(12) Patent Application Publication (10) Pub. No.: US 2016/0168090 A1 KARRA (43) Pub

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US 2016O168090A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0168090 A1 KARRA (43) Pub. Date: Jun. 16, 2016

(54) NOVEL INDOLE DERIVATIVES AND THEIR C07D 405/04 (2006.01) USE IN NEURODEGENERATIVE DISEASES C07D 47L/04 (2006.01) C07D 409/4 (2006.01) (71) Applicant: Merck Patent GmbH, Darmstadt (DE) C07D 417/06 (2006.01) C07D 403/04 (2006.01) (72) Inventor: Srinivasa R. KARRA, Pembroke, MA C07D 413/06 (2006.01) (US) C07D 40/06 (2006.01) C07D 405/2 (2006.01) (21) Appl. No.: 14/969,328 C07D 405/4 (2006.01) (52) U.S. Cl. (22) Filed: Dec. 15, 2015 CPC ...... C07D 209/42 (2013.01); C07D405/12 O O (2013.01); C07D 417/12 (2013.01); C07D Related U.S. Application Data 409/12 (2013.01); C07D 403/06 (2013.01); (60) Provisional application No. 62/117,128, filed on Feb. C07D405/04 (2013.01); C07D405/14 17, 2015, provisional application No. 62/091,855, (2013.01); C07D 409/14 (2013.01); C07D filed on Dec. 15, 2014. 417/06 (2013.01); C07D 403/04 (2013.01); C07D 413/06 (2013.01); C07D401/06 Publication Classification (2013.01); C07D 471/04 (2013.01) (51) Int. Cl. (57) ABSTRACT CO7D 209/242 (2006.01) The present invention relates to indole compounds, and phar C07D 417/12 (2006.01) maceutically acceptable compositions thereof, useful as CO7D 409/2 (2006.01) antagonists of P2X7, and for the treatment of P2X7-related CO7D 403/06 (2006.01) disorders. US 2016/01 68090 A1 Jun. 16, 2016

NOVEL INDOLE DERVATIVES AND THEIR

USE IN NEURODEGENERATIVE DISEASES

RELATED APPLICATIONS 0001. This application claims the benefit of U.S. Provi sional Application Ser. No. 62/091,855, filed on Dec. 15, 2014, and U.S. Provisional Application Ser. No. 62/117,128, filed on Feb. 17, 2015. The contents of the aforementioned applications are hereby incorporated by reference in their entireties. ora pharmaceutically acceptable salt thereof, wherein each of X, Y, R and R is as defined and described in embodiments TECHNICAL FIELD OF THE INVENTION herein. 0007 Compounds of the present invention, and pharma 0002 The present invention relates to indole compounds ceutically acceptable compositions thereof, are useful for useful as antagonists of P2X7. The invention also provides treating a variety of diseases, disorders or conditions, associ pharmaceutically acceptable compositions comprising com ated with P2X7 activity. Such diseases, disorders, or condi pounds of the present invention and methods of using said tions include those described herein. compositions in the treatment of various disorders. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS BACKGROUND OF THE INVENTION 1. General Description of Compounds of the 0003. The P2X7 receptor is a ligand-gated ion channel that Invention belongs to the Purinergic Receptor Family. The receptor is 0008. In certain embodiments, the present invention pro expressed on many cell types related to the immune and vides antagonists of P2X7. In some embodiments, such com nervous systems. In the nervous system P2X7 is expressed on pounds include those of the formulae described herein, or a microglia, oligodendrocytes and astrocytes. Brief activation pharmaceutically acceptable salt thereof, wherein each vari of the P2X7 receptor channel with its endogenous ligand ATP able is as defined and described herein. leads to several downstream events including the processing and release of the proinflammatory cytokine IL 1-3 from 2. Compounds and Definitions monocytes and macrophages. P2X7 activation also plays an 0009 Compounds of this invention include those important role in regulating the glutamate releasefuptake in described generally above, and are further illustrated by the astrocytes. classes, Subclasses, and species disclosed herein. As used 0004 P2X7 receptors are ionotropic receptors activated herein, the following definitions shall apply unless otherwise by ATP, which may regulate neurotransmission in the CNS by indicated. For purposes of this invention, the chemical ele activating presynaptic and/or postsynaptic P2X7 receptors on ments are identified in accordance with the Periodic Table of central and peripheral neurons and glia (Deuchars S. A. et al., the Elements, CAS version, Handbook of Chemistry and J. Neurosci. 21:7143-7152, (2001), Kanjhan R. et al., J. Physics, 75" Ed. Additionally, general principles of organic Comp. Neurol. 407:11-32 (1997), Le K. T. et al., Neuro chemistry are described in "Organic Chemistry. Thomas science 83:177-190 (1998)). Activation of the P2X7 receptor Sorrell, University Science Books, Sausalito: 1999, and on cells of the immune system (macrophages, mast cells and “March's Advanced Organic Chemistry”, 5" Ed., Ed. Smith, lymphocytes) leads to release of interleukin-1B (IL-1B), giant M. B. and March, J., John Wiley & Sons, New York: 2001, the cell formation, degranulation, and L-selectin shedding. ATP entire contents of which are hereby incorporated by refer is able to increase local release and process of IL-1 in rats CCC. through a P2X7 receptor mediated mechanism following 0010. The term “aliphatic' or “aliphatic group', as used lipopolysaccharide (LPS) intraperitoneal injections (Griffiths herein, means a straight-chain (i.e., unbranched) or branched, et al., J. Immunology Vol. 154, pages 2821-2828 (1995); substituted or unsubstituted hydrocarbon chain that is com Solle et al., J. Biol. Chemistry, Vol. 276, pages 125-132, pletely saturated or that contains one or more units of unsat (2001)). uration, or a monocyclic hydrocarbon or bicyclic hydrocar bon that is completely saturated or that contains one or more 0005 Antagonism of the P2X7 receptor is considered to units of unsaturation, but which is not aromatic (also referred be an attractive therapeutic approach for the treatment of to herein as "carbocycle” “cycloaliphatic' or “cycloalkyl). multiple Sclerosis and Alzheimer's disease, due to its signifi that has a single point of attachment to the rest of the mol cant role in dampening the CNS inflammation and Supporting ecule. Unless otherwise specified, aliphatic groups contain neuroprotection. 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodi SUMMARY OF THE INVENTION ments, aliphatic groups contain 1-4 aliphatic carbonatoms. In still other embodiments, aliphatic groups contain 1-3 ali 0006. It has now been found that compounds of this inven phatic carbon atoms, and in yet other embodiments, aliphatic tion, and pharmaceutically acceptable compositions thereof, groups contain 1-2 aliphatic carbon atoms. In some embodi are effective as antagonists of P2X7. Such compounds have ments, “cycloaliphatic' (or “carbocycle' or “cycloalkyl) general formula I: refers to a monocyclic C-C, hydrocarbon that is completely US 2016/01 68090 A1 Jun. 16, 2016

saturated or that contains one or more units of unsaturation, eroaralkoxy’, refer to groups having 5 to 10 ring atoms, but which is notaromatic, that has a single point of attachment preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 telectrons to the rest of the molecule. Exemplary aliphatic groups are shared in a cyclic array; and having, in addition to carbon linear or branched, substituted or unsubstituted C-C alkyl, atoms, from one to five heteroatoms. The term "heteroatom’ C-Cs alkenyl, C-C alkynyl groups and hybrids thereofsuch refers to nitrogen, oxygen, or Sulfur, and includes any oxi as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alk dized form of nitrogen or Sulfur, and any quaternized form of enyl. a basic nitrogen. Heteroaryl groups include, without limita 0011. The term “lower alkyl refers to a Castraight or tion, thienyl, furanyl, pyrrolyl, imidazolyl pyrazolyl, triaz branched alkyl group. Exemplary lower alkyl groups are olyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert isothiazolyl, thiadiazolyl pyridyl, pyridazinyl, pyrimidinyl, butyl. pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridi 0012. The term “lower haloalkyl refers to a Castraight nyl. The terms "heteroaryland "heteroar-”, as used herein, or branched alkyl group that is substituted with one or more also include groups in which a heteroaromatic ring is fused to halogen atoms. one or more aryl, cycloaliphatic, or heterocyclyl rings, where 0013 The term "heteroatom' means one or more of oxy the radical or point of attachment is on the heteroaromatic gen, Sulfur, nitrogen, or phosphorus (including, any oxidized ring. Nonlimiting examples include indolyl, isoindolyl, ben form of nitrogen, Sulfur, or phosphorus; the quaternized form Zothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimi of any basic nitrogen or, a Substitutable nitrogen of a hetero dazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, cyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, NH (as in pyrrolidinyl) or NR" (as in N-substituted pyrrolidi carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenox nyl)). azinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and 0014. The term “unsaturated’, as used herein, means that pyrido 2,3-b-1,4-oxazin-3 (4H)-one. A heteroaryl group is a moiety has one or more units of unsaturation. optionally mono- or bicyclic. The term "heteroaryl' is used 0015. As used herein, the term “bivalent Cls (or C) interchangeably with the terms "heteroaryl ring”, “heteroaryl saturated or unsaturated, straight or branched, hydrocarbon group', or "heteroaromatic”, any of which terms include chain', refers to bivalent alkylene, alkenylene, and alky rings that are optionally substituted. The term "heteroaralkyl nylene chains that are straight or branched as defined herein. refers to an alkyl group substituted by a heteroaryl, wherein 0016. The term “alkylene' refers to a bivalent alkyl group. the alkyland heteroaryl portions independently are optionally An “alkylene chain” is a polymethylene group, i.e., -(CH2) substituted. , wherein n is a positive integer, preferably from 1 to 6. 0021. As used herein, the terms "heterocycle”, “heterocy from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A clyl', "heterocyclic radical, and "heterocyclic ring are used Substituted alkylene chain is a polymethylene group in which interchangeably and refer to a stable 5- to 7-membered mono one or more methylene hydrogen atoms are replaced with a cyclic or 7-10-membered bicyclic heterocyclic moiety that is substituent. Suitable substituents include those described either saturated or partially unsaturated, and having, in addi below for a substituted aliphatic group. tion to carbon atoms, one or more, preferably one to four, 0017. The term “alkenylene' refers to a bivalent alkenyl heteroatoms, as defined above. When used in reference to a group. A Substituted alkenylene chain is a polymethylene ring atom of a heterocycle, the term "nitrogen' includes a group containing at least one double bond in which one or Substituted nitrogen. As an example, in a saturated or partially more hydrogen atoms are replaced with a Substituent. Suit unsaturated ring having 0-3 heteroatoms selected from oxy able substituents include those described below for a substi gen, Sulfur or nitrogen, the nitrogen is N (as in 3,4-dihydro tuted aliphatic group. The term “alkynylene' refers to a biva 2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N-sub lent alkynyl group. A Substituted alkynylene chain is a group stituted pyrrolidinyl). containing at least one triple bond in which one or more 0022. A heterocyclic ring can be attached to its pendant hydrogenatoms are replaced with a substituent. Suitable sub group at any heteroatom or carbonatom that results in a stable stituents include those described below for a substituted ali structure and any of the ring atoms can be optionally substi phatic group. tuted. Examples of Such saturated or partially unsaturated 0018. The term “halogen” means F, Cl, Br, or I. heterocyclic radicals include, without limitation, tetrahydro 0019. The term “aryl used alone or as part of a larger furanyl, tetrahydropyranyl, tetrahydrothiophenyl pyrrolidi moiety as in “aralkyl”, “aralkoxy’, or “aryloxyalkyl, refers nyl, piperidinyl, pyrrolinyl, morpholinyl, tetrahydroquinoli to monocyclic and bicyclic ring systems having a total offive nyl, tetrahydroisoquinolinyl, decahydroquinolinyl, to fourteen ring members, wherein at least one ring in the oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, system is aromatic and wherein each ring in the system con oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The tains three to seven ring members. The term “aryl is used terms "heterocycle”, “heterocyclyl, "heterocyclyl ring, interchangeably with the term “aryl ring. In certain embodi "heterocyclic group”, “heterocyclic moiety', and "heterocy ments of the present invention, “aryl” refers to an aromatic clic radical, are used interchangeably herein, and also ring system. Exemplary aryl groups are phenyl, biphenyl, include groups in which a heterocyclyl ring is fused to one or naphthyl, anthracyl and the like, which optionally includes more aryl, heteroaryl, or cycloaliphatic rings, such as indoli one or more substituents. Also included within the scope of nyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydro the term “aryl', as it is used herein, is a group in which an quinolinyl, where the radical or point of attachment is on the aromatic ring is fused to one or more non-aromatic rings. Such heterocyclyl ring. A heterocyclyl group is optionally mono as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or or bicyclic. The term "heterocyclylalkyl refers to an alkyl tetrahydronaphthyl, and the like. group substituted by a heterocyclyl, wherein the alkyl and 0020. The terms "heteroaryland “heteroar-”, used alone heterocyclyl portions independently are optionally Substi or as part of a larger moiety, e.g., "heteroaralkyl, or "het tuted. US 2016/01 68090 A1 Jun. 16, 2016

