) embodiments, R5 is -O-(C1-4 alkylene)-(C5-6 cycloalkyl). In certain embodiments, R5 is -O-(C1-3 alkylene)-(C4-6 cycloalkyl). In certain embodiments, R5 is -O-(C1-2 alkylene)-(C3-5 cycloalkyl). In certain embodiments, R5 is -(C1-6 alkylene)-(C1-6 alkoxyl). In certain embodiments, R5 is - (C1-4 alkylene)-(C3-6 alkoxyl). In certain embodiments, R5 is -(C2-6 alkylene)-(C3-6 alkoxyl). In certain embodiments, R5 is -(C1-4 alkylene)-(C5-6 alkoxyl). In certain embodiments, R5 is -(C1-3 alkylene)-(C4-6 alkoxyl). In certain embodiments, R5 is -(C1-2 alkylene)-(C3-5 alkoxyl). In certain embodiments, R5 is -(C1-6 alkylene)-(C3-6 halocycloalkyl). In certain embodiments, R5 is -(C1-4 alkylene)-(C3-6 halocycloalkyl). In certain embodiments, R5 is -(C2-6 alkylene)-(C3-6 halocycloalkyl). In certain embodiments, R5 is -(C1-4 alkylene)-(C5-6 halocycloalkyl). In certain embodiments, R5 is -(C1-3 alkylene)-(C4-6 halocycloalkyl). In certain embodiments, R5 is -(C1-2 alkylene)-(C3-5 halocycloalkyl). [0125] In certain embodiments, R5 is selected from those depicted in Table 1. [0126] As defined geneally above, A1 is phenyl or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the phenyl and heteroaryl are substituted with n occurrences of R5 [0127] In certain embodiments, A1 is phenyl substituted with n occurrences of R5. [0128] In certain embodiments, A1 is 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl are substituted with n occurrences of R5. In certain embodiments, A1 is pyridinyl substituted with n occurrences of R5. In certain embodiments, A1 is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, thiophenyl, or pyridinyl, each of which is substituted with n occurrences of R5. In certain embodiments, A1 is pyrazolyl, imidazolyl, oxazolyl, or isoxazolyl, each of which is substituted with n occurrences of R5. In certain embodiments, A1 is pyrazolyl substituted with n occurrences of R5. [0129] In certain embodiments, A1 is selected from those depicted in Table 1. [0130] As defined generally above, X1 is -(C1-4 alkylene)-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -(C1-3 alkylene)-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -(C1-2 alkylene)-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -(C2-4 alkylene)-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -(C3-4 alkylene)-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -(C1-4 alkylene)-(C3-4 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is
29 30816081 398813-004WO (206432) -(C1-4 alkylene)-(C4-5 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -(C1-3 alkylene)-(C3-4 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -(C1-2 alkylene)-(C3-4 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -CH2-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -CH2CH2-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A1. [0131] In certain embodiments, X1 is -CH2-(C3 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -CH2-(C4 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -CH2-(C5 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -CH2CH2-(C3 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -CH2CH2-(C4 cycloalkylene)-***, wherein *** is a point of attachment to A1. In certain embodiments, X1 is -CH2CH2-(C5 cycloalkylene)-***, wherein *** is a point of attachment to A1. [0132] In certain embodiments, X1 is
Figure imgf000031_0001
, wherein *** is a point of attachment to A1. [0133] As defined generally above, m is 0, 1, 2, or 3. In certain embodiments, m is 1, 2, or 3. In certain embodiments, m is 0, 2, or 3. In certain embodiments, m is 0, 1, or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 2 or 3. In certain embodiments, m is 0 or 1. In certain embodiments, m is 0 or 3. In certain embodiments, m is 0 or 2. In certain embodiments, m is 1 or 2. In certain embodiments, m is 1 or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. [0134] As defined generally above, n is 0, 1, or 2. In certain embodiments, n is 1 or 2. In certain embodiments, n is 0 or 2. In certain embodiments, n is 0 or 1. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. [0135] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments.
30 30816081 398813-004WO (206432) [0136] In certain embodiments, the compound of Formula I is further defined by Formula Ia or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above:
Figure imgf000032_0001
[0137] In certain embodiments, the compound of Formula I is further defined by Formula Ib or Ic or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above:
Figure imgf000032_0002
[0138] In certain embodiments, the compound of Formula I is further defined by Formula Id or Ie or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above:
Figure imgf000032_0003
Id Ie.
31 30816081 398813-004WO (206432) [0139] In certain embodiments, the compound of Formula I is further defined by Formula If or Ig, or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above:
Figure imgf000033_0001
[0140] In certain embodiments, the compound of Formula I is further defined by Formula Ih or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above:
Figure imgf000033_0002
[0141] In certain embodiments, the compound of Formula I is further defined by Formula Ii, Ij, Ik, or Il or a pharmaceutically acceptable salt thereof, where indicated variables are as defined in the description of Formula I above:
Figure imgf000033_0003
Ik Il.
32 30816081 398813-004WO (206432) Exemplary Specific Compounds [0142] In certain embodiments, the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1. TABLE 1. Exemplary Compounds Exam le Structure
Figure imgf000034_0001
Stereoisomer 1
33 30816081 398813-004WO (206432) Example Structure
Figure imgf000035_0001
Stereoisomer 1
34 30816081 398813-004WO (206432) Example Structure
Figure imgf000036_0001
Synthetic Methods [0143] Methods for preparing compounds described herein are illustrated in the following synthetic Scheme. The Scheme is given for the purpose of illustrating the invention, and not intended to limit the scope or spirit of the invention. Starting materials shown in the Scheme can be obtained from commercial sources or can be prepared based on procedures described in the literature. [0144] Scheme 1 illustrates a general method for preparing dihydropyrrolo-pyrimidines C. 6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidine A is coupled to carboxylic acid B using amide-bond forming conditions (e.g., HATU mediated acid amine coupling) to afford dihydropyrrolo- pyrimidines C.
35 30816081 398813-004WO (206432) SCHEME 1.
Figure imgf000037_0001
Figure imgf000037_0003
[0145] In the Scheme, it is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). Protecting group chemistry and strategy is well known in the art, for example, as described in detail in “Protecting Groups in Organic Synthesis”, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference. The modular synthetic route illustrated in Scheme 1 can also be readily modified by one of skill in the art to provide additional compounds by conducting functional group transformations on the intermediate and final compounds. Such functional group transformations are well known in the art, as described in, for example, “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992). Compounds Useful in Synthetic Procedures [0146] Another aspect of the invention provides compounds that are useful in the synthetic procedures. For example, one aspect of the invention provides a compound of Formula II:
Figure imgf000037_0002
(II) or a salt thereof; wherein: R1A is C1-4 alkoxyl, -N(R5A)2, -O-(C3-6 cycloalkyl), C1-6 alkyl, or C3-6 cycloalkyl;
36 30816081 398813-004WO (206432) R2A is cyano, C1-4 alkyl, C1-4 haloalkyl, halogen, or hydrogen; R3A and R4A are independently hydrogen or C1-4 alkyl; R5A represents independently for each occurrence hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R5A attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom; and Z1 is hydrogen or -C(O)2(C1-6 alkyl). [0147] The definitions of variables in Formula II above encompass multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [0148] In certain embodiments, the compound is a compound of Formula II. [0149] As defined generally above, R1A is C1-4 alkoxyl, -N(R5A)2, -O-(C3-6 cycloalkyl), C1-6 alkyl, or C3-6 cycloalkyl. In certain embodiments, R1A
Figure imgf000038_0001
. In certain
Figure imgf000038_0002
embodiments, R1A is . In certain embodiments, R1A
Figure imgf000038_0003
. In certain embodiments, R1A is C1-4 alkoxyl. In certain embodiments, R1A is -N(R5A)2. In certain embodiments, R1A is -O-(C3-6 cycloalkyl). In certain embodiments, R1A is C1-6 alkyl. In certain embodiments, R1A is C3-6 cycloalkyl. In certain embodiments, R1A is selected from the groups depicted in the compounds in Table 1-A below. [0150] As defined generally above, R2A is cyano, C1-4 alkyl, C1-4 haloalkyl, halogen, or hydrogen. In certain embodiments, R2A is methyl, chloro, or cyano. In certain embodiments, R2A is methyl. In certain embodiments, R2A is chloro. In certain embodiments, R2A is cyano. In certain embodiments, R2A is C1-4 alkyl. In certain embodiments, R2A is C1-4 haloalkyl. In certain embodiments, R2A is halogen. In certain embodiments, R2A is hydrogen. In certain embodiments, R2A is selected from the groups depicted in the compounds in Table 1-A below. [0151] As defined generally above, R3A and R4A are independently hydrogen or C1-4 alkyl. In certain embodiments, R3A is hydrogen. In certain embodiments, R3A is C1-4 alkyl. In certain embodiments, R3A is selected from the groups depicted in the compounds in Table 1-A below. In certain embodiments, R4A is hydrogen. In certain embodiments, R4A is C1-4 alkyl. In certain
37 30816081 398813-004WO (206432) embodiments, R4A is hydrogen or methyl. In certain embodiments, R4A is methyl. In certain embodiments, R4A is selected from the groups depicted in the compounds in Table 1-A below. [0152] As defined generally above, R5A represents independently for each occurrence hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R5A attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, R5A is hydrogen. In certain embodiments, R5A is C1-6 alkyl. In certain embodiments, R5A is C3-6 cycloalkyl. In certain embodiments, R5A is -(C1-6 alkylene)-(C3-6 cycloalkyl). In certain embodiments, two occurrences of R5A attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom. In certain embodiments, R5A is selected from the groups depicted in the compounds in Table 1-A below. [0153] As defined generally above, Z1 is hydrogen or -C(O)2(C1-6 alkyl). In certain embodiments, Z1 is hydrogen or tert-butoxycarbonyl. In certain embodiments, Z1 is hydrogen. In certain embodiments, Z1 is tert-butoxycarbonyl. In certain embodiments, Z1 is -C(O)2(C1-6 alkyl). In certain embodiments, Z1 is selected from the groups depicted in the compounds in Table 1-A below. [0154] The description above describes multiple embodiments relating to compounds of Formula II. The patent application specifically contemplates all combinations of the embodiments. [0155] Another aspect of the invention provides a compound in Table 1-A below. TABLE 1-A.