0023. As used herein, the term “partially unsaturated —(CH),C(O)SR: —(CH2)C(O)OSiR —(CH). refers to a ring moiety that includes at least one double or 4OC(O)R: OC(O)(CH). SR, SC(S)SR;-(CH), SC triple bond. The term “partially unsaturated is intended to (O)R: -(CH2)C(O)NR: C(S)NR: C(S)SR; encompass rings having multiple sites of unsaturation, but is –SC(S)SR, -(CH), OC(O)NR: C(O)N(OR)R; not intended to include aryl or heteroaryl moieties, as herein C(O)C(O)R: C(O)CHC(O)R: C(NOR)R; defined. —(CH) SSR; —(CH). S(O).R. —(CH), S(O) 0024. As described herein, certain compounds of the OR; —(CH)OS(O).R. —S(O)NR; —(CH)S invention contain “optionally Substituted moieties. In gen (O)R; N(R)S(O)NR: N(R)S(O).R. N(OR) eral, the term “substituted, whether preceded by the term R; C(NH)NR: -P(O).R. -P(O)R: OP(O)R: “optionally or not, means that one or more hydrogens of the —OP(O)(OR); SiR —(C straight or branched alky designated moiety are replaced with a suitable Substituent. lene)O N(R); or —(C straight or branched alkylene)C “Substituted' applies to one or more hydrogens that are either (O)O N(R), wherein each R is optionally substituted as explicit or implicit from the structure (e.g., defined below and is independently hydrogen, Caliphatic, —CHPh, —O(CH). Ph, NH(CH). Ph, —CH-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, N partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or Sulfur, or, 2 notwithstanding the definition above, two independent occur rences of R, taken together with their intervening atom(s), form a 3-12-membered Saturated, partially unsaturated, or refers to at least aryl mono- or bicyclic ring having 0-4 heteroatoms indepen dently selected from nitrogen, oxygen, or Sulfur, which is optionally substituted as defined below. 0026 Suitable monovalent substituents on R (or the ring formed by taking two independent occurrences of R together with their intervening atoms), are independently deuterium, O-O". halogen, -(CH.) R,-(haloR), -(CH), OH,-(CH.) OR, (CH), CH(OR), O(haloR), CN, N., refers to at least (CH),C(O)R. —(CH),C(O)CH, -(CH),C(O) OR. -(CH), SR, -(CH), SH, -(CH), NH, (CH)NHR'. (CH)NR, NO, SiR, —OSiR –C(O)SR,-(C, a straight or branched alky lene)C(O)OR, or - SSR wherein each R is unsubsti tuted or where preceded by “halo' is substituted only with one O O C O O or more halogens, and is independently selected from Ca aliphatic, —CHPh. —O(CH). Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 het Unless otherwise indicated, an “optionally substituted group eroatoms independently selected from nitrogen, oxygen, or has a suitable substituent at each substitutable position of the sulfur. Suitable divalent substituents on a saturated carbon group, and when more than one position in any given struc atom of R include —O and —S. ture is substituted with more than one substituent selected 0027 Suitable divalent substituents on a saturated carbon from a specified group, the Substituent is either the same or atom of an “optionally substituted group include the follow different at every position. Combinations of substituents ing: —O, =S, —NNR* =NNHC(O)R*, =NNHC(O) envisioned by this invention are preferably those that result in OR*, =NNHS(O).R*, —NR*, —NOR*, O(C(R*,)). the formation of stable or chemically feasible compounds. 3O—, or —S(C(R)). S- , wherein each independent The term “stable', as used herein, refers to compounds that occurrence of R is selected from hydrogen, Caliphatic are not substantially altered when subjected to conditions to which is substituted as defined below, or an unsubstituted allow for their production, detection, and, in certain embodi 5-6-membered saturated, partially unsaturated, or aryl ring ments, their recovery, purification, and use for one or more of having 0-4 heteroatoms independently selected from nitro the purposes disclosed herein. gen, oxygen, or Sulfur. Suitable divalent Substituents that are 0.025 Suitable monovalent substituents on a substitutable bound to vicinal substitutable carbons of an “optionally sub carbon atom of an “optionally Substituted’ group are inde stituted group include: —O(CR) O—, wherein each pendently deuterium; halogen; —(CH) R. —(CH). independent occurrence of R* is selected from hydrogen, 4OR; —O(CH) R. —O—(CH2)C(O)CR; —(CH). Caliphatic which is optionally Substituted as defined 4CH(OR); —(CH). SR; —(CH), Ph, which are below, or an unsubstituted 5-6-membered saturated, partially optionally substituted with R: —(CH)O(CH). Ph unsaturated, or aryl ring having 0-4 heteroatoms indepen which is optionally substituted with R: —CH=CHPh. dently selected from nitrogen, oxygen, or Sulfur. which is optionally substituted with R: —(CH), O(CH) 0028 Suitable substituents on the aliphatic group of R* o-pyridyl which is optionally substituted with R: NO; include halogen, Ro, -(haloR), OH, OR, —O(ha —CN: N.; —(CH), N(R); —(CH), N(R)C(O)R: loR), CN, C(O)OH, C(O)CR, NH, NHR, N(R)C(S)R;-(CH)N(R)C(O)NR: N(R)C(S) —NR, or - NO, wherein each R is unsubstituted or NR: (CH)N(R)C(O)OR: N(R)N(R)C(O)R; where preceded by “halo' is substituted only with one or N(R)N(R)C(O)NR; N(R)N(R)C(O)OR; more halogens, and is independently C aliphatic, —(CH) C(O)R; —C(S)R; —(CH2)C(O)OR; —CHPh, —O(CH). Ph, or a 5-6-membered saturated, US 2016/01 68090 A1 Jun. 16, 2016 partially unsaturated, or aryl ring having 0-4 heteroatoms (O)NH, -NHC(O)NH-alkyl, -NHC(O)NH- alkenyl, independently selected from nitrogen, oxygen, or Sulfur. - NHC(O)NH- alkenyl, -NHC(O)NH carbocyclyl, 0029 Suitable substituents on a substitutable nitrogen of - NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, - NHC(O) an “optionally substituted” group include - R. —NR, NH heterocyclyl, NHC(S)NH, -NHC(S)NH- alkyl, C(O)R, C(O)CR, C(O)C(O)R, C(O)CHC(O) - NHC(S)NH-alkenyl, -NHC(S)NH-alkynyl, - NHC R, S(O).Rf, S(O)NR, C(S)NR, C(NH)NR, (S)NH carbocyclyl, -NHC(S)NH-aryl, - NHC(S)NH or - N(R)S(O).R; wherein each Rf is independently heteroaryl, - NHC(S)NH-heterocyclyl, -NHC(NH)NH2, hydrogen, Caliphatic which is optionally Substituted as - NHC(NH)NH- alkyl, -NHC(NH)NH-1-alkenyl, defined below, unsubstituted—OPh, oran unsubstituted 5-6- - NHC(NH)NH-alkenyl, -NHC(NH)NH-carbocyclyl, membered Saturated, partially unsaturated, or aryl ring hav NHC(NH)NH-aryl, NHC(NH)NH-heteroaryl, NHC ing 0-4 heteroatoms independently selected from nitrogen, (NH)NH– heterocyclyl, - NHC(NH) - alkyl, -NHC oxygen, or Sulfur, or, notwithstanding the definition above, (NH)– alkenyl, -NHC(NH)– alkenyl, -NHC(NH)– two independent occurrences of R, taken together with their carbocyclyl, - NHC(NH)-aryl, -NHC(NH)-heteroaryl, intervening atom(s) form an unsubstituted 3-12-membered - NHC(NH)-heterocyclyl, saturated, partially unsaturated, oraryl mono- or bicyclic ring 0041 –C(NH)NH- alkyl, -C(NH)NH- alkenyl, having 0-4 heteroatoms independently selected from nitro - C(NH)NH- alkynyl, -C(NH)NH carbocyclyl, gen, oxygen, or Sulfur. - C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH 0030) Suitable substituents on the aliphatic group of Rt are heterocyclyl, independently halogen, R, -(haloR), OH, OR, 0042 S(O)—alkyl, —S(O)—alkenyl, —S(O)—alky O(haloR), CN, C(O)OH, C(O)OR, NH, nyl, S(O)— carbocyclyl. —S(O)-aryl, - S(O)-heteroaryl, NHR, NR, or - NO, wherein each R is unsubsti —S(O)-heterocyclyl —SONH, -SONH- alkyl, tuted or where preceded by “halo' is substituted only with one —SONH alkenyl, -SONH alkynyl, -SONH or more halogens, and is independently Caliphatic, carbocyclyl, -SONH aryl, -SONH heteroaryl, —CHPh, —O(CH). Ph, or a 5-6-membered saturated, —SONH heterocyclyl, partially unsaturated, or aryl ring having 0-4 heteroatoms 0043 – NHSO - alkyl, -NHSO - alkenyl, independently selected from nitrogen, oxygen, or Sulfur. —NHSO - alkynyl, - NHSO carbocyclyl, - NHSO 0031. In certain embodiments, the terms “optionally sub aryl, - NHSO-heteroaryl, - NHSO-heterocyclyl, stituted”, “optionally substituted alkyl. “optionally substi 0044) —CH-NH, -CHSOCH, tuted"optionally substituted alkenyl,”“optionally substituted 0045 -mono-, di-, or tri-alkylsilyl, alkynyl', “optionally substituted carbocyclic.” “optionally 0046 -alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -het substituted aryl', 'optionally substituted heteroaryl.” eroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, “optionally substituted heterocyclic,” and any other option -carbocyclic, -heterocyclic, polyalkoxyalkyl, polyalkoxy, ally Substituted group as used herein, refer to groups that are -methoxymethoxy, -methoxyethoxy, —SH. —S - alkyl, substituted or unsubstituted by independent replacement of —S—alkenyl, - S - alkynyl. —S-carbocyclyl. —S-aryl, one, two, or three or more of the hydrogenatoms thereon with —S-heteroaryl, S-heterocyclyl, or methylthiomethyl. typical Substituents including, but not limited to: 0047. As used herein, the term “pharmaceutically accept 0032 —F. —Cl, —Br. —I, deuterium, able salt” refers to those salts which are, within the scope of 0033 —OH, protected hydroxy, alkoxy, oxo, thiooxo, Sound medical judgment, Suitable for use in contact with the 0034 - NO, CN, CFs, N. tissues of humans and lower animals without undue toxicity, 0035 – NH, protected amino, -NH alkyl, -NH alk irritation, allergic response and the like, and are commensu enyl, - NH alkynyl, - NH cycloalkyl, -NH -aryl, - NH rate with a reasonable benefit/risk ratio. Pharmaceutically -heteroaryl, -NH -heterocyclic, -dialkylamino, -diary acceptable salts are well known in the art. For example, S. M. lamino, -diheteroarylamino, Berge et al., describe pharmaceutically acceptable salts in 0036 —O— alkyl, —O— alkenyl, —O— alkynyl, detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incor —O— cycloalkyl, —O-aryl, -O-heteroaryl, -O-heterocy porated herein by reference. Pharmaceutically acceptable clic, salts of the compounds of this invention include those derived 0037 –C(O) = alkyl, -C(O) = alkenyl, -C(O)— from Suitable inorganic and organic acids and bases. alkynyl, —C(O)— carbocyclyl. —C(O)-aryl, —C(O)—het Examples of pharmaceutically acceptable, nontoxic acid eroaryl, —C(O)-heterocyclyl, addition salts are salts of an amino group formed with inor 0038 –CONH – CONH-alkyl, -CONH-alkenyl, ganic acids such as hydrochloric acid, hydrobromic acid, —CONH-alkynyl, -CONH-carbocyclyl, -CONH-aryl, phosphoric acid, Sulfuric acid and perchloric acid or with —CONH-heteroaryl, -CONH-heterocyclyl, organic acids such as acetic acid, oxalic acid, maleic acid, 0039) —OCO alkyl, OCO alkenyl, —OCO tartaric acid, citric acid, Succinic acid or malonic acid or by alkynyl, —OCO carbocyclyl, —OCO-aryl, —OCO using other methods used in the art Such as ion exchange. heteroaryl, —OCO-heterocyclyl, –OCONH, Other pharmaceutically acceptable salts include adipate, algi –OCONH- alkyl, OCONH- alkenyl, - OCONH nate, ascorbate, aspartate, benzenesulfonate, benzoate, bisul alkynyl, OCONH carbocyclyl - OCONH- aryl, fate, borate, butyrate, camphorate, camphorsulfonate, citrate, –OCONH-heteroaryl, OCONH-heterocyclyl, cyclopentanepropionate, digluconate, dodecylsulfate, 0040 NHC(O)-alkyl, -NHC(O)—alkenyl, -NHC ethanesulfonate, formate, fumarate, glucoheptonate, glycero (O)— alkynyl, —NHC(O)— carbocyclyl, - NHC(O)-aryl, phosphate, gluconate, hemisulfate, heptanoate, hexanoate, —NHC(O)-heteroaryl, - NHC(O)-heterocyclyl, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lac —NHCO alkyl, - NHCO - alkenyl, NHCO-alky tate, laurate, lauryl Sulfate, malate, maleate, malonate, meth nyl, NHCO carbocyclyl. —NHCO aryl, anesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, —NHCO. heteroaryl, - NHCO. heterocyclyl, - NHC oleate, oxalate, palmitate, pamoate, pectinate, persulfate, US 2016/01 68090 A1 Jun. 16, 2016