Figure imgf000039_0001
Figure imgf000039_0002
- cyano met y
38 30816081 398813-004WO (206432) [0156] In certain embodiments, R1A is . In certain embodiments, R2A is methyl, chloro, or cyano. In certain embodiments, R is hydrogen. In certain embodiments, R4A is hydrogen or methyl. In certain embodiments, Z1 is hydrogen or tert-butoxycarbonyl. II. Therapeutic Applications [0157] Another aspect of the invention provides a method of treating a muscarinic acetylcholine receptor mediated disorder, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to treat the muscarinic acetylcholine receptor mediated disorder. In certain embodiments, the particular compound of Formula I is a compound defined by one of the embodiments described in Section I, above. [0158] Methods described herein may be further defined according to additional features, such as the identity of the muscarinic acetylcholine receptor mediated disorder and/or the subject. [0159] Muscarinic acetylcholine receptor mediated disorders can be treated or prevented by modulating the muscarinic system. Such diseases include those in which direct activation of muscarinic acetylcholine receptors themselves or inhibition of cholinesterase enzymes provides a therapeutic effect. Exemplary muscarinic acetylcholine receptor medicated disorders include schizophrenia, movement disorders, mood disorders, cognitive disorders, attention disorders, addictive disorders, and pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from schizophrenia, movement disorders, mood disorders, cognitive disorders, attention disorders, addictive disorders, and neurologic disorders. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is a movement disorder, mood disorder, or cognitive disorder. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from attention disorders and addictive disorders. [0160] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is schizophrenia or a related disorder. Disorders related to schizophrenia include schizo-affective disorder, psychosis disorders, psychosis associated with Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, psychosis associated with Parkinson’s disease, psychotic depression,
39 30816081 398813-004WO (206432) bipolar disorder, bipolar with psychosis, Huntington’s disease, Lewy Body dementia, cerebral amyloid angiopathy, or any other disease with psychotic features. [0161] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from a schizo-affective disorder, psychosis, delusional disorders, psychosis associated with Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch- Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, cerebral amyloid angiopathy, and Lewy Body dementia. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from a schizo-affective disorder, psychosis, psychosis associated with Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, cerebral amyloid angiopathy, and Lewy Body dementia. [0162] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is a movement disorder. Exemplary movement disorders include Gilles de la Tourette’s syndrome, Friederich’s ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington’s chorea, dyskinesia, restless leg syndrome, and other diseases or disorders whose symptoms include excessive movements, tics, and spasms. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from Gilles de la Tourette’s syndrome, Friederich’s ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington’s chorea, dyskinesia, and restless leg syndrome. [0163] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is a mood disorder. Exemplary mood disorders include major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, bipolar disorder, mania, and anxiety. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, bipolar disorder, mania, and anxiety. [0164] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is a cognitive disorder. Exemplar cognitive disorders are diseases or disorders marked by a cognitive deficit (e.g., having abnormal working memory, problem-solving abilities, etc.), such as Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, Parkinson’s Disease, Parkinson's Disease-levodopa-induced dyskinesia, cerebral amyloid angiopathy, dementia (e.g., AIDS-
40 30816081 398813-004WO (206432) related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, and idiopathic dementia), Pick’s disease, tauopathies, synucleinopathies, confusion, mild cognitive impairment, cognitive deficit associated with fatigue, learning disorders, traumatic brain injury, autism, age-related cognitive decline, and Cushing’s Disease, a cognitive impairment associated with autoimmune diseases. [0165] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, Parkinson’s Disease, Parkinson's Disease-levodopa-induced dyskinesia,cerebral amyloid angiopathy, dementia (e.g., AIDS-related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, and idiopathic dementia), Pick’s disease, tauopathies, synucleinopathies, confusion, mild cognitive impairment, cognitive deficit associated with fatigue, learning disorders, traumatic brain injury, autism, age-related cognitive decline, and Cushing’s Disease. [0166] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is an attention disorder. Exemplary attention disorders are diseases or conditions marked by having an abnormal or decreased attention span, such as attention deficit and hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down’s Syndrome, growth delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss Syndrome. [0167] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down’s Syndrome, growth delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss Syndrome [0168] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is an addictive disorder. Exemplary addictive disorders are diseases or conditions marked by addiction or substance dependence as defined by the Diagnostic & Statistical Manual V (DSM- 5). Such disorders are often characterized by physical dependence, withdrawal, and tolerance to a substance. Such substances include but are not limited to alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, and cannabis. Addictive disorders also encompass behaviors that a patient does compulsively or continually despite clear negative consequences. For instance, ludomania (gambling addiction or compulsive gambling) is recognized by those skilled in the art as being an addictive behavior that often has devastating consequences. In certain embodiments, the addictive behavior may be Internet Gaming Disorder (gaming addiction), as defined in the DSM-5.
41 30816081 398813-004WO (206432) [0169] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is addiction to one of the following substances: alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, or cannabis; ludomania; and Internet Gaming Disorder. [0170] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is a neurologic disorder. Exemplary neurologic disorders are pain, physical suffering, or discomfort caused by illness or injury. Pain is a subjective experience, and the perception of pain is performed as part of the central nervous system (CNS). Usually, noxious (peripheral) stimuli are transmitted to the CNS beforehand, but the pain is not always associated with nociception. A broad variety of clinical pain exists, derived from different underlying pathophysiological mechanisms, and needs different treatment approaches. Several major types of clinical pain have been characterized: acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain. [0171] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is acute pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is chronic pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is neuropathic pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is inflammatory pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is nociceptive pain. In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is inflammatory pain or nociceptive pain. [0172] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is selected from a schizo-affective disorder, psychosis, psychosis associated with Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, psychosis associated with Parkinson’s disease, Parkinson's Disease-levodopa-induced dyskinesia, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, cerebral amyloid angiopathy, Lewy Body dementia, Gilles de la Tourette’s syndrome, Friederich’s ataxia, amyotrophic lateral sclerosis, progressive supranuclear palsy, Huntington’s chorea, dyskinesia, restless leg syndrome, major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, mania, anxiety, Alzheimer’s disease, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch- Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorder, Parkinson’s Disease, Parkinson's Disease-levodopa-induced dyskinesia, dementia (including, but not limited to, AIDS-related
42 30816081 398813-004WO (206432) dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, and idiopathic dementia), Pick’s disease, tauopathies, synucleinopathies, confusion, mild cognitive impairment, cognitive deficit associated with fatigue, learning disorders, traumatic brain injury, autism, age-related cognitive decline, Cushing’s Disease, hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down’s Syndrome, growth delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, and Strauss Syndrome, and addiction to one of the following substances: alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, or cannabis, ludomania, Internet Gaming Disorder, acute pain, chronic pain, neuropathic pain, inflammatory pain, and nociceptive pain. [0173] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is schizophrenia, psychosis, mild cognitive impairment, Alzheimer's Disease, Parkinson's Disease, Parkinson's Disease-levodopa-induced dyskinesia, Huntington's Disease, dyskinesia, cerebral amyloid angiopathy, dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, a prion disorder, amyotrophic lateral sclerosis, progressive supranuclear palsy, autism, addiction, or a sleep disorder. [0174] In certain embodiments, the muscarinic acetylcholine receptor mediated disorder is a schizo-affective disorder, psychosis, a delusional disorder, psychosis associated with Alzheimer’s disease, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, Lewy Body dementia, Gilles de la Tourette’s syndrome, Friederich’s ataxia, Huntington’s chorea, restless leg syndrome, major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, bipolar disorder, mania, anxiety, Alzheimer’s disease, Parkinson’s Disease, dementia, Pick’s disease, tauopathies, synucleinopathies, confusion, cognitive deficit associated with fatigue, a learning disorder, traumatic brain injury, autism, age-related cognitive decline, Cushing’s Disease, attention deficit and hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down’s Syndrome, growth delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, Strauss Syndrome, or agitation associated with neurodegeneration. Method of Activating a Muscarinic Acetylcholine Receptor [0175] Another aspect of the invention provides a method of activating a muscarinic acetylcholine receptor. The method comprises contacting a muscarinic acetylcholine receptor with an effective amount of a compound described herein, such as a compound of Formula I, to activate the muscarinic acetylcholine receptor, as further described in the detailed description.
43 30816081 398813-004WO (206432) [0176] In certain embodiments, the muscarinic acetylcholine receptor is muscarinic acetylcholine receptor M4. Subjects [0177] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. Medical Uses [0178] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as a muscarinic acetylcholine receptor mediated disorder. [0179] Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein, such as a muscarinic acetylcholine receptor mediated disorder. Assay for Evaluating Compound Biological Activity in Rats [0180] Compounds may be tested for ability to impact behavior activity of rats according to the following procedures. Animals: Adult male, Sprague Dawley rats (Envigo, Indianapolis, IN, USA) are housed in a colony maintained at 23 °C with 12 h light/dark cycles (lights on at 0600 hours). All animals weigh 290 - 330 g at the beginning of the study and are equally divided into 5 groups (n=8 per group) and received one of the treatment conditions listed below. Behavioral Procedures: Studies are conducted in MedAssociates open field chambers (27.3 cm x 27.3 cm x 20.3 cm, MedAssociates, St. Albans, VT) in which movement is automatically tracked and recorded by 16 beam arrays. The administration pretreatment of the test article is determined to coincide with Tmax at the time of the amphetamine-evoked session with optimal route of administration. All groups are subcutaneously treated with 0.5 mg/kg amphetamine (AMP). The test article is tested in three dose groups with a half-log increase between doses. Risperidone (0.55 mg/kg, 30 minutes, s.c.) may be used as a positive control and is administered to group 5. To determine the role of test article on AMP-evoked hyperlocomotion, rats are placed in the open area and allowed to habituate for 30 min before being s.c. dosed with 0.5 mg/kg AMP. Locomotor data (distance traveled) is recorded as 5- minute bins throughout the 90-minute session. The dose of AMP is chosen based on the selective increase in locomotor behavior relative to stereotypes. The dose of risperidone is chosen that produced reliable effects and served as a positive control. Statistical Analysis:
44 30816081 398813-004WO (206432) Spontaneous locomotion (prior to AMP administration) is calculated as the total distance traveled during the first 30 minutes of the experimental session. AMP-evoked responses are calculated as the total distance traveled during the last 60 minutes of the experimental session which commenced immediately after AMP administration. Locomotor data may be analyzed by a one-way ANOVA. When there is a significant overall ANOVA, post hoc comparisons may be made by Dunnett’s test with statistical significance determined as p < 0.05. IV. Combination Therapy [0181] Another aspect of the invention provides for combination therapy. Compounds described herein (such as a compound of Formula I, or other compounds in Section I) or their pharmaceutically acceptable salts may be used in combination with additional therapeutic agents to treat medical disorders, such as a muscarinic acetylcholine receptor mediated disorder. [0182] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co- administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically. [0183] One or more other therapeutic agent may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent and a compound or composition of the invention are administered as a multiple dosage regimen more than 24 hours apart.