3-phenylpropionate, phosphate, pivalate, propionate, Stear part and in the preparation part in the present text, replacing a ate, Succinate, Sulfate, tartrate, thiocyanate, p-toluene non-isotope-labeled reactant by a readily available isotope Sulfonate, undecanoate, Valerate salts, and the like. labeled reactant. Compounds of the invention may be substi 0048 Salts derived from appropriate bases include alkali tuted by F, for use as PET imaging agents. metal, alkaline earth metal, ammonium and N(Calkyl). I0052 Deuterium (H) can also beincorporated into a com salts. Representative alkali or alkaline earth metal salts pound of the formula I for the purpose in order to manipulate include Sodium, lithium, potassium, calcium, magnesium, the oxidative metabolism of the compound by way of the and the like. Further pharmaceutically acceptable salts primary kinetic isotope effect. The primary kinetic isotope include, when appropriate, nontoxic ammonium, quaternary effect is a change of the rate for a chemical reaction that ammonium, and amine cations formed using counterions results from exchange of isotopic nuclei, which in turn is Such as halide, hydroxide, carboxylate, Sulfate, phosphate, caused by the change in ground state energies necessary for nitrate, loweralkyl sulfonate and aryl sulfonate. covalent bond formation after this isotopic exchange. 0049. Unless otherwise stated, structures depicted herein Exchange of a heavier isotope usually results in a lowering of are also meant to include all isomeric (e.g., enantiomeric, the ground state energy for a chemical bond and thus causes diastereomeric, tautomers, and geometric (or conforma a reduction in the rate in rate-limiting bond breakage. If the tional)) forms of the structure; for example, the R and S bond breakage occurs in or in the vicinity of a saddle-point configurations for each asymmetric center, Z and E double region along the coordinate of a multi-product reaction, the bond isomers, and Z and E conformational isomers. There product distribution ratios can be altered substantially. For fore, single stereochemical isomers as well as enantiomeric, explanation: if deuterium is bonded to a carbon atom at a diastereomeric, and geometric (or conformational) mixtures non-exchangeable position, rate differences ofk/k, 2-7 are of the present compounds are within the scope of the inven typical. If this rate difference is successfully applied to a tion. Unless otherwise stated, all tautomeric forms of the com-pound of the formula I that is susceptible to oxidation, compounds of the invention are within the scope of the inven the profile of this compound in vivo can be drastically modi tion. fied and result in improved pharmacokinetic properties. 0050 Additionally, unless otherwise stated, structures 0053 When discovering and developing therapeutic depicted herein are also meant to include compounds that agents, the person skilled in the art is able to optimize phar differ only in the presence of one or more isotopically macokinetic parameters while retaining desirable in vitro enriched atoms. For example, compounds having the present properties. It is reasonable to assume that many compounds structures including the replacement of hydrogen by deute with poor pharmacokinetic profiles are Susceptible to oxida rium or tritium, or the replacement of a carbon by a C- or tive metabolism. In vitro liver microsomal assays currently '''C-enriched carbon are within the scope of this invention. In available provide valuable information on the course of oxi Some embodiments, the group comprises one or more deute dative metabolism of this type, which in turn permits the rium atoms. rational design of deuterated compounds of the formula I with 0051. There is furthermore intended that a compound of improved stability through resistance to Such oxidative the formula I includes isotope-labeled forms thereof. An iso metabolism. Significant improvements in the pharmacoki tope-labeled form of a compound of the formula I is identical netic profiles of compounds of the formula I are thereby to this compound apart from the fact that one or more atoms obtained, and can be expressed quantitatively in terms of of the compound have been replaced by an atom or atoms increases in the in vivo half-life (t/2), concen-tra-tion at maxi having anatomic mass or mass number which differs from the mum therapeutic effect (C), area under the dose response atomic mass or mass number of the atom which usually curve (AUC), and F; and in terms of reduced clearance, dose occurs naturally. Examples of isotopes which are readily and materials costs. commercially available and which can be incorporated into a 0054 The following is intended to illustrate the above: a compound of the formula I by well-known methods include compound of the formula I which has multiple potential sites isotopes of hydrogen, carbon, nitrogen, oxygen, phos-phorus, of attack for oxidative metabolism, for example benzylic fluo-rine and chlorine, for example H, H, C, C, N, hydrogen atoms and hydrogen atoms bonded to a nitrogen *O, 7O, P, P, S, F and CI, respectively. A com atom, is prepared as a series of analogues in which various pound of the formula I, a prodrug, thereof or a pharmaceuti combinations of hydrogen atoms are replaced by deuterium cally acceptable salt of either which contains one or more of atoms, so that some, most or all of these hydrogenatoms have the above-mentioned isotopes and/or other isotopes of other been replaced by deuterium atoms. Half-life determinations atoms is intended to be part of the present invention. An enable favorable and accurate determination of the extent of isotope-labeled compound of the formula I can be used in a the extent to which the improvement in resistance to oxidative number of beneficial ways. For example, an isotope-labeled metabolism has improved. In this way, it is determined that compound of the formula I into which, for example, a radio the half-life of the parent compound can be extended by up to isotope, such as H or ''C, has been incorporated, is suitable 100% as the result of deuterium-hydrogen exchange of this for medicament and/or Substrate tissue distribution assays. type. These radioisotopes, i.e. tritium (H)and carbon-14 (''C), are 0055 Deuterium-hydrogen exchange in a compound of particularly preferred owing to simple preparation and excel the formula I can also be used to achieve a favorable modifi lent detectability. Incorporation of heavier isotopes, for cation of the metabolite spectrum of the starting compound in example deuterium (H), into a compound of the formula I order to diminish or eliminate undesired toxic metabolites. has therapeutic advantages owing to the higher metabolic For example, if a toxic metabolite arises through oxidative stability of this isotope-labeled compound. Higher metabolic carbon-hydrogen (C-H) bond cleavage, it can reasonably be stability translates directly into an increased in vivo half-life assumed that the deuterated analogue will greatly diminish or or lower dosages, which under most circumstances would eliminate production of the unwanted metabolite, even if the represent a preferred embodiment of the present invention. particular oxidation is not a rate-determining step. Further An isotope-labeled compound of the formula I can usually be information on the state of the art with respect to deuterium prepared by carrying out the procedures disclosed in the hydrogen exchange may be found, for example in Hanzlik et synthesis schemes and the related description, in the example al., J. Org. Chem. 55,3992-3997, 1990, Reider et al., J. Org. US 2016/01 68090 A1 Jun. 16, 2016

Chem.52,3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, dently selected from nitrogen, oxygen, or Sulfur, a 5-6 1985, Gillette et al, Biochemistry 33(10) 2927-2937, 1994, membered monocyclic heteroaryl ring having 1-4 heteroa and Jarman et al. Carcinogenesis 16(4), 683-688, 1993. toms independently selected from nitrogen, oxygen, or 0056. As used herein, the term “modulator” is defined as a sulfur, a fused 7-10 membered bicyclic saturated, partially compound that binds to and/or inhibits the target with mea unsaturated ring, aryl, or heteroaryl ring; each of which is Surable affinity. In certain embodiments, a modulator has an optionally substituted by 1-5 of R'; or R' is SOR, ICso and/or binding constant of less about 50 LM. In certain —SOR, C(O)R, COR, or -C(O)N(R); each of embodiments, a modulator has an ICs and/or binding con which is optionally substituted by 1-5 of R"; stant of less than about 5 uM. In certain embodiments, a I0065 R is Caliphatic, Caryl, a 3-8 membered satu modulator has an ICso and/or binding constant of between rated or partially unsaturated carbocyclic ring, a 3-7 mem about 1 to about 5uM. In certain embodiments, a modulator bered heterocylic ring having 1-4 heteroatoms indepen has an ICso and/or binding constant of less than about 1 uM. dently selected from nitrogen, oxygen, or Sulfur, a 5-6 In certain embodiments, a modulator has an ICs and/or bind membered monocyclic heteroaryl ring having 1-4 heteroa ing constant of between about 500 to about 1000 nM. In toms independently selected from nitrogen, oxygen, or certain embodiments, a modulator has an ICs and/or binding sulfur, a fused 7-10 membered bicyclic saturated, partially constant of less than about 500 nM. In certain embodiments, unsaturated ring, aryl, or heteroaryl ring; each of which is a modulator has an ICso and/or binding constant of between optionally substituted by 1-5 of R"; or R is SO.R. about 100 to about 500 nM. In certain embodiments, a modu —SOR, —C(O)R,-COR, or -C(O)N(R): lator has an ICso and/or binding constant of less than about I0066 each R is independently —R, halogen, -haloalkyl, 100 nM. In certain embodiments, a modulator has an ICso -hydroxyalkyl, —OR, —SR, —CN, NO. —SOR, and/or binding constant of between about 10 to about 100 nM. —SOR, C(O)R, COR, C(O)N(R), NRC(O)R, In certain embodiments, a modulator has an ICso and/or bind - NRC(O)N(R) - NRSOR, or - N(R): ing constant of less than about 10 nM. 0067 each R is independently hydrogen, Caliphatic, 0057 The terms “measurable affinity” and “measurably Co aryl, a 3-8 membered saturated or partially unsatur inhibit, as used herein, means a measurable change in P2X7 ated carbocyclic ring, a 3-7 membered heterocylic ring activity between a sample comprising a compound of the having 1-4 heteroatoms independently selected from nitro present invention, or composition thereof, and P2X7, and an gen, oxygen, or Sulfur, or a 5-6 membered monocyclic equivalent sample comprising P2X7, in the absence of said heteroaryl ring having 1-4 heteroatoms independently compound, or composition thereof. selected from nitrogen, oxygen, or sulfur, each of which is 0.058 Combinations of substituents and variables envi optionally substituted; or sioned by this invention are only those that result in the 0068 two R groups on the same atom are taken together formation of stable compounds. The term “stable', as used with the atom to which they are attached to form a Co herein, refers to compounds which possess stability Sufficient aryl, a 3-8 membered saturated or partially unsaturated to allow manufacture and which maintains the integrity of the carbocyclic ring, a 3-7 membered heterocylic ring having compound for a sufficient period of time to be useful for the 1-4 heteroatoms independently selected from nitrogen, purposes detailed herein (e.g., therapeutic or prophylactic oxygen, or Sulfur, or a 5-6 membered monocyclic het administration to a subject). eroaryl ring having 1-4 heteroatoms independently 0059. The recitation of a listing of chemical groups in any selected from nitrogen, oxygen, or Sulfur, each of which is definition of a variable herein includes definitions of that optionally substituted. variable as any single group or combination of listed groups. I0069. In certain embodiments, R' is Caliphatic which is The recitation of an embodiment for a variable herein optionally substituted by 1-5 of R". In certain embodiments, includes that embodiment as any single embodiment or in R" is C1-alkyl. In certain embodiments, R' is Coalkenyl. In combination with any other embodiments orportions thereof. certain embodiments, R' is C, alkynyl. I0070. In certain embodiments, R is methyl, ethyl, n-pro 3. Description of Exemplary Compounds pyl, i-propyl. n-butyl, S-butyl, t-butyl, straight chain or 0060 According to one aspect, the present invention pro branched pentyl, straight chain or branched hexyl, each of vides a compound of formula I, which is optionally substituted by 1-5 of R". In certain embodiments, R' is ethenyl, n-propenyl, i-propenyl, n-bute

nyl, S-butenyl, t-butenyl, straight chain or branched pentenyl, straight chain or branched hexenyl, each of which is option ally substituted by 1-5 of R". In certain embodiments, R is ethynyl. n-propynyl, i-propynyl. n-butynyl, S-butynyl, t-bu tynyl, straight chain or branched pentynyl, straight chain or branched hexynyl, each of which is optionally substituted by 1-5 of R?. (0071. In certain embodiments, R' is a Cso aryl, a 3-8 membered Saturated or partially unsaturated carbocyclic ring, 0061 or a pharmaceutically acceptable salt thereof, a 3-7 membered heterocylic ring having 1-4 heteroatoms wherein: independently selected from nitrogen, oxygen, or Sulfur, a 5-6 0062 X is CR or N: membered monocyclic heteroaryl ring having 1-4 heteroat 0063 Y is C1 or CF; oms independently selected from nitrogen, oxygen, or Sulfur, I0064) R' is Caliphatic, Cso aryl, a 3-8 membered satu a fused 7-10 membered bicyclic saturated, partially unsatur rated or partially unsaturated carbocyclic ring, a 3-7 mem ated ring, aryl, or heteroaryl ring; each of which is optionally bered heterocylic ring having 1-4 heteroatoms indepen substituted by 1-5 of R: US 2016/01 68090 A1 Jun. 16, 2016

I0072. In certain embodiments, R' is a 3-7 membered het -continued erocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or Sulfur, which is optionally Substi tuted by 1-5 of R". 0073. In certain embodiments, R' is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep tyl, adamantyl, cyclooctyl, 3.3.0 bicyclooctanyl, 4.3.0 bi cyclononanyl, 4.4.0 bicyclodecanyl, 2.2.2 bicyclooctanyl. fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, ben Zothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimida Zolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1.5.2- dithiazinyl, dihydrofuro 2,3-btetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-in dazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-in dolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochro manyl, isolindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1.2.3-oxadiazolyl, 1.2, 4-oxadiazolyl: 1.2.5oxadiazolyl, 1,3,4-oxadiazolyl, oxazo lidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathi nyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pte ridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazoli nyl, pyrazolyl pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofura nyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1.2.5- thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5- thiadiazolyl, 1.3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1.2.5- triazolyl, 1.3,4-triazolyl, oxetanyl, aZetidinyl, 2-azaspiro3. 3]heptane, or Xanthenyl; each of which is optionally substi tuted by 1-5 of R". I0074) In certain embodiments, R' is pyrrolidinyl, tetrahy drofuranyl, aZetidinyl, or 2-azaspiro 3.3 heptane Xanthenyl: each of which is optionally substituted by 1-5 of R". 0075. In certain embodiments, R is -SOR, -SOR, —C(O)R, —COR, or —C(O)N(R); each of which is optionally substituted by 1-5 of R". 0076. In certain embodiments, R is –C(O)R, COR, or —C(O)N(R); each of which is optionally substituted by 1-5 of R. 0077. In certain embodiments, R is A - A -s /- /-/-/- A- a-- a-- US 2016/01 68090 A1 Jun. 16, 2016 -continued / C / C / XO \ty

NH.

(0078. In certain embodiments, R is Caliphatic, which is optionally substituted by 1-5 of R". In certain embodi ments, R' is C. alkyl. In certain embodiments, R' is C. alkenyl. In certain embodiments, R' is C, alkynyl. (0079. In certain embodiments, R is methyl, ethyl, n-pro pyl, i-propyl. n-butyl, s-butyl, t-butyl, straight chain or branched pentyl, straight chain or branched hexyl, each of which is optionally substituted by 1-5 of R". 0080. In certain embodiments, R is Cso aryl, a 3-8 mem bered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms inde pendently selected from nitrogen, oxygen, or Sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroat oms independently selected from nitrogen, oxygen, or Sulfur, a fused 7-10 membered bicyclic saturated, partially unsatur ated ring, aryl, or heteroaryl ring; each of which is optionally substituted by 1-5 of R. I0081. In certain embodiments, R is a 3-8 membered satu rated or partially unsaturated carbocyclic ring, or a 3-7 mem bered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or Sulfur, each of which is A C/-O/-C optionally substituted by 1-5 of R". I0082 In certain embodiments, R is - SOR, -SOR, —C(O)R, COR, or - C(O)N(R). I0083. In certain embodiments, R is /- vo A-O/-O-

/a/- CF3 /-O. AuC US 2016/01 68090 A1 Jun. 16, 2016

-continued -continued

US 2016/01 68090 A1 Jun. 16, 2016 10

-continued -continued

US 2016/01 68090 A1 Jun. 16, 2016

-continued orapharmaceutically acceptable salt thereof, wherein R is as defined above and described in embodiments, classes and Subclasses above and herein, singly or in combination. I0088. In certain embodiments, the present invention pro vides a compound of formula V:

I0084. In certain embodiments, each of R', R, and R', is as defined above and described in embodiments, classes and Subclasses above and herein, singly or in combination. 0085. In certain embodiments, the present invention pro vides a compound of formula II, II O C orapharmaceutically acceptable salt thereof, wherein R is as defined above and described in embodiments, classes and N N H - H(R)-s: Subclasses above and herein, singly or in combination. I0089. In certain embodiments, the present invention pro N vides a compound of formula VI: V R1 or a pharmaceutically acceptable salt thereof, wherein each of VI R" and R is as defined above and described in embodiments, O classes and Subclasses above and herein, singly or in combi C R2; nation. N Y I0086. In certain embodiments, the present invention pro N H vides a compound of formula III: N III O C R2; N1 O

N orapharmaceutically acceptable salt thereof, wherein R is as C3 defined above and described in embodiments, classes and \- Subclasses above and herein, singly or in combination. NN 0090. In certain embodiments, the present invention pro / vides a compound of formula VII: orapharmaceutically acceptable salt thereof, wherein R is as defined above and described in embodiments, classes and VII Subclasses above and herein, singly or in combination. O 0087. In certain embodiments, the present invention pro C vides a compound of formula IV: N1 R2; IV N H O C N N1 R2; N H O

N or a pharmaceutically acceptable salt thereof, wherein R is as s defined above and described in embodiments, classes and Subclasses above and herein, singly or in combination. US 2016/01 68090 A1 Jun. 16, 2016

0091. In certain embodiments, the present invention pro 0095. In certain embodiments, the present invention pro vides a compound of formula VIII: vides a compound of formula XI:

VIII XI O O C R2 C R2 N1 N1 N H N H

N N H Sky N N H orapharmaceutically acceptable salt thereof, wherein R is as defined above and described in embodiments, classes and orapharmaceutically acceptable salt thereof, wherein R is as Subclasses above and herein, singly or in combination. defined above and described in embodiments, classes and 0092. In certain embodiments, the present invention pro Subclasses above and herein, singly or in combination. vides a compound of formula IX: 0096. In certain embodiments, the present invention pro IX vides a compound of formula XIII: O XIII C R2 N1 C N H NSk), orapharmaceutically acceptable salt thereof, wherein R is as defined above and described in embodiments, classes and Subclasses above and herein, singly or in combination. 0093. In certain embodiments, the present invention pro orapharmaceutically acceptable salt thereof, wherein R is as vides a compound of formula X: defined above and described in embodiments, classes and X O Subclasses above and herein, singly or in combination. C 0097. In certain embodiments, the invention provides a N1 R2; compound selected from Table 1: N H TABLE 1

N F 1 F

O H NH C N CH orapharmaceutically acceptable salt thereof, wherein R is as defined above and described in embodiments, classes and N OH Subclasses above and herein, singly or in combination. 0094. In certain embodiments, the present invention pro N vides a compound of formula XI: XI O f-, C N1 R2; N H O H C N "in CH N N OH NH N F or a pharmaceutically acceptable salt thereof, wherein R is as - defined above and described in embodiments, classes and F Subclasses above and herein, singly or in combination. US 2016/01 68090 A1 Jun. 16, 2016

TABLE 1-continued TABLE 1-continued

O CI NH Hó

F O H Cl N

F O C NH F

F 12 F O H CI Cl N . NNH CH3 N OH N HOS US 2016/01 68090 A1 Jun. 16, 2016 15

TABLE 1-continued TABLE 1-continued

F 13 18 H C N F C NH

HO O N S-1)HO N

19 C Y-u-ONH

. O -CH3

O H 15 e C N

HO A.

C O NH %. N HO 16 N C HN-7 C

/e HC

21 17 HO S/ AOn CH3 C. e HC-O US 2016/01 68090 A1 Jun. 16, 2016 16

TABLE 1-continued TABLE 1-continued

22 26 O Cl CH N OH

O / H3C

O C NH \uO

O-NCH, Cl NH F 24 F F

O Cl NH

ONCH,

25 28

C NH

O-NCH,

US 2016/01 68090 A1 Jun. 16, 2016 18

TABLE 1-continued TABLE 1-continued

O 38

C NH

43 39 C

40 F O H C N

41 45 C -6,OH US 2016/01 68090 A1 Jun. 16, 2016 19

TABLE 1-continued TABLE 1-continued 46 50

Cl CH

Cl NH CH

47 51

48 O Cl 52

49 53

OH C NH US 2016/01 68090 A1 Jun. 16, 2016 20

TABLE 1-continued TABLE 1-continued

H 54 58 O HO CI H N

O 3 N

N O N

2) O H 59 CI NH

H N

Cl NH

O N N & 7. 60 O 2

O Cl NH 56 F N O C NH N

O 61

y US 2016/01 68090 A1 Jun. 16, 2016 21

TABLE 1-continued TABLE 1-continued

66 62 O CI F Nw' F

67 O F CI H N F HO 63

68 O C NH US 2016/01 68090 A1 Jun. 16, 2016 22

TABLE 1-continued TABLE 1-continued 70

C NH

71 75

72 76

77 73

C C NH US 2016/01 68090 A1 Jun. 16, 2016 23

TABLE 1-continued TABLE 1-continued

CH 78 82

C NH Q O C NH N CH N N & N O 2)

79 83 O C C NH CH3

N HO

O H O | Hó F NH F N C. F F O-N- F O

81 85

O C) O HO F C NH C NH F 2)N 2.N US 2016/016.8090 A1 Jun. 16, 2016 24

TABLE 1-continued TABLE 1-continued

86 O H 90 CI N c HO CH, 2)

F F 91

O CI NH 87 F it' Cl O c F F C. 2) F 92 2) F NH

OH 88 C. O C NH HO 2)

93 C.N 2) C. Y-QHO CH

89 2)O

O F 94 C H N CH N OH N C. 2)O 2) US 2016/016.8090 A1 Jun. 16, 2016 25

TABLE 1-continued TABLE 1-continued

95 F 99

1OO F 96 O F O H C NH C N F F N OH F

97 101 O Cl H N ()

102

98 F CH3 O H OH C N Cl NH US 2016/01 68090 A1 Jun. 16, 2016 26

TABLE 1-continued TABLE 1-continued H-m- 103 H3C CH 107

-CH3 C NH HO O OH CI NH N N

108 F 104 HO F

O C NH O Cl N

* O 105

109

O CI C

C.N o CH3 106

110 HO

O O C.l Cl NH * O US 2016/01 68090 A1 Jun. 16, 2016 27

TABLE 1-continued TABLE 1-continued HCN N-CH3 111 F 115

C C NH N OH

F 116 O F 112 CI NH

F 117 O

113 Cl uO< O Cl H N N CH N

F 118

F 114 Cl O H Cl N F N OH US 2016/01 68090 A1 Jun. 16, 2016 28

TABLE 1-continued TABLE 1-continued

F 119 124 O NH F O CI Cl NH HO N N F F

N N

\ HN CH3

120 O CI NH HO 125 F F O N CI NH HO F F () N NH

F 121 O NH Cl NH F

N O F 126 c C NH F NH N

F 122 O H N C N F

O1. NH

NHr O 127 CI O F 123 CI F N N N F N

F NH US 2016/01 68090 A1 Jun. 16, 2016 29

TABLE 1-continued TABLE 1-continued

F 128 O F 132 F C NH F

O C NH N

N N \. O

O HC O CH3 C OH

F F 129

litt. H C NNew w ( ) OH 134

F F 130 lit. ( O ) H C N OH O F 135 N C NH F

N O N N N.) F 131 F 136 O H O F C N C NH F N OH N OH N NS N cy US 2016/01 68090 A1 Jun. 16, 2016 30

TABLE 1-continued TABLE 1-continued

137 141 O R F H Cl N CH3 H N CI O y C.F F o

138 F 142 H N F O H Cl N CH3 CI R HO c

139 143

O H Cl N Cl R Y-C,OH CH o

140 144 Cl NH N F y HO CH, CI R o o US 2016/01 68090 A1 Jun. 16, 2016 31

TABLE 1-continued TABLE 1-continued F 151 F 147 O F

F 152 O H C N F

148

F 153 O

149 C 154

155 150 C US 2016/01 68090 A1 Jun. 16, 2016 32

TABLE 1-continued TABLE 1-continued R F F 160 O C NH

O C NH-O- N N N l NH

146

157

O C NH

N CH C. F F

O ( NH F 162 O H C RuOC,

F 158 O C -uC< C.N

l NH 163

159 O C NH HO

N F F

NH US 2016/01 68090 A1 Jun. 16, 2016 33

TABLE 1-continued TABLE 1-continued

F 164 170 O O uCf. N

167 171 C.O uOf N

168

172 N '. 169 F

C NH F 173 O C NH F OH N N

CH O US 2016/016.8090 A1 Jun. 16, 2016 34

TABLE 1-continued TABLE 1-continued

O 174 178 O CI NH HO F F N Ns K)