45 30816081 398813-004WO (206432) Additional Therapeutics Agents for Treating a Muscarinic Acetylcholine Receptor Mediated Disorder [0184] Various pharmaceutically active agents may be selected for use in conjunction with the compounds of the presentinvention, depending on the disease, disorder, or condition to be treated. Pharmaceutically active agents that may be used in combination with the compositions of the present invention include, without limitation: [0185] (i) acetylcholinesterase inhibitors, such as donepezil hydrochloride (ARICEPT, MEMAC), physostigmine salicylate (ANTILIRIUM), physostigmine sulfate (ESERINE), metrifonate, neostigmine, ganstigmine, pyridostigmine (MESTINON), ambenonium (MYTELASE), demarcarium, Debio 9902 (also known as ZT-1; Debiopharm), rivastigmine (EXELON), ladostigil, NP-0361, galantamine hydrobromide (RAZADYNE, RIMINYL, NIVALIN), tacrine (COGNEX), tolserine, velnacrine maleate, memoquin, huperzine A (HUP- A; NeuroHitech), phenserine, edrophonium (ENLON, TENSILON), and INM-176; [0186] (ii) amyloid-B (or fragments thereof), such as AB1.15 conjugated to pan HLA DR- binding epitope (PADRE), ACC-001 (Elan/Wyeth), ACI-01, ACI-24, AN-1792, Afhtope AD- 01, CAD106, and V-950; [0187] (iii) antibodies to amyloid-B (or fragments thereof), such as ponezumab, solanezumab, bapineuzumab (also known as AAB-001), AAB-002 (Wyeth/Elan), ACI-01-Ab7, BAN- 2401, intravenous Ig (GAMMAGARD), LY2062430 (humanized m266; Lilly), R1450 (Roche), ACU-5A5, huCO91, and those disclosed in International Patent Publication Nos WO04/032868, WO05/025616, WO06/036291, WO06/ 069081, WO06/118959, in US Patent Publication Nos US2003/0073655, US2004/0192898, US2005/0048049, US2005/0019328, in European Patent Publication Nos EP0994728 and 1257584, and in U.S. Pat. No.5,750,349; [0188] (iv) amyloid-lowering or -inhibiting agents (including those that reduce amyloid production, accumulation and fibrillization) such as dimebon, davunetide, eprodisate, leuprolide, SK-PC-B70M, celecoxib, lovastatin, anapsos, oxiracetam, pramiracetam, varenicline, nicergoline, colostrinin, bisnorcymserine (also known as BNC), NICS-15 (Humanetics), E-2012 (Eisai), pioglitazone, clioquinol (also known as PBT1), PBT2 (Prana Biotechnology), flurbiprofen (ANSAID, FROBEN) and its R-enantiomer tarenflurbil 34 (FLURIZAN), nitroflurbiprofen, fenoprofen (FENOPRON, NALFON), ibuprofen (ADVIL, MOTRIN, NUROFEN), ibuprofen lysinate, meclofenamic acid, meclofenamate sodium (MECLOMEN), indomethacin (INDOCIN), diclofenac sodium (VOLTAREN), diclofenac potassium, sulindac (CLINORIL), sulindac sulfide, diflunisal (DOLOBID), naproxen (NAPROSYN), naproxen sodium (ANAPROX, ALEVE), ARC031 (Archer Pharmaceuticals), CAD-106 (Cytos), LY450139 (Lilly), insulin-degrading enzyme (also known as insulysin), the
46 30816081 398813-004WO (206432) gingko biloba extract EGb-761 (ROKAN, TEBONIN), tramiprosate (CEREBRIL, ALZHEMED), eprodisate (FIBRILLEX, KIACTA), compound W [3,5-bis(4- nitrophenoxy)benzoic acid], NGX- 96992, neprilysin (also known as neutral endopeptidase (NEP)), scyllo-inositol (also known as scyllitol), atorvastatin (LIPITOR), simvastatin (ZOCOR), KLVFF-(EEX)3, SKF-74652, ibutamoren mesylate, BACE inhibitors such as ASP- 1702, SCH-745966, JNJ-715754, AMG-0683, AZ-12304146, BMS-782450, GSK-188909, NB-533, E2609 and TTP-854; gamma secretase modulators such as ELND-007; and RAGE (receptor for advanced glycation end-products) inhibitors, such as TTP488 (Transtech) and TTP4000 (Transtech), and those disclosed in U.S. Pat. No.7,285,293, including PTI-777; [0189] (v) alpha-adrenergic receptor agonists, such as guanfacine (INTUNIV, TENEX), clonidine (CATAPRES), metaraminol (ARAMINE), methyldopa (ALDOMET, DOPAMET, NOVOMEDOPA), tizanidine (ZANAFLEX), phenylephrine (also known as neosynephrine), methoxamine, cirazoline, guanfacine (INTUNIV), lofexidine, xylazine, modafinil (PROVIGIL), adrafinil, and armodafinil (NUVIGIL); [0190] (vi) beta-adrenergic receptor blocking agents (beta blockers), such as carteolol, esmolol (BREVIBLOC), labetalol (NORMODYNE, TRANDATE), oxprenolol (LARACOR, TRASACOR), pindolol (VISKEN), propanolol (INDERAL), sotalol (BETAPACE, SOTALEX, SOTACOR), timolol (BLOCADREN, TIMOPTIC), acebutolol (SECTRAL, PRENT), nadolol (CORGARD), metoprolol tartrate (LOPRESSOR), metoprolol succinate (TOPROL-XL), atenolol (TENORMIN), butoxamine, and SR 59230A (Sanofi); [0191] (vii) anticholinergics, such as amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate (COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL), orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN), scopolamine (TRANSDERMSCOP), scopolamine methylbromide (PARMINE), dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOMINE), tolterodine (DETROL), oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), penthienate bromide, propantheline (PRO-BANTHINE), cyclizine, imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON), trimipramine (SURMONTIL), and glycopyrrolate (ROBINUL) [0192] (viii) anticonvulsants, such as carbamazepine (TEGRETOL, CARBATROL), oxcarbazepine (TRILEPTAL), phenytoin sodium (PHENYTEK), fosphenytoin (CEREBYX, PRODILANTIN), divalproex sodium (DEPAKOTE), gabapentin (NEURONTIN), pregabalin (LYRICA), topirimate (TOPAMAX), valproic acid (DEPAKENE), valproate sodium (DEPACON), 1-benzy1-5-bromouracil, progabide, beclamide, zonisamide (TRERIEF, EXCEGRAN), CP-465022, retigabine, talampanel, and primidone (MYSOLINE);
47 30816081 398813-004WO (206432) [0193] (ix) antipsychotics, such as lurasidone (LATUDA, also known as SM-13496; Dainippon Sumitomo), aripiprazole(ABILIFY), chlorpromazine (THORAZINE), haloperidol (HALDOL), iloperidone (FANAPTA), flupentixol decanoate (DEPIXOL, FLUANXOL), reserpine (SERPLAN), pimozide (ORAP), fluphenazine decanoate, fluphenazine hydrochloride, prochlorperazine (COMPRO), asenapine (SAPHRIS), loxapine (LOXITANE), molindone (MOBAN), perphenazine, thioridazine, thiothixine, trifluoperazine (STELAZINE), ramelteon, clozapine (CLOZARIL), norclozapine (ACP-104), risperidone (RISPERDAL), paliperidone (INVEGA), melperone, olanzapine (ZYPREXA), quetiapine (SEROQUEL), talnetant, amisulpride, ziprasidone (GEODON), blonanserin (LONASEN), and ACP-103 (Acadia Pharmaceuticals); [0194] (x) calcium channel blockers such as lomerizine, ziconotide, nilvadipine (ESCOR, NIVADIL), diperdipine, amlodipine (NORVASC, ISTIN, AMLODIN), felodipine (PLENDIL), nicardipine (CARDENE), nifedipine (ADALAT, PROCARDIA), MEM 1003 and its parent compound nimodipine (NIMOTOP), nisoldipine (SULAR), nitrendipine, lacidipine (LACIPIL, MOTENS), lercanidipine (ZANIDIP), lifarizine, diltiazem (CARDIZEM), verapamil (CALAN, VERELAN), AR-R 18565 (AstraZeneca), and enecadin; [0195] (xi) catechol O-methyltransferase (COMT) inhibitors, such as nitecapone, tolcapone (TASMAR), entacapone (COMTAN), and tropolone; [0196] (xii) central nervous system stimulants, such as atomoxetine, reboxetine, yohimbine, caffeine, phenmetrazine, phendimetrazine, pemoline, fencamfamine (GLUCOENERGAN, REACTIVAN), fenethylline (CAPTAGON), pipradol (MERETRAN), deanol (also known as dimethylaminoethanol), methylphenidate (DAYTRANA), methylphenidate hydrochloride (RITALIN), dexmethylphenidate (FOCALIN), amphetamine (alone or in combination with other CNS stimulants, e.g., ADDERALL (amphetamine aspartate, amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate)), dextroamphetamine sulfate (DEXEDRINE, DEXTROSTAT), methamphetamine (DESOXYN), lisdexamfetamine (VYVANSE), and benzphetamine (DIDREX); [0197] (xiii) corticosteroids, such as prednisone (STERAPRED, DELTASONE), prednisolone (PRELONE), predisolone acetate (OMNIPRED, PRED MILD, PRED FORTE), prednisolone sodium phosphate (ORAPRED ODT), methylprednisolone (MEDROL); methylprednisolone acetate (DEPOMEDROL), and methylprednisolone sodium succinate (A- METHAPRED, SOLU-MEDROL); [0198] (xiv) dopamine receptor agonists, such as apomorphine (APOKYN), bromocriptine (PARLODEL), cabergoline (DOSTINEX), dihydrexidine, dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN), terguride spergolide (PERMAX), piribedil
48 30816081 398813-004WO (206432) (TRIVASTAL, TRASTAL), pramipexole (MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO), SKF-82958 (Glaxo- SmithKline), cariprazine, pardoprunox and sarizotan; (xv) dopamine receptor antagonists, such as chlorpromazine, fluphenazine, haloperidol, loxapine, risperidone, thioridazine, thiothixene, trifluoperazine, tetrabenazine (NITOMAN, XENAZINE), 7-hydroxyamoxapine, droperidol (INAPSINE, DRIDOL, DROPLETAN), domperidone (MOTILIUM), L-741742, L-745870, raclopride, SB-277011A, SCH-23390, ecopipam, SKF-83566, and metoclopramide (REGLAN); [0199] (xvi) dopamine reuptake inhibitors such as bupropion, safinamide, nomifensine maleate (MERITAL), vanoxerine (also known as GBR-12909) and its decanoate ester DBL- 583, and amineptine; [0200] (xvii) gamma-amino-butyric acid (GABA) receptor agonists, such as baclofen (LIORESAL, KEMSTRO), siclofen, pentobarbital (NEMBUTAL), progabide (GABRENE), and clomethiazole; [0201] (xviii) histamine 3 (H3) antagonists such as ciproxifan, tiprolisant, S-38093, irdabisant, pitolisant, GSK-239512, GSK-207040, JNJ-5207852, JNJ-17216498, HPP-404, SAR-110894, trans-N-ethy1-3-fluoro-3-[3-fluoro-4-(pyrrolidin- l- ylmethyl)phenyThcyclobutanecarboxamide (PF-3654746 and those disclosed in US Patent Publication Nos US2005-0043354, US2005-0267095, US2005-0256135, US2008-0096955, US2007-1079175, and US2008- 0176925; International Patent Publication Nos WO2006/ 15 138431, and WO2007/088462; and U.S. Pat. No.7,115, 600); [0202] (xix) immunomodulators such as glatiramer acetate (also known as copolymer-1; COPAXONE), MBP-8298 (synthetic myelin basic protein peptide), dimethyl fumarate, fingolimod (also known as FTY720), roquinimex (LINOMIDE), laquinimod (also known as ABR-215062 and SAIK-MS), ABT-874 (human anti-1L-12 antibody; Abbott), rituximab (RITUXAN), alemtuzumab (CAMPATH), daclizumab (ZENAPAX), and natalizumab (TYSABRI); [0203] (xx) immunosuppressants such as methotrexate (TREXALL, RHEUMATREX), mitoxantrone (NOVANTRONE), mycophenolate mofetil (CELLCEPT), mycophenolate sodium (MYFORTIC), azathioprine (AZASAN, IMURAN), mercaptopurine (PURI- NETHOL), cyclophosphamide (NEOSAR, CYTOXAN), chlorambucil (LEUKERAN), cladribine (LEUSTATIN, MYLINAX), alpha-fetoprotein, etanercept (ENBREL), and 4- (benzyloxy)-5-[(5-undecy1- 2H-pyrrol-2-ylidene)methyl]-1H, 1 'H-2,2' -bipyrrole (also known as PNU-156804); [0204] (xxi) interferons, including interferon beta-la (AVONEX, REBIF) and interferon beta-lb (BETASERON, BETAFERON);