O 175

O 179 C s C. KON 176

Cl Nf HG F 18O N F F C -NH F

N N t K)N s

177 F 181 H O CI -N F C NH HO F F N N N ? Y- CH ( ) O US 2016/01 68090 A1 Jun. 16, 2016 35

TABLE 1-continued TABLE 1-continued

182 186

187 183 CI

184 188

185

189 C C NH US 2016/01 68090 A1 Jun. 16, 2016 36

TABLE 1-continued TABLE 1-continued

F 190 O 194

O -O- C NH HO C NH N CH3

N O N F

F 195 O F F 191 O H O C N F C NH

192 F 196 C O O NH HO C NH F F F

N N Hic-( CH3

O 193 C O F 197 N C NH F N H F N N F S N

US 2016/01 68090 A1 Jun. 16, 2016 38

TABLE 1-continued TABLE 1-continued 210 215

C O NH O C NH// HO X rN\, N N 2 4. N N N

211 216 O O N C NH-O- HO y A. O) 212 217 N

S-OHO %

218 213 C N-V 4N

214 c 219 NC N o4. N US 2016/01 68090 A1 Jun. 16, 2016 39

TABLE 1-continued TABLE 1-continued

CH3 220 225

C O rN\, 4. N

226 221

N-V 4. N

O 222 O F 227

HO 2 C uO< CH N

223

228 rN\, 4

He1"

F 224 229 O C NH HO F rN\, 4. N US 2016/01 68090 A1 Jun. 16, 2016 40

TABLE 1-continued amount of compound in compositions of this invention is such that is effective to measurably modulate P2X7 in a F 230 biological sample or in a patient. In certain embodiments, the O amount of compound in compositions of this invention is such that is effective to measurably modulate P2X7 in a biological sample or in a patient. In certain embodiments, a N N composition of this invention is formulated for administration to a patient in need of Such composition. 2 N N 0102 The term “patient' or “subject', as used herein, means an animal, preferably a mammal, and most preferably a human. 0103) The term “pharmaceutically acceptable carrier, adjuvant, or vehicle' refers to a non-toxic carrier, adjuvant, or O'NCH, vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically F 166 acceptable carriers, adjuvants or vehicles that are used in the F. compositions of this invention include, but are not limited to, O H ion exchangers, alumina, aluminum Stearate, lecithin, serum C N proteins, such as human serum albumin, buffer Substances Such as phosphates, glycine, Sorbic acid, potassium Sorbate, N OH partial glyceride mixtures of Saturated vegetable fatty acids, water, salts or electrolytes, such as protamine Sulfate, diso N dium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, Zinc salts, colloidal silica, magnesium tri silicate, polyvinyl pyrrolidone, cellulose-based Substances, polyethylene glycol, Sodium carboxymethylcellulose, poly acrylates, waxes, polyethylene-polyoxypropylene-block O polymers, polyethylene glycol and wool fat. 0104. A pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of 0098. In some embodiments, the present invention pro a compound of this invention that, upon administration to a vides a compound selected from those depicted above, or a recipient, is capable of providing, either directly or indirectly, pharmaceutically acceptable salt thereof. a compound of this invention oran inhibitorily active metabo 0099 Various structural depictions may show a heteroa lite or residue thereof. tom without an attached group, radical, charge, or counterion. Those of ordinary skill in the art are aware that such depic 0105 Compositions of the present invention are adminis tions are meant to indicate that the heteroatom is attached to tered orally, parenterally, by inhalation spray, topically, rec hydrogen (e.g., tally, nasally, buccally, vaginally or via an implanted reser voir. The term “parenteral as used herein includes Subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intrale sional and intracranial injection or infusion techniques. Pref erably, the compositions are administered orally, intraperito * neally or intravenously. Sterile injectable forms of the compositions of this invention include aqueous or oleaginous is understood to be Suspension. These Suspensions are formulated according to techniques known in the art using Suitable dispersing or wet ting agents and Suspending agents. The sterile injectable preparation is also be a sterile injectable solution or Suspen sion in a non-toxic parenterally acceptable diluent or solvent, w ). for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that are employed are water, Ringer's Solution and isotonic sodium chloride solution. In 0100. In certain embodiments, the compounds of the addition, Sterile, fixed oils are conventionally employed as a invention were synthesized in accordance with Schemes Solvent or Suspending medium. below. More specific examples of compounds made utilizing 0106 For this purpose, any bland fixed oil employed the Schemes are provided in the Examples below. includes synthetic mono- or di-glycerides. Fatty acids. Such as oleic acid and its glyceride derivatives are useful in the 4. Uses, Formulation and Administration preparation of injectables, as are natural pharmaceutically Pharmaceutically Acceptable Compositions acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or sus 0101. According to another embodiment, the invention pensions also contain a long-chain alcohol diluent or dispers provides a composition comprising a compound of this inven ant, Such as carboxymethyl cellulose or similar dispersing tion or a pharmaceutically acceptable derivative thereof and a agents that are commonly used in the formulation of pharma pharmaceutically acceptable carrier, adjuvant, or vehicle. The ceutically acceptable dosage forms including emulsions and US 2016/01 68090 A1 Jun. 16, 2016

Suspensions. Other commonly used Surfactants, such as 0114. The amount of compounds of the present invention Tweens, Spans and other emulsifying agents or bioavailabil that are optionally combined with the carrier materials to ity enhancers which are commonly used in the manufacture of produce a composition in a single dosage form will vary pharmaceutically acceptable solid, liquid, or other dosage depending upon the host treated, the particular mode of forms are also be used for the purposes of formulation. administration. Preferably, provided compositions should be 0107 Pharmaceutically acceptable compositions of this formulated so that a dosage of between 0.01-100 mg/kg body invention are orally administered in any orally acceptable weight/day of the compound can be administered to a patient dosage form. Exemplary oral dosage forms are capsules, receiving these compositions. tablets, aqueous Suspensions or Solutions. In the case oftab 0.115. It should also be understood that a specific dosage lets for oral use, carriers commonly used include lactose and and treatment regimen for any particular patient will depend corn Starch. Lubricating agents, such as magnesium Stearate, upon a variety of factors, including the activity of the specific are also typically added. For oral administration in a capsule compound employed, the age, body weight, general health, form, useful diluents include lactose and dried cornstarch. sex, diet, time of administration, rate of excretion, drug com When aqueous Suspensions are required for oral use, the bination, and the judgment of the treating physician and the active ingredient is combined with emulsifying and Suspend severity of the particular disease being treated. The amount of ing agents. If desired, certain Sweetening, flavoring or color a compound of the present invention in the composition will ing agents are optionally also added. also depend upon the particular compound in the composi 0108. Alternatively, pharmaceutically acceptable compo tion. sitions of this invention are administered in the form of Sup positories for rectal administration. These can be prepared by Uses of Compounds and Pharmaceutically Acceptable mixing the agent with a suitable non-irritating excipient that Compositions is solid at room temperature but liquid at rectal temperature 0116. In certain embodiments, the invention provides a and therefore will melt in the rectum to release the drug. Such method for antagonizing P2X7 in a positive manner in a materials include cocoa butter, beeswax and polyethylene patient or in a biological sample comprising the step of glycols. administering to said patient or contacting said biological 0109 Pharmaceutically acceptable compositions of this sample with a compound according to the invention. invention are also administered topically, especially when the 0117. In certain embodiments, the invention is directed to target of treatment includes areas or organs readily accessible the use of compounds of the invention and/or physiologically by topical application, including diseases of the eye, the skin, acceptable salts thereof, for antagonizing P2X7. The com or the lower intestinal tract. Suitable topical formulations are pounds are characterized by such a high affinity to P2X7. readily prepared for each of these areas or organs. which ensures a reliable binding and preferably antagoniza 0110 Topical application for the lower intestinal tract can tion of P2X7. In certain embodiments, the substances are be effected in a rectal suppository formulation (see above) or mono-specific in order to guarantee an exclusive and directed in a suitable enema formulation. Topically-transdermal recognition with the single P2X7 target. In the context of the patches are also used. present invention, the term “recognition' without being 0111 For topical applications, provided pharmaceutically limited thereto relates to any type of interaction between acceptable compositions are formulated in a suitable oint the specific compounds and the target, particularly covalent ment containing the active component Suspended or dis or non-covalent binding or association, such as a covalent Solved in one or more carriers. Exemplary carriers for topical bond, hydrophobic/hydrophilic interactions, van der Waals administration of compounds of this aremineral oil, liquid forces, ion pairs, hydrogen bonds, ligand-receptor interac petrolatum, white petrolatum, propylene glycol, polyoxyeth tions, and the like. Such association may also encompass the ylene, polyoxypropylene compound, emulsifying wax and presence of other molecules Such as peptides, proteins or water. Alternatively, provided pharmaceutically acceptable nucleotide sequences. The present receptor/ligand-interac compositions can be formulated in a suitable lotion or cream tion is characterized by high affinity, high selectivity and containing the active components Suspended or dissolved in minimal or even lacking cross-reactivity to other target mol one or more pharmaceutically acceptable carriers. Suitable ecules to exclude unhealthy and harmful impacts to the carriers include, but are not limited to, mineral oil, Sorbitan treated subject. monostearate, polysorbate 60, cetyl esters wax, cetearyl alco 0118. In certain embodiments, the present invention hol, 2-octyldodecanol, benzyl alcohol and water. relates to a method for antagonizing P2X7 with at least one 0112 Pharmaceutically acceptable compositions of this compound of formula (I) according to the invention and/or invention are optionally administered by nasal aerosol or physiologically acceptable salts thereof, under conditions inhalation. Such compositions are prepared according to such that said P2X7 receptor is antagonized. In certain techniques well-known in the art of pharmaceutical formula embodiments, the system is a cellular system. In other tion and are prepared as solutions in Saline, employing benzyl embodiments, the system is an in-vitro translation which is alcohol or other suitable preservatives, absorption promoters based on the protein synthesis without living cells. The cel to enhance bioavailability, fluorocarbons, and/or other con lular system is defined to be any subject provided that the ventional solubilizing or dispersing agents. Subject comprises cells. Hence, the cellular system can be 0113 Most preferably, pharmaceutically acceptable com selected from the group of single cells, cell cultures, tissues, positions of this invention are formulated for oral administra organs and animals. In certain embodiments, the method for tion. Such formulations may be administered with or without antagonizing P2X7 is performed in-vitro. The prior teaching food. In some embodiments, pharmaceutically acceptable of the present specification concerning the compounds of compositions of this invention are administered without food. formula (I), including any embodiments thereof, is valid and In other embodiments, pharmaceutically acceptable compo applicable without restrictions to the compounds according to sitions of this invention are administered with food. formula (I) and their salts when used in the method for US 2016/01 68090 A1 Jun. 16, 2016 42 antagonizing P2X7. The prior teaching of the present speci Such cases include, for example, prevention and therapy of fication concerning the compounds of formula (I), including Swelling, exacerbation of pain and bone metabolism in rheu any embodiments thereof, is valid and applicable without matoid arthritis, prevention and therapy of inflammatory restrictions to the compounds according to formula (I) and bowel diseases, chronic obstructive pulmonary disease their salts when used in the method for antagonizing P2X7. (COPD) and osteoarthritis, prevention and therapy of inflam 0119. In certain embodiments, the compounds according matory pain and cancer pain and IL-1-associated diseases to the invention exhibit an advantageous biological activity, Such as Crohn's disease, emphysema, acute respiratory dis which is easily demonstrated in cell culture-based assays, for tress syndrome, adult respiratory distress syndrome, asthma, example assays as described herein or in prior art (cf. e.g. WO bronchitis, chronic pulmonary inflammatory diseases, silico 2002/09706, which is incorporated herein by reference). In sis, pulmonary sarcoidosis, allergic reactions, allergic contact Such assays, the compounds according to the invention pref hypersensitivity, eczema, contact dermatitis, psoriasis, Sun erably exhibit and cause an agonistic effect. burn, cancer, tissue ulceration, restenosis, periodontal dis 0120 In certain embodiments, the invention provides a ease, epidermolysis bullosa, osteoporosis, bone resorption method for preventing, treating or ameliorating in a Subject a disease, loosening of artificial joint implants, atherosclerosis, disease, disorder, or condition that is causally related to the aortic aneurysm, congestive heart failure, myocardial infarc aberrant activity of P2X7 receptor, which comprises admin tion, stroke, cerebral ischemia, head trauma, neurotrauma, istering to the Subject a therapeutically effective amount of a spinal cord injury, neurodegenerative disorder, Alzheimer's compound of any formulae herein, or a pharmaceutically disease, Parkinson's disease, migraine, depression, periph acceptable Salt thereof. In certain embodiments, the disease eral neuropathy, pain, cerebral amyloid angiopathy, nootropic or disorder is an autoimmune, inflammatory or cardiovascu or cognition enhancement, amyotrophic lateral Sclerosis, lar disease or disorder. multiple Sclerosis, ocular angiogenesis, corneal injury, macu 0121. In certain embodiments, the disease or disorder is a lar degeneration, corneal Scarring, Scleritis, abnormal wound neurodegenerative disease or disorder, including Parkinson's healing, burns, autoimmune diseases, Huntington's disease, disease, multiple sclerosis (MS); Alzheimer's disease, dis diabetes, AIDS, cachexia, sepsis, septic shock, endotoxin eases and disorders which are mediated by or result in neu shock, conjunctivitis shock, gram-negative sepsis, toxic roinflammation Such as, for example traumatic brain injury, shock syndrome, cerebral malaria, cardiac and renal reperfu and encephalitis; centrally-mediated neuropsychiatric dis sion injury, thrombosis, glomerulonephritis, graft-Versus eases and disorders such as, for example depression mania, host reaction, homograft rejection, organ transplant toxicity, bipolar disease, anxiety, Schizophrenia, eating disorders, ulcerative colitis or muscle degeneration. sleep disorders and cognition disorders; epilepsy and seizure 0.125. In certain embodiments, the present invention disorders; prostate, bladder and bowel dysfunction Such as, encompasses a method of treating a patient Suffering from a for example urinary incontinence, urinary hesitancy, rectal mood disorder, including those Suffering from a treatment hypersensitivity, fecal incontinence, benign prostatic hyper resistant form of depression, comprising administering a trophy and inflammatory bowel disease; respiratory and air therapeutically effective amount of a modulator of P2X7 way disease and disorders such as, for example, allergic rhini receptor activity to a subject suffering from said affective tis, asthma and reactive airway disease and chronic disorder. It is understood that the mood disorder may be one obstructive pulmonary disease; diseases and disorders which among many of the disorders affecting mood and behavior. are mediated by or result in inflammation Such as, for For example, mood disorders comprise depressive disorder example rheumatoid arthritis and osteoarthritis, myocardial (that includes major depressive disorder, dysthymic disor infarction, various autoimmune diseases and disorders, uvei der), bipolar disorder (includes bipolar I disorder, bipolar II tis and atherosclerosis; itch/pruritus such as, for example disorder, cyclothymic disorder), mood disorder due to a gen psoriasis; obesity; lipid disorders; cancer, blood pressure; eral medical condition and Substance-induced mood disorder spinal cord injury; and renal disorders. (American Psychiatric Association: Diagnostic and Statisti 0122. In certain embodiments, the disease or disorder is cal Manual of Mental Disorders (DSM-IV-TR), Fourth Edi pain, including acute, inflammatory and neuropathic pain, tion, Text Revision. Washington, D.C., American Psychiatric chronic pain, dental pain and headache including migraine, Association, pages 345-428, 2000). In certain embodiments, cluster headache and tension headache. the disorder is a depressive disorder. The present invention 0123. In certain embodiments, the disease or disorder is also encompasses a method of treating a patient Suffering rheumatoid arthritis, osteoarthritis, psoriasis, allergic derma from an anxiety disorder. Anxiety disorders include: panic titis, asthma, hyperresponsiveness of the airway, chronic attack, agoraphobia, specific phobia, Social phobia, obses obstructive pulmonary disease (COPD), bronchitis, septic sive-compulsive disorder, posttraumatic stress disorder, acute shock, glomerulonephritis, irritable bowel disease, Crohn's stress disorder, and generalized anxiety disorder. disease, ulcerative colitis, atherosclerosis, growth and 0.126 In certain embodiments, the disease or disorder is metastases of malignant cells, myoblastic leukaemia, diabe pain, selected from pain associated with postmastectomy tes, neurodegenerative disease, Alzheimer's disease, multiple pain syndrome, stump pain, phantom limb pain, oral neuro Sclerosis, meningitis, osteoporosis, burn injury, ischaemic pathic pain, Charcot's pain, toothache, Venomous Snakebite, heart disease, stroke, peripheral vascular disease, Varicose spider bite, insect sting, postherpetic neuralgia, diabetic neu veins, glaucoma, bipolar disorder, and neuropathic pain con ropathy, reflex sympathetic dystrophy, trigeminal neuralgia, ditions such as diabetic neuropathy, post-herpatic neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgis, Guillain low back pain, chemotherapy-induced neuropathic pain, Barre syndrome, meralgia paresthetica, burning-mouth Syn fibromyalgia and spinal cord injury pain. drome, bilateral peripheral neuropathy, causalgia, Sciatic 0.124. In certain embodiments, the present invention is neuritis, peripheral neuritis, polyneuritis, segmental neuritis, used when the use of compounds which inhibit the P2X7 Gombault's neuritis, neuronitis, cervicobrachial neuralgia, receptor are expected to improve pathological conditions. cranial neuralgia, egniculate neuralgia, glossopharyngial US 2016/01 68090 A1 Jun. 16, 2016

neuralgia, migranous neuralgia, idiopathic neuralgia, inter 0.137 The invention further relates to combination thera costals neuralgia, mammary neuralgia, mandibular joint neu pies wherein a compound of the invention, or a pharmaceu ralgia, Morton's neuralgia, nasociliary neuralgia, occipital tically acceptable salt thereof, or a pharmaceutical composi neuralgia, red neuralgia, Sluder's neuralgia splenopalatine tion or formulation comprising a compound of the invention, neuralgia, Supraorbital neuralgia, Vidian neuralgia, sinus is administered concurrently or sequentially or as a combined headache, tension headache, labor, childbirth, intestinal gas, preparation with another therapeutic agent or agents, for the menstruation, cancer, and trauma. treatment of one or more of the conditions listed. 0127. In certain embodiments, the disease or disorder is 0.138 A compound of Formula (I) of the present invention associated with inflammation, including rheumatoid arthritis, can be administered as sole active agent or can be admin osteoarthritis, uveitis, asthma, myocardial infarction, trau Stered in combination with other agents. These agents include matic brain injury; septic shock, atherosclerosis, chronic pull non-steroidal anti-inflammatory drug (NSAIDS) such as monary obstructive disease (COPD), acute spinal cord injury, celecoxib, rofecoxib, cimicoxib, etoricoxib, lumiracoxib, inflammatory bowel disease and immune dysfunction Valdecoxib, deracoxib, N-(2-cyclohexyloxynitrophenyl) 0128. In certain embodiments, the disease or disorder is methane sulphonamide, COX189, ABT963, JTE-522, associated with pain responses or imbalances in the mainte GW-406381, LAS-34475, CS-706, PAC-10649, SVT-2016, nance of basal activity of sensory nerves. The amine com GW-644784, tenidap, acetylsalicylic acid (aspirin), amox pounds of the invention have use as analgesics for the treat iprin, benorilate, choline magnesium salicylate, diflunisal, ment of pain of various geneses or etiology, for example faislamine, methyl salicylate, magnesium salicylate, salicyl acute, inflammatory pain (Such as pain associated with salicylate (salsalatee), diclofenac, aceclofenac, acemetacin, osteoarthritis and rheumatoid arthritis); various neuropathic bromfenac, etodolac, indometacin, nabumetone, Sulindac, pain syndromes (such as post-herpetic neuralgia, trigeminal tolimetin, ibuprofen, carprofen, fenbufen, fenoprofen, flurbi neuralgia, reflex sympathetic dystrophy, diabetic neuropathy, profen, ketoprofen, ketorolac, loxoprofen, naproxen, Guillian Barre Syndrome, fibromyalgia, phantom limb pain, oxaprozin, tiaprofenic acid, Suprofen, mefenamic acid, post-masectomy pain, peripheral neuropathy, HIV neuropa meclofenamic acid, phenylbutaZone, azapropaZone, metami thy, and chemotherapy-induced and other iatrogenic neuro Zole, oxyphenbutaZone, Sulfinpyrazone, piroXicam, lornoxi pathies); visceral pain, (Such as that associated with gastroe cam, meloxicam, tenoxicam, nimeSulide, licofelone, or sophageal reflex disease, irritable bowel syndrome, paracetamol. inflammatory bowel disease, pancreatitis, and various gyne 0.139. A compound of Formula (I) of the present invention cological and urological disorders), dental pain and headache can be combined with agents such as TNFO, inhibitors such as (such as migraine, cluster headache and tension headache). anti-TNF monoclonal antibodies (such as Remicade, CDP 0129. In certain embodiments, the disease or disorder is 870 and D2E7) and TNF receptor immunoglobulin molecules arthritis, uveitis, asthma, myocardial infarction, traumatic (such as Enbrel), low dose methotrexate, lefunomide: brain injury, acute spinal cord injury, or inflammatory bowel ciclesonide; hydroxychloroquine, d-penicillamine, auranofin disease. or parenteral or oral gold. 0130. In certain embodiments, the disease or disorder is 0140. A compound of Formula (I) of the present invention MS. can also be administered in combination with an inhibitor of 0131. In certain embodiments, the disease or disorder is proTNFalpha convertase enzyme (TACE) such as 3-Amino Parkinson's disease. N-hydroxy-a-(2-methylpropyl)-3-4-(2-methyl-4-quinoli 0132. In certain embodiments, the disease or disorder is nyl)methoxyphenyl-2-oxo-1-pyrrolidineacetamide, 2(S).3 rheumatoid arthritis. (S)-Piperidinedicarboxamide, N3-hydroxy-1-methyl-N2-4- 0133. In certain embodiments, the disease or disorder is (2-methyl-4-quinolinyl)methoxyphenyl, traumatic brain injury. 3-Thiomorpholinecarboxamide, 4-4-(2-butynyloxy)phe 0134. In certain embodiments, the disease or disorder is nylsulfonyl-N-hydroxy-2,2-dimethyl, 5-Hexenoic acid, pain. 3-(hydroxyamino)carbonyl-2-(2-methylpropyl)-6-phenyl-, 0135) In other embodiments, the invention provides com 2-(2-methylpropyl)-2-(methylsulfonyl)hydrazide, (2R.3S, pounds of the invention for use as a pharmaceutical especially 5E), 2-Piperidinecarboxamide, N.5-dihydroxy-1-4-(1- in the treatment or prevention of the aforementioned condi naphthalenylmethoxy)phenylsulfonyl-, (2R,5R), tions and diseases. Also provided herein is the use of the Pentanamide, 3-(formylhydroxyamino)-4-methyl-2-(2-me present compounds in the manufacture of a medicament for thylpropyl)-N-(1S,2S)-2-methyl-1-(2-pyridinylamino)car the treatment or prevention of one of the aforementioned bonylbutyl-, (2R.3S).2-Propenamide, N-hydroxy-3-3- conditions and diseases. The present invention also provides (4-methoxyphenyl)sulfonyl(1-methylethyl)amino the use of a compound of the invention or a pharmaceutically phenyl)-3-(3-pyridinyl)-, (2E), Benzamide, N-(2,4-dioxo-1, acceptable salt thereof for the manufacture of a medicament 3,7-triazaspiro4.4 non-9-yl)-4-(2-methyl-4-quinolinyl) for the treatment of conditions or diseases selected from me-thoxy, Benzamide, N-(1-acetyl-4-piperidinyl)(2.5- P2X7 receptor mediated conditions or diseases. dioxo-4-imidazolidinyl)methyl-4-(2-methyl-4-quinolinyl) 0136. When used to prevent the onset of a P2X7 related methoxy, or 2.4-Imidazolidinedione, 5-methyl-5-4-(2- disease/disorder, the compounds of this invention will be methyl-4-quinolinyl)methoxyphenylsulfonylmethyl. administered to a patient at risk for developing the condition, 0.141. A compound of Formula (I) of the present invention typically on the advice and under the Supervision of a physi can also be administered in combination with a corticosteroid cian, at the dosage levels described above. Patients at risk for Such as budesonide, corticosterone, cortisol, cortisone developing a particular condition generally include those that acetate, prednisone, prednisolone, methylprednisolone, dex have a family history of the condition, or those who have been amethasone, betamethasone, triamcinolone, beclometaSone, identified by genetic testing or screening to be particularly fludrocortisone acetate, deoxycorticosterone acetate (doca), Susceptible to developing the condition. or aldosterone. US 2016/01 68090 A1 Jun. 16, 2016 44