49 30816081 398813-004WO (206432) [0205] (xxii) levodopa (or its methyl or ethyl ester), alone or in combination with a DOPA decarboxylase inhibitor (e.g., carbidopa (SINEMET, CARBILEV, PARCOPA), benserazide (MADOPAR), a-methyldopa, monofluromethyldopa, difluoromethyldopa, brocresine, or m- hydroxybenzylhydrazine); [0206] (xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine (NAMENDA, AXURA, EBIXA), amantadine (SYMMETREL), acamprosate (CAMPRAL), besonprodil, ketamine (KETALAR), delucemine, dexanabinol, dexefaroxan, dextromethorphan, dextrorphan, traxoprodil, CP-283097, himantane, idantadol, ipenoxazone, L-701252 (Merck), lancicemine, levorphanol (DROMORAN), LY-233536 and LY-235959 (both Lilly), methadone, (DOLOPHINE), neramexane, perzinfotel, phencyclidine, tianeptine (STABLON), dizocilpine (also known as MK-801), EAB-318 (Wyeth), ibogaine, voacangine, tiletamine, riluzole (RILUTEK), aptiganel (CERESOTAT), gavestinel, and remacimide; [0207] (xxiv) monoamine oxidase (MAO) inhibitors, such as selegiline (EMSAM), selegiline hydrochloride (1-deprenyl, ELDEPRYL, ZELAPAR), dimethylselegilene, brofaromine, phenelzine (NARDIL), tranylcypromine (PARNATE), moclobemide (AURORIX, MANERIX), befloxatone, safinamide, isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT), iproniazide (MARSILID, IPROZID, IPRONID), CHF-3381 (Chiesi Farmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM), bifemelane, desoxypeganine, harmine (also known as telepathine or banasterine), harmaline, linezolid (ZYVOX, ZYVOXID), and pargyline (EUDATIN, SUPIRDYL); [0208] (xxv) muscarinic receptor (particularly Ml subtype) agonists, such as cevimeline, levetiracetam, bethanechol chloride (DUVOID, URECHOLINE), itameline, pilocarpine (SALAGEN), NGX267, arecoline, L-687306 (Merck), L-689660 (Merck), furtrethonium iodide (FURAMON, FURANOL), furtrethonium benzensulfonate, furtrethonium p- toluenesulfonate, McN-A-343, oxotremorine, sabcomeline, AC-90222 (Acadia Pharmaceuticals), and carbachol (CARBASTAT, MIOSTAT, CARBOPTIC); [0209] (xxvi) neuroprotective drugs such as bosutinib, condoliase, airmoclomol, lamotrigine, perampanel, aniracetam, minaprime, riluzole, N-hydroxy-1,2,4,9-tetrahydro-3H- carbazol- 3-imine, desmoteplase, anatibant, astaxanthin, neuropeptide NAP (e.g., AL-108 and AL-208; both Allon Therapeutics), neurostrol, perampenel, ispronicline, bis(4-B- Dglucopyranosyloxybenzy1)- 2-B-D-glucopyranosy1-2- isobutyltartrate (also known as dactylorhin B or DHB), formobactin, xaliproden (xAPRILA), lactacystin, dimeboline hydrochloride (DIMEBON), disufenton (CEROVIVE), arundic acid (ONO-2506, PROGLIA, CEREACT), citicoline (also known as cytidine 5'-diphosphocholine), edaravone (RADICUT), AEOL-10113 and AEOL-10150 (both Aeolus Pharmaceuticals), AGY-94806 (also known as
50 30816081 398813-004WO (206432) SA-450 and Msc-1), granulocyte-colony stimulating factor (also known as AX-200), BAY-38- 7271 (also known as KN-387271; Bayer AG), ancrod (VIPRINEX, ARWIN), DP-b99 (D- Pharm Ltd), HF-0220 (17-B-hydroxyepiandrosterone; Newron Pharmaceuticals), HF-0420 (also known as oligotropin), pyridoxal 5'-phosphate (also known as MC-1), microplasmin, S- 18986, piclozotan, NP031112, tacrolimus, L-seryl-L-methionyl-L-alanyl-L-lysyl-L-glutamyl- glycyl- L-valine, AC-184897 (Acadia Pharmaceuticals), ADNF-14 (National Institutes of Health), stilbazulenyl nitrone, SUNN8075 (Daiichi Suntory Biomedical Research), and zonampanel; [0210] (xxvii) nicotinic receptor agonists, such as epibatidine, bupropion, CP-601927, varenicline, ABT-089 (Abbott), ABT-594, AZD-0328 (AstraZeneca), EVP-6124, R3487 (also known as MEM3454; Roche/Memory Pharmaceuticals), R4996 (also known as MEM63908; Roche/Memory Pharmaceuticals), TC-4959 and TC-5619 (both Targacept), and RJR-2403; [0211] (xxviii) norepinephrine (noradrenaline) reuptake inhibitors, such as atomoxetine (STRATTERA), doxepin (APONAL, ADAPIN, SINEQUAN), nortriptyline (AVENTYL, PAMELOR, NORTRILEN), amoxapine (ASENDIN, DEMOLOX, MOXIDIL), reboxetine (EDRONAX, VESTRA), viloxazine (VIVALAN), maprotiline (DEPRILEPT, LUDIOMIL, PSYMION), bupropion (WELLBUTRIN), and radaxafine; [0212] (xxix) phosphodiesterase (PDE) inhibitors, including but not limited to, (a) PDE1 inhibitors (e.g., vinpocetine (CAVINTON, CERACTIN, INTELECTOL) and those disclosed in U.S. Pat. No.6,235,742, (b) PDE2 inhibitors (e.g., erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), BAY 60-7550, and those described in U.S. Pat. No.6,174,884), (c) PDE3 inhibitors (e.g., anagrelide, cilostazol, milrinone, olprinone, parogrelil, and pimobendan), (d) PDE4 inhibitors (e.g., apremilast, ibudilastroflumilast, rolipram, Ro 20-1724, ibudilast (KETAS), piclamilast (also known as RP73401), CDP840, cilomilast (ARIFLO), roflumilast, tofimilast, oglemilast (also known as GRC 3886), tetomilast (also known as OPC-6535), lirimifast, theophylline (UNIPHYL, THEOLAIR), arofylline (also known as LAS-31025), doxofylline, RPR-122818, or mesembrine), and (e) PDES 38 inhibitors (e.g., sildenafil (VIAGRA, REVATIO), tadalafil (CIALIS), vardenafil (LEVITRA, VIVANZA), udenafil, avanafil, dipyridamole (PERSANTINE), E-4010, E-4021, E-8010, zaprinast, iodenafil, mirodenafil, DA- 8159, and those disclosed in International Patent Applications WO2002/020521, WO2005/049616, WO2006/120552, WO2006/126081, WO2006/126082, WO2006/126083, and WO2007/122466), (f) PDE7 inhibitors; (g) PDE8 inhibitors; (h) PDE9 inhibitors (e.g., BAY 73-6691 (Bayer AG) and those disclosed in US Patent Publication Nos US2003/ 0195205, US2004/0220186, US2006/0111372, US2006/ 0106035, and U.S. Ser. No. 12/118,062 (filed May 9, 2008)), (i) PDE10 inhibitors such as 2-({4-[1-methy1-4-(pyridin-4-
51 30816081 398813-004WO (206432) y1)-1H-pyrazol-3-yl]phenoxylmethyl)quinolin-3(4H)-one and SCH-1518291; and (j) PDEll inhibitors; [0213] (xxx) quinolines, such as quinine (including its hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate salts), chloroquine, sontoquine, hydroxychloroquine (PLAQUENIL), mefloquine (LARIAM), and amodiaquine (CAMOQUIN, FLAVOQUINE); [0214] (xxxi) B-secretase inhibitors, such as ASP-1702, SCH- 745966, JNJ-715754, AMG- 0683, AZ-12304146, BMS- 782450, GSK-188909, NB-533, LY-2886721, E-2609, HPP- 854, (+)-phenserine tartrate (POSIPHEN), LSN-2434074 (also known as LY-2434074), KMI-574, SCH-745966, AcrER (N2-acetyl-D-arginyl-L-arginine), loxistatin (also known as E64d), and CA074Me; [0215] (xxxii) y-secretase inhibitors and modulators, such as BMS-708163 (Avagacest), WO20060430064 (Merck), DSP8658 (Dainippon), ITI-009, L-685458 (Merck), ELANG, ELAN-Z, 4-chloro-N-[(2S)-3-ethy1-1 -hydroxypentan-2- yl]benzenesulfonam ide; [0216] (xxxiii) serotonin (5-hydroxytryptamine) lA (5-HT,A) receptor antagonists, such as spiperone, levo-pindolol, BMY 7378, NAD-299, S-(-)-UH-301, NAN 190, lecozotan; [0217] (xxxiv) serotonin (5-hydroxytryptamine) 2C (5-HT2c) receptor agonists, such as vabicaserin and zicronapine; [0218] (xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT4) receptor agonists, such as PRX- 03140 (Epix); [0219] (xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT,) receptor antagonists, such as A- 964324, AVI-101, AVN-211, mianserin (TORVOL, BOLVIDON, NORVAL), methiothepin (also known as metitepine), ritanserin, ALX-1161, ALX- 1175, MS-245, LY-483518 (also known as SGS518; Lilly), MS-245, Ro 04-6790, Ro 43-68544, Ro 63-0563, Ro 65-7199, Ro 65-7674, SB-399885, SB-214111, SB-258510, SB-271046, SB-357134, SB-699929, SB- 271046, SB-742457 (GlaxoSmithKline), Lu AE58054 (Lundbeck A/S), and PRX-07034 (Epix); 50 [0220] (xxxvii) serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram (CELEXA, CIPRAMIL), escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC), fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine, desvenlafaxine (PRISTIQ), brasofensine, vilazodone, cariprazine, neuralstem and tesofensine;
52 30816081 398813-004WO (206432) [0221] (xxxviii) trophic factors, such as nerve growth factor (NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN), neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic factor (BDNF), neublastin, meteorin, and glial-derived neurotrophic factor (GDNF), and agents that stimulate production of trophic factors, such as propentofylline, idebenone, PYM50028 (COGANE; Phytopharm), and AIT-082 (NEOTROFIN); [0222] (xxxix) Glycine transporter-1 inhibitors such as paliflutine, ORG-25935, JNJ- 17305600, and ORG-26041; [0223] (xl) AMPA-type glutamate receptor modulators such as perampanel, mibampator, selurampanel, GSK-729327, N- { (3 S,4 S)-4 - [4 -(5-cyanothiophen-2 -yl)phenoxy] tetrahydro- furan-3-yllpropane-2-sulfonamide, and the like. [0224] (xli) Janus kinase inhibitors (JAK) such as, but not limited to, tofacitinib, ruxolitinib, baricitinib, CYT387, GLPG0634, lestaurtinib, pacritinib, and TG101348. [0225] (xlii) Interleukin-1 receptor-associated kinase 4 inhibitors (IRAK4) such as, but not limited to, PF-06650833. [0226] In certain embodiments, the additional therapeutic agent is an orthosteric agonist of the muscarinic acetylcholine receptor. [0227] In certain embodiments, methods described herein further comprise administering to the subject in need thereof a therapeutically effective amount of an orthosteric agonist of the muscarinic acetylcholine receptor. In certain embodiments, the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject concurrently with a substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I. [0228] In certain embodiments, the subject is administered a pharmaceutical composition comprising (i) the orthosteric agonist of the muscarinic acetylcholine receptor and (ii) a substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I. [0229] In certain embodiments, the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject separately from a substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I. In certain embodiments, the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject via a first pharmaceutical composition, and the substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I, is administered to the subject via a second pharmaceutical composition. [0230] In certain embodiments, the amount of (i) orthosteric agonist of the muscarinic acetylcholine receptor and/or (ii) substituted dihydropyrrolo-pyrimidine compound described
53 30816081 398813-004WO (206432) herein, such as a compound of Formula I, that is administered to the patient is reduced compared to use of either the (i) orthosteric agonist of the muscarinic acetylcholine receptor or (ii) a substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I, in a monotherapy treatment. [0231] Accordingly, another aspect of the invention provides a method for treating a disorder ameliorated by muscarinic receptor activation in a subject in need thereof, wherein the method comprises administering to the subject a substituted dihydropyrrolo-pyrimidine compound described herein, such as a compound of Formula I, in combination with an orthosteric agonist of the muscarinic acetylcholine receptor (e.g., xanomeline or a salt thereof) wherein the orthosteric agonist of the muscarinic acetylcholine receptor and the substituted dihydropyrrolo-pyrimidine compound operate on the same muscarinic acetylcholine receptor subtype. In certain embodiments, the orthosteric agonist of the muscarinic acetylcholine receptor and the substituted dihydropyrrolo-pyrimidine compound operate on the M1 subtype or M4 subtype of the muscarinic acetylcholine receptor. [0232] The terms “muscarinic orthosteric agonist,” “orthosteric muscarinic agonist,” and “muscarinic agonist” refers to agents that activate the muscarinic acetylcholine receptor. “Orthosteric” refers to a site of a receptor in which the endogenous ligand binds to produce its effect. That is, muscarinic orthosteric agonists bind to the site of the muscarinic acetylcholine receptor in which endogenous muscarinic ligands bind to produce their effects. [0233] Muscarinic acetylcholine receptors are G-protein coupled receptors with five different receptor subtypes (M1–M5), each of which is found in the CNS with different tissue distributions. The term “muscarinic acetylcholine receptor” refers to G-protein-linked receptors that bind the neurotransmitter acetylcholine. “M1” means subtype one muscarinic acetylcholine receptor . “M2” means subtype two muscarinic acetylcholine receptor. “M3” means subtype three muscarinic acetylcholine receptor. “M4” means subtype four muscarinic acetylcholine receptor. “M5” means subtype five muscarinic acetylcholine receptor. [0234] An agonist of the muscarinic acetylcholine receptor may be selective or prefer binding to only one muscarinic receptor subtype, partially selective or prefer binding to two to four subtypes, or non-selective, preferring to bind to each of the five subtypes. Agonists of the muscarinic acetylcholine receptor can be parasympathomimetic. Their mechanism of action is different depending on which receptor is activated. For instance, the mood stabilizers lithium and valproic acid, used for treating bipolar depression, may affect the muscarinic system, mainly through the M4 subtype receptor. Genetic evidence directly links the muscarinic system and alcohol addiction.