0142. A compound of Formula (I) of the present invention 0150. A compound of Formula (I) of the present invention can further be administered in combination with a b2-adren can be administered in combination with anticholinergic ergic receptor agonist Such as formoterol, salbutamol (al agents including ipratropium bromide, tiotropium bromide; buterol), levalbuterol, terbutaline, pirbuterol, procaterol, oxitropium bromide; pirenzepine; and telenzepine. The metaproterenol, fenoterol, bitolterol mesylate, salmeterol, present invention still further relates to the combination of a bambuterol, or clenbuterol. compound of the invention together with a b1- to b4-adreno 0143 A compound of Formula (I) of the present invention ceptoragonists including metaproterenol, isoproterenol, iso can further be administered in combination with an antide prenaline, albuterol, salbutamol, formoterol, salmeterol, terb pressant drug Such as Sertraline, escitalopram, fluoxetine, utaline, orciprenaline, bitolterol mesylate, and pirbuterol; or bupropion, paroxetine, Venlafaxine, traZodone, amitriptyline, methylxanthanines including theophylline and aminophyl citalopram, dulloxetine, mirtazapine, nortriptyline, imi line; sodium cromoglycate; or muscarinic receptor (M1, M2, pramine, or lithium. and M3) antagonist. 0144. A compound of Formula (I) of the present invention 0151. A compound of Formula (I) of the present invention can further be administered in combination with an antipsy can be administered in combination with an insulin-like chotic drug Such as chlorpromazine, fluphenazine, perphena growth factor type I (IGF-1) mimetic. Zine, prochlorperazine, thioridazine, trifluoperazine, 0152. A compound of Formula (I) of the present invention mesoridazine, promazine, triflupromazine, levomepro can be administered in combination with an inhaled gluco mazine, promethazine, chlorprothixene, flupenthixol, thio corticoid with reduced systemic side effects, including, pred thixene, Zuclopenthixol, haloperidol, droperidol, pimozide, nisone, prednisolone, flunisolide, triamcinolone acetonide, melperone, benperidol, triperidol, clozapine, olanzapine, ris beclomethasone dipropionate, budesonide, fluticasone propi peridone, quetiapine, Ziprasidone, amisulpride, paliperidone, onate, and mometasone furoate. bifeprunoX, or aripiprazole. 0153. A compound of Formula (I) of the present invention 0145 A compound of Formula (I) of the present invention can be administered in combination with (a) tryptase inhibi can also be administered in combination with a leukotriene tors; (b) platelet activating factor (PAF) antagonists; (c) inter biosynthesis inhibitor. 5-lipoxygenase (5-LO) inhibitor or leukin converting enzyme (ICE) inhibitors; (d) IMPDH 5-lipoxygenase activating protein (FLAP) antagonist, for inhibitors; (e)adhesion molecule inhibitors including VLA-4 example, zileuton; ABT-761; fenleuton; tepoxalin; nicar antagonists; (f) cathepsins; (g) MAP kinase inhibitors: (h) aven: VIA-2291; etalocib. ketoprofen, Abt-79175: Abt glucose-6 phosphate dehydrogenase inhibitors: (i) kinin-B1 85761; N-(5-substituted) thiophene-2-alkylsulfonamides: and B2-receptor antagonists; ) anti-gout agents, e.g., colchi TDT-070; licofelone; PEP-03; tenoxicam: 2,6-di-tert-bu cine; (k) Xanthine oxidase inhibitors, e.g., allopurinol; (1) tylphenol hydrazones; methoxytetrahydropyrians such as uricoSuric agents, e.g., probenecid, Sulfinpyrazone, and ben Zeneca ZD-2138; the compound SB-210661; pyridinyl-sub Zbromarone; (m) growth hormone secretagogues; (n) trans stituted 2-cyanonaphthalene compounds such as L-739-010; forming growth factor (TGFBf3; (o) platelet-derived growth factor (PDGF); (p) fibroblast growth factor, e.g., basic fibro 2-cyanoquinoline compounds such as L-746-530; indole and blast growth factor (bFGF); (q) granulocyte macrophage quinoline compounds such as MK-591, MK-886, and BAYx colony stimulating factor (GM-CSF); (r) capsaicin cream: (s) 1005. Tachykinin NK1 and NK3 receptor antagonists such as NKP 0146 A compound of Formula (I) of the present invention 608C; SB-233412 (talnetant); and D-4418; and (t) elastase can be administered in combination with a receptor antago inhibitors Such as UT-77 and ZD-0892. nists for leukotrienes LTB4, LTC4, LTD4, and LTE, for 0154) A compound of Formula (I) of the present invention example, phenothiazin-3-ones such as L-651.392; amidino can be administered in combination with an inhibitor of compounds such as CGS-25019c.; benzoxalamines such as matrix metalloproteases (MMPs), i.e., the stromelysins, the ontezolast; benzenecarboximidamides such as BIIL 284/260: collagenases, and the gelatinases, as well as aggrecanase; and compounds such as Zafirlukast, ablukast, montelukast, especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), praniukast, verlukast (MK-679), RG-12525, Ro-245913, collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromel iralukast (CGP45715A), BAY X 7195, and masilukast. ysin-2 (MMP-10), and stromelysin-3 (MMP-11). 0147 A compound of Formula (I) of the present invention 0.155. A compound of Formula (I) of the present invention can also be administered in combination with a PDE4 inhibi can be administered in combination with anticancer agents tor including inhibitors of the isoform PDE4D. Such as endostatin and angiostatin or cytotoxic drugs such as 0148. A compound of Formula (I) of the present invention adriamycin, daunomycin, cis-platinum, etoposide, taxol. can also be administered in combination withaantihistaminic taxotere and farnesyltransferase inhibitors, VEGF inhibitors, H1 receptor antagonists including cetirizine, loratadine, COX-2 inhibitors and antimetabolites such as methotrexate desloratadine, fexofenadine, astemizole, azelastine, and chlo antineoplastic agents, especially antimitotic drugs including rpheniramine. A compound of Formula (I) of the present the Vinca alkaloids Such as vinblastine and Vincristine. invention can further be administered in combination with a 0156. A compound of Formula (I) of the present invention gastroprotective H2 receptor antagonist. can be administered in combination with antiviral agents such 0149. A compound of Formula (I) of the present invention as Viracept, AZT, aciclovir and famciclovir, and antisepsis can yet further be administered in combination with an al compounds Such as Valant. and a2-adrenoceptor agonist vasoconstrictor sympathomi 0157. A compound of Formula (I) of the present invention metic agent, including propylhexedrine, phenylephrine, phe can be administered in combination with cardiovascular nylpropanolamine, pseudoephedrine, naphazoline hydro agents such as calcium channel blockers, lipid lowering chloride, oxymetazoline hydrochloride, tetrahydrozoline agents such as stating, fibrates, beta-blockers, ACE inhibitors, hydrochloride, Xylometazoline hydrochloride, and ethyl Angiotensin-2 receptor antagonists and platelet aggregation norepinephrine hydrochloride. inhibitors. US 2016/01 68090 A1 Jun. 16, 2016