54 30816081 398813-004WO (206432) [0235] In certain embodiments, the agonist of the muscarinic acetylcholine receptor is an orthosteric agonist of the muscarinic acetylcholine receptor. In certain embodiments, the orthosteric agonist of the muscarinic acetylcholine receptor is a compound in the following table or a pharmaceutically acceptable salt thereof: Muscarinic Acet lcholine Rece tor Subt e
Figure imgf000056_0001
L 687,306 X
55 30816081 398813-004WO (206432) Muscarinic Acetylcholine Receptor Subtype
Figure imgf000057_0001
xanome ne
56 30816081 398813-004WO (206432) Muscarinic Acetylcholine Receptor Subtype
Figure imgf000058_0001
[0236] In certain embodiments, the agonist of the muscarinic acetylcholine receptor is an orthosteric agonist of the muscarinic acetylcholine receptor selected from 77-LH-28-1, A 72055, AF 125, AF 150(S), aceclidine, alvameline, arecoline, bethanechol, carbachol, cevimeline, CI 1017, CMI 1145, CMI 936, FPL 14995, furmethide, HTL-0016878, iperoxo, itrameline, KST 5452, L 670,548, L 687,306, L 689,660, L 686,986, methacholine, N- desmethylclozapine, MCD 386, milameline, NC 111585, nebracetam, NGX267, ORG 20091, oxotremorine, PD 142505, PD 151832, PDC 008004, pilocarpine, RU 35963, sabcomeline, SR 46559A, talsaclidine, tazomeline, thiopilocarpine, tremorine, vedaclidine, xanomeline, WAY- 131256, WAY-132983, YM 796, YM 954, or a pharmaceutically acceptable salt thereof. [0237] In certain embodiments, the agonist of the muscarinic acetylcholine receptor is an orthosteric agonist of the muscarinic acetylcholine receptor selected from xanomeline or a pharmaceutically acceptable salt thereof. Xanomeline has activity towards both the M1 and M4 muscarinic acetylcholine receptors. [0238] In certain embodiments, the agonist of the muscarinic acetylcholine receptor is a M1 orthosteric agonist of the muscarinic acetylcholine receptor selected from 77-LH-28-1, A 72055, AF 125, AF 150(S), alvameline, bethanechol, carbachol, cevimeline, CI 1017, FPL 14995, iperoxo, itrameline, KST 5452, L 687,306, L 689,660, L 686,986, methacholine, N- desmethylclozapine, MCD 386, milameline, NC 111585, nebracetam, NGX267, ORG 20091, oxotremorine, PD 142505, PD 151832, pilocarpine, sabcomeline, SR 46559A, talsaclidine, tazomeline, thiopilocarpine, tremorine, vedaclidine, xanomeline, WAY-131256, WAY-132983, YM 796, YM 954, or a pharmaceutically acceptable salt thereof. [0239] In certain embodiments, methods described herein further comprise administering to the subject in need thereof a therapeutically effective amount of an orthosteric antagonist of the muscarinic acetylcholine receptor. In certain embodiments, the orthosteric antagonist of the muscarinic acetylcholine receptor is trospium chloride.
57 30816081 398813-004WO (206432) Additional Considerations [0240] The doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician. In certain embodiments, the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disorder. In other embodiments, the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder. In certain embodiments, the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration. [0241] In certain embodiments, the compound described herein (such as a compound of Formula I, or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy. [0242] Another aspect of this invention is a kit comprising a therapeutically effective amount of the compound described herein (such as a compound of Formula I, or other compounds in Section I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above. III. Pharmaceutical Compositions and Dosing Considerations [0243] As indicated above, the invention provides pharmaceutical compositions, which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or
58 30816081 398813-004WO (206432) intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, or other compounds in Section I) and a pharmaceutically acceptable carrier. [0244] The phrase “therapeutically effective amount” as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment. [0245] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0246] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. [0247] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. [0248] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of
59 30816081 398813-004WO (206432) active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. [0249] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention. [0250] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. [0251] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. [0252] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as
60 30816081 398813-004WO (206432) crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [0253] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [0254] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. [0255] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
61 30816081 398813-004WO (206432) [0256] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. [0257] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [0258] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. [0259] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate. [0260] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required. [0261] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [0262] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [0263] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to
62 30816081 398813-004WO (206432) increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. [0264] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. [0265] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [0266] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. [0267] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. [0268] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively,
63 30816081 398813-004WO (206432) delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. [0269] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. [0270] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier. [0271] The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred. [0272] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. [0273] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. [0274] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
64 30816081 398813-004WO (206432) [0275] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art. [0276] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. [0277] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. [0278] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. [0279] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone. [0280] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
65 30816081 398813-004WO (206432) [0281] The invention further provides a unit dosage form (such as a tablet or capsule) comprising a compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. EXAMPLES [0282] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention. General Synthetic and Analytical Methods [0283] Analytical data is included within the procedures below, in the illustrations of the general procedures, or in the tables of examples. Unless otherwise stated, all 1H NMR data were collected on a Bruker Avance 400 MHz equipped with 5 mm QNP probe or Bruker Avance III 400 MHz, 5 mm BBFO probe or Fourier 300 MHz, 5 mm dual probe instruments and chemical shifts are quoted in parts per million (ppm). LC/MS was performed on Acquity UPLC H-Class (quaternary pump/PDA detector) coupled to QDa Mass Spectrometer or Acquity UPLC (binary pump/PDA detector) coupled to ZQ Mass Spectrometer or Acquity UPLC with Waters DAD coupled to SQD2 Mass Spectrometer. LC/MS data is referenced to LC/MS conditions using the method number provided in Table 1. Table 1. LC/MS Analysis Methods , c 5 y d N o m e ,
Figure imgf000067_0001
100 x 2.1 mm plus guard cartridge, maintained at 40 oC. Mobile phase:
66 30816081 398813-004WO (206432) Method Conditions m 0 , % n y , c 5 y
Figure imgf000068_0001
Purification Methods [0284] For the general procedures, intermediate and final compounds may be purified by any technique or combination of techniques known to one skilled in the art. Some examples that are not limiting include flash chromatography performed on the COMBIFLASH® Companion purification system or the Biotage SP1 purification system, products were purified using an Isolute® SPE Si II cartridge, (‘Isolute SPE Si cartridge’ refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles with average size of 50 µm and nominal 60Å porosity), and a solvent or combination of solvents (heptane, EtOAc, DCM, MeOH, MeCN, water, etc.) that elutes the desired compounds; RP-HPLC purification performed on Waters Mass Directed FractionLynx systems (2767 autosampler, System Fluidics Organiser, 2998 Photodiode array, 2545 pump, 3x515 pump, QDa mass spectrometer), Gilson system (GX281 autosampler, 322 pump, 155 UV/vis detector), Interchim PuriFlash 4125 coupled to a UV DAD (see Table 2 for some non-limiting conditions); SFC purification performed on a Waters Thar Prep100 system (P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquid handler with Stacked Injection Module) or Waters Thar Investigator semi preparative system (Waters Fluid Delivery Module, 2998 UV/VIS detector, Waters Fraction Collection Module) (see Table 2 for some non-limiting conditions); recrystallization from an appropriate solvent (MeOH, EtOH, IPA, EtOAc, toluene, etc.) or combination of solvents (EtOAc/heptane, EtOAc/MeOH, etc.); precipitation from a combination of solvents (DMF/water, DMSO/DCM,
67 30816081 398813-004WO (206432) EtOAc/heptane, etc.); trituration with an appropriate solvent (EtOAc, DCM, MeCN, MeOH, EtOH, IPA, n-PrOH, etc.); extractions by dissolving a compound in a liquid and washing with an appropriately immiscible liquid (DCM/water, EtOAc/water, DCM/saturated NaHCO3, EtOAc/saturated NaHCO3, DCM/10% aqueous HCl, EtOAc/10% aqueous HCl, etc.); and/or distillation (simple, fractional, Kugelrohr, etc.). Descriptions of these techniques can be found in the following references: Gordon, A. J. and Ford, R. A. "The Chemist’s Companion”, 1972; Palleros, D. R. “Experimental Organic Chemistry”, 2000; Still, W. C., Kahn and M. Mitra, A. J. Org. Chem. 1978, 43(14), 2923-2925; Yan, B. “Analysis and Purification Methods in Combinatorial Chemistry” 2003; Harwood, L. M., Moody, C. J. and Percy, J. M. “Experimental Organic Chemistry: Standard and Microscale, 2nd Edition”, 1999. Table 2. RP-HPLC and SFC Purification Methods x 0 l , 0 ; r % 0 ; r % , 0 l ,
Figure imgf000069_0001
centered around a specific focused gradient.
68 30816081 398813-004WO (206432) Method Conditions x ; r % 0 ; r % 0 ; c d 0 ; r %
Figure imgf000070_0001
Abbreviations oC Degrees Celsius CataCXium(R) A Di(1-adamantyl)-n-butylphosphine DAD Diode array detector DCM Dichloromethane DEA Diethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EtOAc Ethyl acetate EtOH Ethanol H Hour(s)
69 30816081 398813-004WO (206432) HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate HCl Hydrochloride HCOOH Formic acid IMS Industrial methylated spirits IPA Isopropyl alcohol LC/MS Liquid Chromatography/Mass Spectrometry m/z Mass-to-charge ratio MeCN Acetonitrile MeOH Methanol MgSO4 Magnesium sulphate MHz Megahertz Min Minute(s) MS Mass Spectrometer Na2SO4 Sodium sulphate NaHCO3 Sodium bicarbonate NaOH Sodium hydroxide NH4HCO3 Ammonium bicarbonate NH4OH Ammonium hydroxide NMR Nuclear Magnetic Resonance Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) RP-HPLC Reverse Phase-High Performance Liquid Chromatography Rt Retention time RT Room temperature SFC Supercritical Fluid Chromatography TBME tert-Butyl methyl ether THF Tetrahydrofuran UPLC Ultra Performance Liquid Chromatography EXAMPLE 1 – Synthesis of Compound Int-6: 2-([trans-2-(Pyridin-3- yl)cyclopropyl])acetic acid [0285] The title compound was prepared according to the following procedures. Preparation of Int-1: tert-Butyl 2-chloro-4-cyclopropoxy-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate
70 30816081 398813-004WO (206432) [0286] To a solution of tert-butyl 2,4-dichloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (1 g, 3.5 mmol) and cyclopropanol (200 mg, 3.5 mmol) in THF (10 mL) at 0 oC under a nitrogen atmosphere was added sodium hydride (60%, 152 mg, 3.8 mmol) portionwise. The reaction stirred at 0 oC for 1 h. The reaction mixture was allowed to warm to RT and next quenched stirred at RT for 16 h. The reaction mixture was quenched by the addition of distilled water, allowed to warm to RT and next partitioned with EtOAc. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford the title compound as a pale yellow solid (737 mg, 69%). LC/MS (Table 1, Method A): Rt = 1.59 min; m/z = 312 [M+H]+. Preparation of Int-2: tert-Butyl 4-cyclopropoxy-2-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate
Figure imgf000072_0001
[0287] To a suspension of tert-butyl 2-chloro-4-cyclopropoxy-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate (Int-1, 737 mg, 2.4 mmol), Pd(dppf)Cl2 complex with DCM (193 mg, 0.24 mmol) and potassium carbonate (980 mg, 7.1 mmol) in 1,4-dioxane (24 mL) under a nitrogen atmosphere was added trimethylboroxine (0.50 mL, 82 mmol). The reaction was heated to 100 oC and stirred at 100 oC for 2 h. The reaction mixture was allowed to cool to RT, filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo and purified directly by flash column chromatography (DCM to EtOAc, gradient elution) to afford the title compound as a yellow solid. (588 mg, 85%). LC/MS (Table 1, Method A): Rt = 1.47 min; m/z = 292 [M+H]+. Preparation of Int-3: 4-Cyclopropoxy-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride
Figure imgf000072_0002
71 30816081 398813-004WO (206432) [0288] A reaction vessel was charged with tert-butyl 4-cyclopropoxy-2-methyl-5,7-dihydro- 6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Int-2, 480 mg, 1.7 mmol) and 4 M HCl in 1,4- dioxane (10 mL, 41 mmol) at 0 oC and the reaction was allowed to warm to RT. The reaction stirred at RT for 5 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene to afford the title compound as a pale yellow solid (452 mg, quantitative). LC/MS (Table 1, Method A): Rt = 0.27 min; m/z = 192 [M+H]+. Preparation of Int-4: tert-Butyldimethyl(2-([trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclopropyl])ethoxy)silane
Figure imgf000073_0001
[0289] To a solution of 1 M diethylzinc in hexanes (19 mL, 19 mmol) in DCM (70 mL) at - 40 oC under a nitrogen atmosphere was added diiodomethane (3.1 mL, 39 mmol) via dropwise addition and the reaction stirred -40 oC for 2 h. A solution of trichloroacetic acid (3.1 g, 19 mmol) in DCM (5.0 mL) was then added via dropwise addition and the reaction was allowed to warm to -10 oC. The reaction stirred at -10 oC for 2 h. A solution of trans-4-(tert-butyldimethylsiloxy)- 1-buten-1-ylboronic acid pinacol ester in DCM (5 mL) was then added via dropwise addition and the reaction was allowed to warm to RT. The reaction stirred at RT for 18 h. The reaction mixture was quenched by the addition of cold 10% aqueous citric acid solution and next partitioned with DCM. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a colourless oil (1.4 g, 68%).1H NMR (400 MHz: CDCl3) δ 3.69 – 3.64 (m, 2H), 1.50 – 1.42 (m, 2H), 1.21 (s, 12H), 1.03 – 0.95 (m, 1H), 0.89 (s, 9H), 0.70 – 0.64 (m, 1H), 0.44 – 0.39 (m, 1H), 0.05 (s, 6H), -0.37 - -0.43 (m, 1H). Preparation of Int-5: 3-([trans-2-(2- oxy)ethyl)cyclopropyl])pyridine
Figure imgf000073_0002
[0290] A reaction vessel was charged with palladium(II) acetate (81 mg, 0.36 mmol), cataCXium® A (130 mg, 0.36 mmol) and 2-methyl-2-butanol (30 mL). The reaction was
72 30816081 398813-004WO (206432) degassed, purged with argon (x3) and stirred at RT for 1 h. Degassed distilled water (1.9 mL), cesium carbonate (3.5 g, 11 mmol), 3-bromopyridine (570 mg, 3.6 mmol) and a solution of tert- butyldimethyl(2-([trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl])ethoxy) silane (Int-4, 1.4 g, 4.3 mmol) in degassed 2-methyl-2-butanol (7.6 mL) were added. The reaction was evacuated, purged with argon (x3) and heated to 75 oC. The reaction stirred at 75 oC for 18 h. The reaction mixture was allowed to cool to RT, filtered through celite and washed with EtOAc. The filtrate was next partitioned with EtOAc and the organic layer was separated. The combined organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a yellow oil (644 g, 64%). LC/MS (Table 1, Method A): Rt = 1.24 min; m/z = 278 [M+H]+. Preparation of Int-6: 2-([trans-2-(Pyridin-3-yl)cyclopropyl])acetic acid
Figure imgf000074_0001
[0291] To a solution of 3-([trans-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)cyclopropyl]) pyridine (Int-5, 644 mg, 2.3 mmol) in MeCN (34 mL) was added ruthenium(III) chloride followed by a solution of sodium periodate in distilled water (8.5 mL) and the reaction stirred at RT for 18 h. The reaction mixture was quenched by the addition of 1 M HCl aqueous solution (8.5 mL) and concentrated in vacuo. The residue was suspended in MeCN, filtered through celite and washed with MeCN and the filtrate concentrated in vacuo to afford the title compound as a brown gum. (251 mg, 61%). LC/MS (Table 1, Method A): Rt = 0.23 min; m/z = 178 [M+H]+. EXAMPLE 2 - Synthesis of Compound I-1: 1-(4-Cyclopropoxy-2-methyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)-2-[trans-(2-(pyridin-3-yl)cyclopropyl])ethan-1-one
Figure imgf000074_0002
[0292] To a solution of 4-cyclopropoxy-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride (Int-3, 125 mg, 0.44 mmol), 2-([trans-2-(pyridin-3-yl)cyclopropyl])acetic acid (Int-6, 93 mg, 0.53 mmol) and HATU (301 mg, 0.79 mmol) in DMF (2.5 mL) was added N,N- diisopropylethylamine (0.27 mL, 1.5 mmol). The reaction stirred at RT under a nitrogen
73 30816081 398813-004WO (206432) atmosphere for 18 h. The reaction mixture was next partitioned between EtOAc and aqueous sodium hydrogen carbonate. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH [2M NH3] 90:10, gradient elution) followed by reverse phase HPLC (Table 2, Method 1) followed by SFC purification (Table 2, Method 2) to afford the title compound of unknown absolute configuration-stereoisomer 1, as an off-whie solid (15 mg, 10%).1H NMR (300 MHz: DMSO-d6) δ 8.44 - 8.41 (m, 1H), 8.35 (dd, J=1.6, 4.8 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.27 (dd, J=4.8, 7.9 Hz, 1H), 4.77 (s, 1H), 4.71 (s, 1H), 4.54 (s, 1H), 4.52 - 4.46 (m, 2H), 2.64 - 2.46 (m, 5H, partially obscured by solvent peak), 1.85 - 1.77 (m, 1H), 1.44 - 1.38 (m, 1H), 1.06 - 0.92 (m, 2H), 0.84 - 0.71 (m, 4H). LC/MS (Table 1, Method B): Rt = 3.53 min; m/z = 351 [M+H]+. EXAMPLE 3 - Synthesis of N-Cyclopropyl-2-methyl-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidin-4-amine dihydrochloride [0293] The compound in Table 3 was prepared using a procedure analogous to that described above for preparation of compound Int-3 from compound Int-1. Starting material used is listed in Table 3. Table 3.
Figure imgf000075_0001
4-amine dihydrochloride EXAMPLE 4 - Synthesis of Additional Compounds [0294] The compounds in Table 4 were prepared using procedures analogous to that described above for preparation of compound I-1. Starting material used is listed in Table 4.
74 30816081 398813-004WO (206432) Table 4: Additional Compounds Compound Yi l Starting Material P ifi i M h ) )
Figure imgf000076_0003
EXAMPLE 5 - Synthesis of Compound Int-10: 4-Methoxy-2-methyl-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidine hydrochloride [0295] The title compound was prepared according to the following procedures. Preparation of Int-8: tert-Butyl 2-chloro-4-methoxy-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine- 6-carboxylate
Figure imgf000076_0001
[0296] To a solution of tert-butyl 2,4-dichloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6- carboxylate (500 mg, 1.7 mmol) in MeOH (5.0 mL) was added sodium methoxide (140 mg, 2.6 mmol) and the reaction stirred at RT for 4 h. The reaction mixture was next partitioned between EtOAc and saturated sodium hydrogen carbonate. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (522 mg, quantitative). LC/MS (Table 1, Method A): Rt = 1.53 min; m/z = 286 [M+H]+. Preparation of Int-9: tert-Butyl 4-methoxy-2-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine- 6-carboxylate
Figure imgf000076_0002
[0297] To a suspension of tert-butyl 2-chloro-4- methoxy-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate (Int-8, 492 mg, 1.7 mmol), Pd(dppf)Cl2 complex with DCM (141 mg, 0.17 mmol) and potassium carbonate (714 mg, 5.2 mmol) in 1,4-dioxane (24 mL) under a
75 30816081 398813-004WO (206432) nitrogen atmosphere was added trimethylboroxine (0.50 mL, 82 mmol). The reaction was degassed for 5 min and heated to 100 oC. The reaction stirred at 100 oC for 3 h. The reaction mixture was allowed to cool to RT and next partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (MgSO4) concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) to afford the title compound as an orange solid (409 mg, 89%). LC/MS (Table 1, Method D): Rt = 1.43 min; m/z = 266 [M+H]+. Preparation of Int-10: 4-Methoxy-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride
Figure imgf000077_0001
[0298] A reaction vessel was charged with tert-butyl 4-methoxy-2-methyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate (Int-9, 409 mg, 1.5 mmol) and 4 M HCl in 1,4-dioxane (7.7 mL, 31 mmol). The reaction stirred at RT for 2 h. The reaction mixture was concentrated in vacuo to afford the title compound as a yellow solid (420 mg, quantitative). LC/MS (Table 1, Method D): Rt = 0.86 min; m/z = 166 [M+H]+. EXAMPLE 6 - Synthesis of Compound I-5: (4-Methoxy-2-methyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidin-6-yl)-2-[trans-(2-(pyridin-3-yl)cyclopropyl])ethan-1-one
Figure imgf000077_0002
[0299] To a solution of 4-methoxy-2-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride (Int-10, 310 mg, 1.5 mmol), 2-([trans-2-(pyridin-3-yl)cyclopropyl])acetic acid (Int-6, 327 mg, 1.8 mmol) and HATU (1.1 g, 2.8 mmol) in DMF (5.0 mL) was added N,N- diisopropylethylamine (0.94 mL, 5.4 mmol). The reaction was stirred at RT for 4 h. The reaction mixture was next partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to MeOH, gradient elution) followed by reverse phase HPLC (Table 2, Method 4) followed by SFC purification (Table 2, Method 5) to afford the title compound of unknown absolute configuration-stereoisomer 1, as an off-white solid (6.4 mg, 1%).1H NMR (400 MHz: DMSO- d6) δ 8.43 (s, 1H), 8.35 (dd, J=1.6, 4.7 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.27 (dd, J=4.8, 7.8 Hz,
76 30816081 398813-004WO (206432) 1H), 4.76 (d, J=6.8 Hz, 2H), 4.54 (d, J=11.2 Hz, 2H), 3.98 (d, J=2.3 Hz, 3H), 2.69-2.54 (m, 5H, partially obscured by solvent peak), 1.85 - 1.79 (m, 1H), 1.43 - 1.38 (m, 1H), 1.05 - 0.92 (m, 2H). LC/MS (Table 1, Method B): Rt = 2.39 min; m/z = 325 [M+H]+. EXAMPLE 7 - Synthesis of (4-Methoxy-2-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)-2-[trans-(2-(pyridin-3-yl)cyclopropyl])ethan-1-one Stereoisomer 2 [0300] The compound in Table 5 was prepared using a procedure analogous to that described in Example 6. Table 5: Additional Compounds C d S i M i l
Figure imgf000078_0001
EXAMPLE 8 - Synthesis of Additional Compounds [0301] The compounds in Table 6 were prepared using procedures analogous described above for preparation of compound Int-6 from compound Int-4. Starting material used is described in Table 6. Table 6: Additional Compounds : - :
Figure imgf000078_0002
elution) [M+H]+
77 30816081 398813-004WO (206432) 2-([trans-2-(2-
Figure imgf000079_0003
EXAMPLE 9 – Synthesis of Int-22: 4-Methoxy-5-methyl-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidine-2-carbonitrile hydrochloride [0302] The title compound was prepared according to the following procedures. Preparation of Int-13: 1-(tert-butyl) 3-ethyl 2-methyl-4-oxopyrrolidine-1,3-dicarboxylate
Figure imgf000079_0001
[0303] To a solution of ethyl 2-(tert-butoxycarbonylamino)acetate (3.0 g, 15 mmol) and ethyl trans-2-butenoate (2.8 mL, 22 mmol) in THF (40 mL) under a nitrogen atmosphere was added a suspension of potassium tert-butoxide (2 g, 18 mmol) in THF (18 mL) and the reaction stirred at RT for 2.5 h. The reaction stirred at RT under a nitrogen atmosphere for 48 h. The reaction mixture was quenched by the addition of 10% citric acid solution and next partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a colourless oil (1.5 g, 38%). LC/MS (Table 1, Method D): Rt = 0.95 min; m/z = 270 [M-H]-. Preparation of Int-14: 1-(tert-Butyl) 3-ethyl 4-amino-2-methyl-2,5-dihydro-1H-pyrrole-1,3- dicarboxylate
Figure imgf000079_0002
[0304] A reaction vessel was charged with ammonium acetate (3.4 g, 45 mmol) followed by a solution of 1-(tert-butyl) 3-ethyl 2-methyl-4-oxopyrrolidine-1,3-dicarboxylate (Int-13, 1.2 g, 4.5 mmol) in IMS (7.5 mL). The reaction was evacuated, purged with argon (x3) and next heated to 80 oC. The reaction stirred at 80 oC for 16 h. The reaction mixture was allowed to cool to RT, filtered and washed with EtOAc. The filtrate was concentrated in vacuo and purified directly by flash column chromatography (cyclohexane to EtOAc, gradient elution) to
78 30816081 398813-004WO (206432) afford the title compound as a brown oil (884 mg, 73%). LC/MS (Table 1, Method D): Rt = 1.43 min; m/z = 269 [M-H]-. Preparation of Int-15: 1-(tert-Butyl) 3-ethyl 2-methyl-4-ureido-2,5-dihydro-1H-pyrrole-1,3- dicarboxylate
Figure imgf000080_0001
[0305] To a solution of 1-(tert-butyl) 3-ethyl 4-amino-2-methyl-2,5-dihydro-1H-pyrrole-1,3- dicarboxylate (Int-14, 884 mg, 3.3 mmol) in 1,2-dichloroethane (23 mL) was added pyridine (1.1 mL, 13 mmol). The reaction was evacuated, purged with argon (x3) and next cooled to 0 oC. Phosgene in toluene (20%, 2.1 mL, 3.9 mmol) was added via dropwise addition and the reaction stirred at RT for 2 h. The reaction was further cooled to -5 oC and ammonia in water (33%, 1.9 mL, 33 mmol) was added. The reaction was allowed to warm RT then heated to 60 oC and the reaction stirred at 60 oC for 16 h. The reaction mixture was allowed to cool to RT and next partitioned between DCM and distilled water. The organic layer was separated. The combined organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford the title compound as a yellow foam (597 mg, 58%). LC/MS (Table 1, Method D): Rt = 1.36 min; m/z = 312 [M-H]-. Preparation of Int-16: tert-Butyl 2,4-dihydroxy-5-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate
Figure imgf000080_0002
[0306] To a solution of 1-(tert-butyl) 3-ethyl 2-methyl-4-ureido-2,5-dihydro-1H-pyrrole-1,3- dicarboxylate (Int-15, 595 mg, 1.9 mmol) in anhydrous MeOH (75 mL) under a nitrogen atmosphere was added 4.37 M sodium methoxide in MeOH (25%, 1 mL, 4.6 mmol) and the reaction stirred at RT for 16 h. The reaction mixture was diluted with distilled water, acidified with 1 M HCl and filtered to afford the title compound as a an off-white solid (446 mg, 88%). LC/MS (Table 1, Method D): Rt = 0.76 min; m/z = 266 [M-H]-.
79 30816081 398813-004WO (206432) Preparation of Int-17: (2,4-Dichloro-5-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6- yl)phosphonic dichloride
Figure imgf000081_0001
[0307] A reaction vessel was charged with tert-butyl 2,4-dihydroxy-5-methyl-5,7-dihydro-6H- pyrrolo[3,4-d]pyrimidine-6-carboxylate (Int-16, 2.25 g, 1.7 mmol), phosphorus(V) oxychloride (30 mL, 322 mmol) and the reaction was heated to 105 oC. The reaction stirred at 105 oC for 16 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene. The residue was purified by flash column chromatography (cyclohexane to EtOac, gradient elution) to afford the title compound as a colourless oil (795 mg, 12%). LC/MS (Table 1, Method D): Rt = 1.62 min; UV only. Preparation of Int-18: (2-Chloro-4-methoxy-5-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin- 6-yl)phosphonic dichloride
Figure imgf000081_0002
[0308] To a solution of (2,4-dichloro-5-methyl-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6- yl)phosphonic dichloride (Int-17, 10 g, 32 mmol) in MeOH (200 mL) was added 4.73 M sodium methoxide in MeOH (25%, 7.5 mL, 33 mmol) and the reaction stirred at RT for 2.5 h. The reaction mixture was next partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a peach solid (5.9 g, 56%). Material advanced to next step without full characterisation. Preparation of Int-19: 2-Chloro-4-methoxy-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride
Figure imgf000081_0003
[0309] To a solution of (2-chloro-4-methoxy-5-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidin-6-yl)phosphonic dichloride (Int-18, 5.9 g, 19 mmol) in 1,4-dioxane (100 mL) was
80 30816081 398813-004WO (206432) added 4 M HCl in 1,4-dioxane (85 mL, 340 mmol) and the reaction stirred at RT under a nitrogen atmosphere for 25 h. The reaction mixture was concentrated in vacuo and azeotroped with MeCN to afford the title compound as a purple solid (6.1 g, quantitative).LC/MS (Table 1, Method D): Rt = 1.61 min; m/z = 200 [M+H]+. Preparation of Int-20: tert-Butyl 2-chloro-4-methoxy-5-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate
Figure imgf000082_0001
[0310] To a solution of 2-chloro-4-methoxy-5-methyl-6,7-dihydro-5H-pyrrolo[3,4- d]pyrimidine hydrochloride (Int-19, 6.1 g, 19 mmol) and triethylamine (14 mL, 97 mmol) in THF (125 mL) was added a solution of di-tert-butyl dicarbonate (8.4 g, 39 mmol) in THF (50 mL). The reaction stirred at RT for 3 h. The reaction mixture was next concentrated in vacuo and purified directly by flash column chromatography (cyclohexane to TBME, gradient elution) to afford the title compound as a pale brown gum (3.6 g, 62%). LC/MS (Table 1, Method D): Rt = 1.56 min; m/z = 300 [M+H]+. Preparation of Int-21: tert-Butyl 2-cyano-4-methoxy-5-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate
Figure imgf000082_0002
[0311] To a solution of tert-butyl 2-chloro-4-methoxy-5-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate (Int-20, 299 mg, 1.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (448 mg, 4.0 mmol) in DMF (4.2 mL) and distilled water (2.2 mL) was added sodium cyanide (195 mg, 4.0 mmol). The reaction stirred at 40 oC for 1 h. The reaction mixture was allowed to cool to RT and next partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layer was washed with 5% LiCl aqueous solution, saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a colourless oil (205 mg, 70%). LC/MS (Table 1, Method D): Rt = 1.84 min; m/z = 291 [M+H]+.
81 30816081 398813-004WO (206432) Preparation of Int-22: 4-Methoxy-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2- carbonitrile hydrochloride
Figure imgf000083_0001
[0312] To a solution of tert-butyl 2-cyano-4-methoxy-5-methyl-5,7-dihydro-6H-pyrrolo[3,4- d]pyrimidine-6-carboxylate (Int-21, 1.1 g, 3.6 mmol) in DCM (1.5 mL) was added 4 M HCl in 1,4-dioxane (22 mL, 90 mmol) and the reaction stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and azeotroped with MeCN to afford the title compound as an off- white solid (827 mg, 91%). Material advanced to next step without characterisation. EXAMPLE 10 - Synthesis of Compound I-7: 6-(2-[trans-(2-(3,5-Difluorophenyl) cyclopropyl)]acetyl)-4-methoxy-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2- carbonitrile
Figure imgf000083_0002
[0313] To a solution of 2-([trans-2-(3,5-Difluorophenyl)cyclopropyl])acetic acid (Int-11, 54 mg, 0.25 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.59 mmol) in DMF (1.3 mL) was added 4-methoxy-5-methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-carbonitrile hydrochloride (Int-22, 44 mg, 0.2 mmol) and HATU (104 mg, 0.27 mmol) in DMF (1.3 mL). The reaction stirred at RT for 4.5 h. The reaction mixture was next partitioned between EtOAc and saturated sodium hydrogen carbonate. The organic layer was separated. The combined organic layer was washed with saturated brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) followed by flash column chromatography (cyclohexane to TMBE, gradient elution) to afford the title compound of as an off-white solid (34 mg, 42%).1H NMR (400 MHz: CDCl3) δ 6.64 - 6.55 (m, 3H), 5.46 - 5.33 (m) and 5.22 - 5.16 (m, together 1H), 5.00 (dd, J=2.0, 18.5 Hz) and 4.80 - 4.65 (m, together 2H), 4.12 (s, 3H), 2.55 - 2.45 (m, 2H), 1.83 - 1.75 (m, 1H), 1.57 (d, J=1.0 Hz, 3H, partially obscured by solvent peak), 1.52 - 1.43 (m, 1H), 1.10 - 0.86 (m, 2H). LC/MS (Table 1, Method C): Rt = 5.05 min; m/z = 385 [M+H]+.
82 30816081 398813-004WO (206432) EXAMPLE 11 - Synthesis of Additional Compounds [0314] The compounds in Table 7 were prepared using procedures analogous to that described above for preparation of compound I-7. Starting material used is listed in Table 7. Table 7: Additional Compounds Comppund Starting Material )
Figure imgf000084_0001
EXAMPLE 12 – Compound Characterization [0315] Physical characterization data for exemplary compounds is provided in Table 8 below. Table 8: 1H NMR and LC/MS Data C d = = =
Figure imgf000084_0002
- 1.36 (m, 1H), 1.05 - 0.92 (m, 2H) 3 + 1H), 1.46 25 [M+H]
83 30816081 398813-004WO (206432) Compound 1H NMR Data LC/MS Method = = = = =
Figure imgf000085_0001
EXAMPLE 13 – Muscarinic Acetylcholine Receptor Activation [0316] Exemplary compounds were tested for ability to activate the muscarinic acetylcholine receptor. Experimental procedures and results are provided below. Part I – Experimental Procedures for Human and Rat M4 PAM pERK Assay [0317] Chinese hamster ovary (CHO) cells expressing either hM4 or rM4 receptors were frozen in assay ready vials (5x106 cells / vial) after bulking-up in culture. The day before an assay, vial(s) were thawed and cells seeded in 384 well white proxiplates at 1000 / well for hM4 cells and at 2000 / well for rM4 cells, in 10 µL of growth media (Hams/F12 with glutamax and 10% FCS) and incubated overnight at 37°C / 5% CO2. [0318] On the following morning, the growth media was removed by ‘flicking out’ over a bin, patting the inverted plate onto tissue, and then replacing with 10 µL of wash media (Hams/F12 with glutamax and 8 mM HEPES, NB: serum free). Then, the wash media was
84 30816081 398813-004WO (206432) removed in the same way and replaced with 8 µL / well of the serum free media. Plates were then re-incubated for a further 4 hours at 37°C / 5% CO2. [0319] Compounds for testing were solubilized to 10 mM in DMSO and compound addition plates, consisting of ten-point concentration response curves (CRC) in duplicate points (10 µM top concentration, ½ log dilution series), were prepared by acoustic dispensing and the compound management group. [0320] After the 4-hour incubation in serum free media, a 4 µL aliquot of the 3x compound solution containing an EC20 of acetylcholine (10 nM final concentration) was added to the cell plate using a 384 well plate to plate transfer. Then, the plate lid was replaced, and the cells incubated for 5 mins at 37°C / 5% CO2. Following this final incubation, all cellular processes were stopped by the addition of 4 µL / well of lysis and blocking buffer and plates were incubated for 30 minutes at RT on an orbital shaker (gentle setting). Then, a final addition of 4 µL / well of antibody detection mix, containing both the Europium-Cryptate (donor) and d2 (acceptor) tagged detection components, was added followed by a further 2-hour incubation at RT, and then the plate was read using a TR-FRET (time resolved fluorescence resonance energy transfer) based protocol . Part II – Experimental Procedures for M4 GTP ^S PAM Assay [0321] The M4 GTP ^S PAM method was used. Membranes were prepared for GTPgS binding assays from CHO-K1 cells stably expressing human M4 receptor. Briefly, cells were grown in 5-layer cell culture flasks. Cells were washed with 50 mL of PBS and then dissociated with 0.05% trypsin. Dissociated cells were then collected by centrifugation at 650 x g for 8 minutes at 4oC. Pellets were washed again in PBS by centrifugation and resuspended in 30 mL of 20mM HEPES, 10mM EDTA, pH 7.4. After sitting on ice for 30 min, membranes were collected by centrifugation at 50000 x g for 15’ at 4oC, resuspended in 30mL of 20mM HEPES, 0.1mM EDTA, pH 7.4 and collected again by centrifugation. Pellets were then washed twice by centrifugation in 30 mL of 20mM HEPES, pH 7.4, and stored at -80oC until the day of the assay. On the day of the assay, pellets were thawed on ice and resuspended in 1 mL of 20 mM HEPES, pH 7.4, 10 mM MgCl2, 100 mM NaCl using dounce homogenization. Membrane protein concentration is determined by BCA protein assay (Promega, Madison, WI) according to Promega guidelines. [0322] On the day of the assay, serial dilutions of test PAM compounds were brought up in assay buffer (20 mM HEPES, 10 mM MgCl2, 100 mM NaCl) at 4X final assay concentration. 25 ml/well of membrane homogenates (containing 5 mg of membrane protein) were prepared
85 30816081 398813-004WO (206432) in assay buffer supplemented with GDP at 4X final assay concentration (final assay concentration of GDP is 5uM for M2 and 0.1uM for M4) and dispensed into 96 well polypropylene, U-bottom Greiner plates.25 ml of vehicle or test PAM compound at 4x of final assay concentration diluted in the assay buffer were added to membrane and plates are incubated for 10-15 minutes at room temperature with gentle shaking. Then, 25 mL of EC20 acetylcholine in assay buffer at 4x final assay concentration was added to assay plates (EC20 final assay concentrations was 40 nM for human M4). [0323] Plates were then incubated, with shaking, for an additional 10-15 minutes.25 mL of 0.4 nM 35S-GTP (Perkin Elmer, Waltham, MA) in assay buffer was added to assay mixtures. The binding reaction is left on the shaker for 1 hour at room temperature. Membranes in assay reactions were then transferred to GF/C filter plates (Unifilter, Perkin Elmer) and washed three times using a FilterMate Harvester (Perkin Elmer) with cold assay buffer containing no GDP. Filter plates were then dried at 40o C overnight followed by the addition of 20 mL/ well of Beta Plate Scintillation liquid. Plates are top and bottom sealed before being read on TopCount scintillation counter (Perkin Elmer, Waltham, MA). Part III – Results [0324] Results are presented below in Table 9. Compounds having an activity designated as "A" had an EC50 <100 nM; compounds having an activity designated as "B" had an EC50 in the range of 100 nM to 500 nM; compounds having an activity designated as "C" had an EC50 of from greater than 500 nM to 2000 nM; and compounds having an activity designated as "D" had an EC50 >2000 nM. N/A indicates that no data was available. Table 9.
Figure imgf000087_0001
I-12 A B A
86 30816081 398813-004WO (206432) INCORPORATION BY REFERENCE [0325] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS [0326] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.
87 30816081 398813-004WO (206432)

Claims

Claims: 1. A compound represented by Formula I:
Figure imgf000089_0001
(I) or a pharmaceutically acceptable salt thereof; wherein: R1 is C1-4 alkoxyl, -N(R4)2, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -O-(C3-6 cycloalkyl), or -(C1-6 alkylene)-(C3-6 cycloalkyl); R2 is cyano, C1-4 alkyl, C1-4 haloalkyl, or hydrogen; R3 represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, or halo; R4 represents independently for each occurrence hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R4 attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom; R5 represents independently for each occurrence C1-6 alkyl, halo, C1-6 haloalkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), cyano, hydroxyl, C1-6 hydroxyalkyl, C1-6 alkoxyl, C1-6 haloalkoxyl, -(C1-6 alkylene)-(C1-6 alkoxyl), -(C1-6 alkylene)-(C3-6 cycloalkyl), - (C1-6 alkylene)-(C3-6 halocycloalkyl), or -O-(C1-6 alkylene)-(C3-6 cycloalkyl); A1 is phenyl or a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the phenyl and heteroaryl are substituted with n occurrences of R5; X1 is -(C1-4 alkylene)-(C3-5 cycloalkylene)-***, wherein *** is a point of attachment to A1; m is 0, 1, 2, or 3; and n is 0, 1, or 2.
2. The compound of claim 1, wherein the compound is a compound of Formula I.
3. The compound of claim 1 or 2, wherein X1 is -(C1-2 alkylene)-(C3 cycloalkylene)-***, wherein *** is a point of attachment to A1.
4. The compound of claim 1 or 2, wherein X1 is -(CH2)-(C3 cycloalkylene)-***, wherein *** is a point of attachment to A1.
88 30816081 398813-004WO (206432)
5. The compound of claim 1, wherein the compound is a compound of Formula Ia or a pharmaceutically acceptable salt thereof:
Figure imgf000090_0001
Ia.
6. The compound of any one of claims 1-5, wherein A1 is phenyl substituted with n occurrences of R5.
7. The compound of any one of claims 1-5, wherein A1 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with n occurrences of R5.
8. The compound of any one of claims 1-5, wherein A1 is pyridinyl substituted with n occurrences of R5.
9. The compound of any one of claims 1-8, wherein n is 1.
10. The compound of any one of claims 1-8, wherein n is 2.
11. The compound of any one of claims 1-10, wherein m is 1.
12. The compound of any one of claims 1-10, wherein m is 0.
13. The compound of claim 1, wherein the compound is a compound of Formula Ib or Ic, or a pharmaceutically acceptable salt thereof:
Figure imgf000090_0002
Ib Ic
14. The compound of claim 1, wherein the compound is a compound of Formula Id or Ie, or a pharmaceutically acceptable salt thereof:
89 30816081 398813-004WO (206432)
15. The compound of claim 1, wherein the compound is a compound of Formula If or Ig, or a pharmaceutically acceptable salt thereof:
Figure imgf000091_0001
16. The compound of claim 1, wherein the compound is a compound of Formula Ih, or a pharmaceutically acceptable salt thereof:
Figure imgf000091_0002
Ih.
17. The compound of claim 1, wherein the compound is a compound of Formula Ii, Ij, Ik, or Il, or a pharmaceutically acceptable salt thereof:
Figure imgf000091_0003
Ii Ij
90 30816081 398813-004WO (206432)
18. The compound of any one of claims 1-16, wherein R3 is C1-4 alkyl.
19. The compound of any one of claims 1-16, wherein R3 is methyl.
20. The compound of any one of claims 1-19, wherein R1 is C1-6 alkyl.
21. The compound of any one of claims 1-19, wherein R1 is -N(R4)2 or -O-(C3-6 cycloalkyl).
22. The compound of any one of claims 1-21, wherein R2 is cyano.
23. The compound of any one of claims 1-21, wherein R2 is C1-4 alkyl.
24. The compound of any one of claims 1-21, wherein R2 is methyl.
25. The compound of any one of claims 1-24, wherein R5 represents independently for each occurrence halo, C1-6 haloalkyl, C1-6 alkyl, C3-6 cycloalkyl, -SO2-(C1-6 haloalkyl), -SO2-(C1-6 alkyl), hydroxyl, C1-6 alkoxyl, or -(C1-6 alkylene)-(C1-6 alkoxyl).
26. The compound of any one of claims 1-24, wherein R5 represents independently for each occurrence represents independently for each occurrence halo, C1-6 haloalkyl, C1-6 alkyl, C3- 6 cycloalkyl, -SO2-(C1-6 haloalkyl), or -SO2-(C1-6 alkyl).
27. The compound of any one of claims 1-24, wherein R5 represents independently for each occurrence halo, C1-6 haloalkyl, C1-6 alkyl, or C3-6 cycloalkyl.
28. The compound of any one of claims 1-24, wherein R5 represents independently for each occurrence halo or C1-6 haloalkyl.
29. The compound of any one of claims 1-24, wherein R5 is C1-6 haloalkyl.
30. The compound of any one of claims 1-24, wherein R5 is -CF3.
31. The compound of any one of claims 1-24, wherein R5 is C1-6 alkyl.
32. The compound of any one of claims 1-24, wherein R5 is halo.
33. The compound of any one of claims 1-24, wherein R5 is fluoro.
34. A compound in Table 1 herein, or a pharmaceutically acceptable salt thereof.
91 30816081 398813-004WO (206432)
35. A pharmaceutical composition comprising a compound of any one of claims 1-34 and a pharmaceutically acceptable carrier.
36. A method of treating a muscarinic acetylcholine receptor mediated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-34 to treat the muscarinic acetylcholine receptor mediated disorder.
37. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is a neurologic disorder.
38. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is a movement disorder, mood disorder, or cognitive disorder.
39. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is an attention disorder or addictive disorder.
40. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is schizophrenia, psychosis, mild cognitive impairment, Alzheimer's Disease, Parkinson's Disease, Parkinson's Disease-levodopa-induced dyskinesia, Huntington's Disease, dyskinesia, cerebral amyloid angiopathy, dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, a prion disorder, amyotrophic lateral sclerosis, progressive supranuclear palsy, autism, addiction, or a sleep disorder.
41. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is a schizo-affective disorder, psychosis, a delusional disorder, psychosis associated with Alzheimer’s disease, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, Lewy Body dementia, Gilles de la Tourette’s syndrome, Friederich’s ataxia, Huntington’s chorea, restless leg syndrome, major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, mania, anxiety, Alzheimer’s disease, Parkinson’s Disease, dementia, Pick’s disease, tauopathies, synucleinopathies, confusion, cognitive deficit associated with fatigue, a learning disorder, traumatic brain injury, autism, age-related cognitive decline, Cushing’s Disease, attention deficit and hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG Syndrome, Down’s Syndrome, growth delay due to insulin-like growth factor I (IGF1) deficiency, hepatic encephalopathy syndrome, Strauss Syndrome, or agitation associated with neurodegeneration.
92 30816081 398813-004WO (206432)
42. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is dementia-related psychosis, schizophrenia, Alzheimer’s disease, Parkinson’s disease, depression, a movement disorder, pain, drug addiction, tauopathy, or synucleinopathy.
43. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is schizophrenia.
44. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is pain.
45. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is neuropathic pain.
46. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is inflammatory pain or nociceptive pain.
47. The method of claim 36, wherein the muscarinic acetylcholine receptor mediated disorder is chronic pain.
48. The method of any one of claims 36-47, further comprising administering to the subject in need thereof a therapeutically effective amount of an orthosteric agonist of the muscarinic acetylcholine receptor.
49. The method of claim 48, wherein the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject concurrently with a compound of any one of claims 1-34.
50. The method of claim 48, wherein the subject is administered a pharmaceutical composition comprising (i) the orthosteric agonist of the muscarinic acetylcholine receptor and (ii) a compound of any one of claims 1-34.
51. The method of claim 48, wherein the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject separately from a compound of any one of claims 1- 34.
52. The method of claim 48, wherein the orthosteric agonist of the muscarinic acetylcholine receptor is administered to the subject via a first pharmaceutical composition, and the compound of any one of claims 1-34 is administered to the subject via a second pharmaceutical composition.
53. The method of any one of claims 48-52, wherein the amount of (i) orthosteric agonist of the muscarinic acetylcholine receptor and/or (ii) compound of any one of claims 1-34 that is administered to the patient is reduced compared to use of either the (i) orthosteric agonist of
93 30816081 398813-004WO (206432) the muscarinic acetylcholine receptor or (ii) compound of any one of claims 1-34 in a monotherapy treatment.
54. The method of any one of claims 36-47, further comprising administering to the subject in need thereof a therapeutically effective amount of an orthosteric antagonist of the muscarinic acetylcholine receptor.
55. The method of any one of claims 36-54, wherein the subject is a human.
56. A method of activating a muscarinic acetylcholine receptor, comprising contacting a muscarinic acetylcholine receptor with an effective amount of a compound of any one of claims 1-34 to activate the muscarinic acetylcholine receptor.
57. The method of any one of claims 36-56, wherein the muscarinic acetylcholine receptor is muscarinic acetylcholine receptor M4.
58. A compound represented by Formula II:
Figure imgf000095_0001
or a salt thereof; wherein: R1A is C1-4 alkoxyl, -N(R5A)2, -O-(C3-6 cycloalkyl), C1-6 alkyl, or C3-6 cycloalkyl; R2A is cyano, C1-4 alkyl, C1-4 haloalkyl, halogen, or hydrogen; R3A and R4A are independently hydrogen or C1-4 alkyl; R5A represents independently for each occurrence hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or -(C1-6 alkylene)-(C3-6 cycloalkyl); or two occurrences of R5A attached to the same nitrogen atom are taken together with the nitrogen atom to form a 3-7 membered saturated ring containing 1 nitrogen atom; and Z1 is hydrogen or -C(O)2(C1-6 alkyl).
Figure imgf000095_0002
59. The compound of claim 58, wherein R1A is or .
60. The compound of claim 58 or 59, wherein R2A is methyl, chloro, or cyano.
61. The compound of any one of claims 58-60, wherein R3A is hydrogen.
62. The compound of any one of claims 58-61, wherein R4A is hydrogen or methyl.
94 30816081 398813-004WO (206432)
63. The compound of any one of claims 58-62, wherein R5A is hydrogen.
64. The compound of any one of claims 58-63, wherein Z1 is hydrogen or tert-butoxycarbonyl.
95 30816081 398813-004WO (206432)
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