0158. A compound of Formula (I) of the present invention protease (MMPs), i.e., the Stromelysins, the collagenases, and can be administered in combination with CNS agents such as the gelatinases, as well as aggrecanase; especially collage antidepressants (such as Sertraline), anti-Parkinsonian drugs nase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (such as deprenyl, L-dopa, Requip, Mirapex. MAOB inhibi (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP tors such as selegine and rasagiline, comP inhibitors such as 10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, including agents such as doxycycline. NMDA antagonists, Nicotine agonists, Dopamine agonists 0166 The present invention still further relates to the com and inhibitors of neuronal nitric oxide synthase), and anti bination of a compound of the invention, or a pharmaceuti Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibi cally acceptable salt thereof, and a leukotriene biosynthesis tors, propentofylline or metrifonate. inhibitor. 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase 0159. A compound of Formula (I) of the present invention activating protein (FLAP) antagonist Such as: Zileuton; ABT can be administered in combination with osteoporosis agents 761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a Such as roloxifene, droloxifene, lasofoxifene or fosomax and N-(5-substituted)-thiophene-2-alkylsulfonamide: 2,6-di immunosuppressant agents such as FK-506, rapamycin, tert-butylphenolhydrazones; a methoxytetrahydropyrians cyclosporine, azathioprine, and methotrexate. such as Zeneca ZD-2138; the compound SB-210661; a 0160. In certain embodiments, the compounds of the pyridinyl-Substituted 2-cyanonaphthalene compound such as invention may be combined with agents listed below. L-739,010; a 2-cyanoquinoline compound such as L-746, 0161 Non-steroidal anti-inflammatory agents (hereinaf 530; or an indole or quinoline compound such as MK-591, ter NSAIDs) including non-selective cyclo-oxygenase COX MK-886, and BAY x 1005. 1/COX-2 inhibitors whether applied topically or systemically 0167. The present invention further relates to the combi (such as piroxicam, diclofenac, propionic acids such as nation of a compound of the invention, or a pharmaceutically naproxen, flurbiprofen, fenoprofen, ketoprofen and ibupro acceptable salt thereof, and a receptor antagonist for leukot fen, fenamates such as mefenamic acid, indomethacin, Sulin rienes (LT) B4, LTC4, LTD4, and LTE4. Selected from the dac, azapropaZone, pyrazolones Such as phenylbutaZone, group consisting of the phenothiazin-3-1S Such as L-651,392; salicylates such as aspirin); selective COX-2 inhibitors (such amidino compounds such as CGS-25019c.; benzoxalamines as meloxicam, celecoxib, rofecoxib, Valdecoxib, lumaro Such as ontazolast; benzenecarboximidamides such as BIIL coxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting 284/260; and compounds such as Zafirlukast, ablukast, mon nitric oxide donors (CINODs); glucocorticosteroids (whether telukast, pranlukast, Verlukast (MK-679), RG-12525, administered by topical, oral, intramuscular, intravenous, or Ro-245913, iralukast (CGP 45715A), and BAY x 7195. intra-articular routes); methotrexate; leflunomide; hydroxy 0.168. The present invention still further relates to the com chloroquine; d-penicillamine; auranofinor other parenteral or bination of a compound of the invention, or a pharmaceuti oral gold preparations; analgesics; diacerein; intra-articular cally acceptable salt thereof, and a phosphodiesterase (PDE) therapies such as hyaluronic acid derivatives; and nutritional inhibitor Such as a methylxanthanine including theophylline Supplements such as glucosamine. and aminophylline; a selective PDE isoenzyme inhibitor 0162 The present invention still further relates to the com including a PDE4 inhibitor an inhibitor of the isoform bination of a compound of the invention, or a pharmaceuti PDE4D, or an inhibitor of PDE5. cally acceptable salt thereof, together with a cytokine or ago 0169. The present invention further relates to the combi nist or antagonist of cytokine function, (including agents nation of a compound of the invention, or a pharmaceutically which act on cytokine signalling pathways Such as modula acceptable salt thereof, and a histamine type 1 receptor tors of the SOCS system) including alpha-, beta-, and antagonist Such as cetirizine, loratadine, desloratadine, fex gamma-interferons; insulin-like growth factor type I (IGF-1); ofenadine, acrivastine, terfenadine, astemizole, azelastine, interleukins (IL) including IL1 to 17, and interleukin antago levocabastine, chlorpheniramine, promethazine, cyclizine, or nists or inhibitors such as anakinra; tumour necrosis factor mizolastine; applied orally, topically or parenterally. alpha (TNF-C.) inhibitors such as anti-TNF monoclonal anti 0170 The present invention still further relates to the com bodies (for example infliximab; adalimumab, and CDP-870) bination of a compound of the invention, or a pharmaceuti and TNF receptor antagonists including immunoglobulin cally acceptable salt thereof, and a proton pump inhibitor molecules (such as etanercept) and low-molecular-weight (such as omeprazole) or a gastroprotective histamine type 2 agents such as pentoxyfylline. receptor antagonist. 0163. In addition the invention relates to a combination of 0171 The present invention further relates to the combi a compound of the invention, or a pharmaceutically accept nation of a compound of the invention, or a pharmaceutically able salt thereof, with a monoclonal antibody targeting acceptable salt thereof, and an antagonist of the histamine B-Lymphocytes (such as CD20 (rituximab), MRA-aIL16R type 4 receptor. and T-Lymphocytes, CTLA4-Ig, HuMax 11-15). 0172. The present invention still further relates to the com 0164. The present invention still further relates to the com bination of a compound of the invention, or a pharmaceuti bination of a compound of the invention, or a pharmaceuti cally acceptable salt thereof, and an alpha-1/alpha-2 adreno cally acceptable salt thereof, with a modulator of chemokine ceptoragonist vasoconstrictor sympathomimetic agent. Such receptor function such as an antagonist of CCR1. CCR3. as propylhexedrine, phenylephrine, phenylpropanolamine, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and ephedrine, pseudoephedrine, naphazoline hydrochloride, CCR11 (for the C C family); CXCR1, CXCR2, CXCR3, oxymetazoline hydrochloride, tetrahydrozoline hydrochlo CXCR4 and CXCR5 (for the C X-C family) and CX3CR1 ride, Xylometazoline hydrochloride, tramazoline hydrochlo for the C X3-C family. ride or ethylnorepinephrine hydrochloride. 0.165. The present invention further relates to the combi 0173 The present invention further relates to the combi nation of a compound of the invention, or a pharmaceutically nation of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metallo acceptable salt thereof, and an anticholinergic agents includ US 2016/01 68090 A1 Jun. 16, 2016 46 ing muscarinic receptor (M1, M2, and M3) antagonist Such as as didanosine, lamivudine, stavudine, Zalcitabine or Zidovu atropine, hyoscine, glycopyrrrolate, ipratropium bromide, dine; or a non-nucleoside reverse transcriptase inhibitor Such tiotropium bromide, oxitropium bromide, pirenzepine or as nevirapine or efavirenz. telenzepine. 0.184 The present invention still further relates to the com 0.174. The present invention still further relates to the com bination of a compound of the invention, or a pharmaceuti bination of a compound of the invention, or a pharmaceuti cally acceptable salt thereof, and a cardiovascular agent Such cally acceptable salt thereof, and a beta-adrenoceptoragonist as a calcium channel blocker, a beta-adrenoceptor blocker, an (including beta receptor Subtypes 1-4) such as isoprenaline, angiotensin-converting enzyme (ACE) inhibitor, an angio salbutamol, formoterol, Salmeterol, terbutaline, orciprena tensin-2 receptor antagonist; a lipid lowering agent Such as a line, bitolterol mesylate, or pirbuterol, or a chiral enantiomer statin or a fibrate; a modulator of blood cell morphology such thereof. as pentoxyfylline; thrombolytic, oran anticoagulant such as a 0.175. The present invention further relates to the combi platelet aggregation inhibitor. nation of a compound of the invention, or a pharmaceutically 0185. The present invention further relates to the combi acceptable salt thereof, and a chromone, such as sodium nation of a compound of the invention, or a pharmaceutically cromoglycate or nedocromil sodium. acceptable Salt thereof, and a CNS agent such as an antide 0176 The present invention still further relates to the com pressant (Such as Sertraline), an anti-Parkinsonian drug (Such bination of a compound of the invention, or a pharmaceuti as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB cally acceptable salt thereof, with a glucocorticoid, such as inhibitor Such as selegine and rasagiline, a comP inhibitor flunisolide, triamcinolone acetonide, beclomethasone dipro Such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibi pionate, budesonide, fluticasone propionate, ciclesonide or tor, an NMDA antagonist, a nicotine agonist, a dopamine mometasone furoate. agonist or an inhibitor of neuronal nitric oxide synthase), or 0177. The present invention further relates to the combi an anti-Alzheimer's drug such as donepezil, rivastigmine, nation of a compound of the invention, or a pharmaceutically tacrine, a COX-2 inhibitor, propentofylline or metrifonate. acceptable salt thereof, with an agent that modulates a nuclear 0186 The present invention still further relates to the com hormone receptor such as PPARs, for example rosiglitazone. bination of a compound of the invention, or a pharmaceuti 0.178 The present invention further relates to the combi cally acceptable salt thereof, and an agent for the treatment of nation of a compound of the invention, or a pharmaceutically acute or chronic pain, such as a centrally or peripherally acceptable salt thereof with gabapentin, lidoderm, pregablin acting analgesic (for example an opioid orderivative thereof), and equivalents and pharmaceutically active isomer(s) and carbamazepine, gabapentin, pregabalin, phenyloin, Sodium metabolite(s) thereof. valproate, amitryptiline or other anti-depressant agent-s, 0179 The present invention further relates to the combi paracetamol, CB 1 agonist, muscarinic agonist, TRPV-1 nation of a compound of the invention, or a pharmaceutically antagonist, mGluR5 agonist or a non-steroidal anti-inflam acceptable salt thereof with celecoxib, etoricoxib, lumira matory agent. coxib, rofecoxib, Valdecoxib, diclofenac, loxoprofen, 0187. The present invention further relates to the combi naproxen, paracetamol and equivalents and pharmaceutically nation of a compound of the invention, or a pharmaceutically active isomer(s) and metabolite(s) thereof. acceptable Salt thereof, together with a parenterally or topi 0180. The present invention still further relates to the com cally-applied (including inhaled) local anaesthetic agent Such bination of a compound of the invention, or a pharmaceuti as lignocaine or a derivative thereof. cally acceptable salt thereof, together with an immunoglobu 0188 A compound of the present invention, or a pharma lin (Ig) or Ig preparation or an antagonist or antibody ceutically acceptable salt thereof, can also be used in combi modulating Ig function Such as anti-IgE (for example omali nation with an anti-osteoporosis agent including a hormonal Zumab). agent such as raloxifene, or a biphosphonate such as alendr 0181. The present invention further relates to the combi Onate. nation of a compound of the invention, or a pharmaceutically 0189 The present invention still further relates to the com acceptable salt thereof, and another systemic or topically bination of a compound of the invention, or a pharmaceuti applied anti-inflammatory agent, such as thalidomide or a cally acceptable salt thereof, together with a: (i) tryptase derivative thereof, a retinoid, dithranol or calcipotriol. inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) 0182. The present invention still further relates to the com interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH bination of a compound of the invention, or a pharmaceuti inhibitor, (v) adhesion molecule inhibitors including VLA-4 cally acceptable salt thereof, and combinations of aminosali antagonist; (vi) cathepsin; (vii) kinase inhibitor Such as an cylates and Sulfapyridine such as SulfaSalazine, mesalazine, inhibitor of tyrosine kinase (such as Btk. Itk, Jak3 or MAP, for balsalazide, and olsalazine; and immunomodulatory agents example Gefitinib or Imatinib mesylate), a serine/threonine Such as the thiopurines, and corticosteroids such as budes kinase (such as an inhibitor of a MAP kinase such as p38, onide. JNK, protein kinase A, B or C, or IKK), or a kinase involved 0183 The present invention further relates to the combi in cell cycle regulation (such as a cylindependent kinase); nation of a compound of the invention, or a pharmaceutically (viii) glucose-6 phosphate dehydrogenase inhibitor, (ix) acceptable Salt thereof, together with an antibacterial agent kinin-B1- or B2-receptor antagonist; (X) anti-gout agent, for Such as a penicillin derivative, a tetracycline, a macrollide, a example colchicine; (xi) Xanthine oxidase inhibitor, for beta-lactam, a fluoroquinolone, metronidazole, an inhaled example allopurinol; (xii) uricoSuric agent, for example aminoglycoside; an antiviral agent including acyclovir, fam probenecid, Sulfinpyrazone or benzbromarone; (xiii) growth ciclovir, Valaciclovir, ganciclovir, cidofovir, amantadine, hormone secretagogue; (xiv) transforming growth factor rimantadine, ribavirin, Zanamavir and oseltamavir, a protease (TGFB); (xv) platelet-derived growth factor (PDGF); (xvii) inhibitor Such as indinavir, nelfinavir, ritonavir, and fibroblast growth factor for example basic fibroblast growth saquinavir, a nucleoside reverse transcriptase inhibitor Such factor (bFGF), (Xvii) granulocyte macrophage colony stimu US 2016/01 68090 A1 Jun. 16, 2016 47 lating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachy sense; (viii) an agent used in a gene therapy approach, for kinin NK1 or NK3 receptor antagonist such as NKP-608C, example approaches to replace aberrant genes such as aber SB-233412 (talnetant) or D-4418; (XX) elastase inhibitor such rant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme directed enzyme pro-drug therapy) approaches Such as those inhibitor (TACE); (xxii) induced nitric oxide synthase using cytosine deaminase, thymidine kinase or a bacterial (iNOS) inhibitor; (xxiii) chemoattractant receptor-homolo nitroreductase enzyme and approaches to increase patient gous molecule expressed on TH2 cells, (such as a CRTH2 tolerance to chemotherapy or radiotherapy Such as multi-drug antagonist); (XXiv) inhibitor of P38; (XXV) agent modulating resistance gene therapy; or (ix) an agent used in an immuno the function of Toll-like receptors (TLR), or (xxvi) inhibitor therapeutic approach, for example ex-Vivo and in-vivo of transcription factor activation such as NFkB, API, or approaches to increase the immunogenicity of patient tumour STATS. cells, such as transfection with cytokines such as interleukin 0190. A compound of the invention, or a pharmaceutically 2, interleukin 4 or granulocyte-macrophage colony Stimulat acceptable salt thereof, can also be used in combination with ing factor, approaches to decrease T-cell anergy, approaches an existing therapeutic agent for the treatment of cancer, for using transfected immune cells such as cytokine-transfected example Suitable agents include: dendritic cells, approaches using cytokine-transfected (i) an antiproliferative/antineoplastic drug or a combination tumour cell lines and approaches using anti-idiotypic anti thereof, as used in medical oncology, such as an alkylating bodies. agent (for example cis-platin, carboplatin, cyclophospha mide, nitrogen mustard, melphalan, chlorambucil, buSulphan 0191 The method of the invention can be performed either or a nitrosourea); an antimetabolite (for example an antifolate in-vitro or in-vivo. The susceptibility of a particular cell to such as a fluoropyrimidine like 5-fluorouracilortegafur, ralti treatment with the compounds according to the invention can trexed, methotrexate, cytosine arabinoside, hydroxyurea, be particularly determined by in-vitro tests, whether in the gemcitabine or paclitaxel); an antitumour antibiotic (for course of research or clinical application. Typically, a culture example an anthracycline Such as adriamycin, bleomycin, of the cell is combined with a compound according to the doxorubicin, daunomycin, epirubicin, idarubicin, mitomy invention at various concentrations for a period of time which cin-C, dactinomycin or mithramycin); an antimitotic agent is sufficient to allow the active agents to antagonize P2X7 (for example a vinca alkaloid such as Vincristine, vinblastine, activity, usually between about one hour and one week. In vindesine or vinorelbine, or a taxoid Such as taxol or taxo vitro treatment can be carried out using cultivated cells from tere); or a topoisomerase inhibitor (for example an epipodo a biopsy sample or cell line. phyllotoxin Such as etoposide, teniposide, amsacrine, topote 0.192 The host or subject can belong to any mammalian can or a camptothecin); (ii) a cytostatic agent Such as an species, for example a primate species, particularly humans; antioestrogen (for example tamoxifen, toremifene, ralox rodents, including mice, rats and hamsters; rabbits; horses, ifene, droloxifene or iodoxyfene), an oestrogen receptor cows, dogs, cats, etc. Animal models are of interest for experi down regulator (for example fulvestrant), an antiandrogen mental investigations, providing a model for treatment of (for example bicalutamide, flutamide, nilutamide or cyprot human disease. erone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen 0193 For identification of a signal transduction pathway (for example megestrol acetate), an aromatase inhibitor (for and for detection of interactions between various signal trans example as anastrozole, letrozole, Vorazole or exemestane) or duction pathways, Suitable models or model systems have an inhibitor of 5C.-reductase Such as finasteride; (iii) an agent been developed, for example cell culture models and models which inhibits cancer cell invasion (for example a metallo of transgenic animals. For the determination of certain stages proteinase inhibitor like marimastat or an inhibitor of uroki in the signal transduction cascade, interacting compounds nase plasminogen activator receptor function); (iv) an inhibi can be utilized in order to modulate the signal. The com tor of growth factor function, for example: a growth factor pounds according to the invention can also be used as reagents antibody (for example the anti-erbb2 antibody trastuzumab, for testing P2X7-dependent signal transduction pathways in or the anti-erbb1 antibody cetuximab C225), a farnesyl animals and/or cell culture models or in the clinical diseases transferase inhibitor, a tyrosine kinase inhibitor or a serine/ mentioned in this application. threonine kinase inhibitor, an inhibitor of the epidermal 0194 The use according to the previous paragraphs of the growth factor family (for example an EGFR family tyrosine specification may be either performed in-vitro or in-vivo kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7- models. The modulation can be monitored by the techniques methoxy-6-(3-morpholinopropoxy)guinazolin-4-amine (ge described in the course of the present specification. In certain fitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxy embodiments, the in-vitro use is preferably applied to ethoxy)guinazolin-4-amine (erlotinib, OSI-774) or samples of humans suffering from P2X7-related disorders. 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholi Testing of several specific compounds and/or derivatives nopropoxy)guinazolin-4-amine (CI-1033)), an inhibitor of thereof makes the selection of that active ingredient possible the platelet-derived growth factor family, oran inhibitor of the that is best suited for the treatment of the human subject. The hepatocyte growth factor family; (V) an antiangiogenic agent in-vivo dose rate of the chosen derivative is advantageously such as one which inhibits the effects of vascular endothelial pre-adjusted to the P2X7 Susceptibility and/or severity of growth factor (for example the anti-vascular endothelial cell disease of the respective subject with regard to the in-vitro growth factor antibody bevacizumab, linomide, an inhibitor data. Therefore, the therapeutic efficacy is remarkably of integrin CVB3 function or an angiostatin); (vi) a vascular enhanced. Moreover, the Subsequent teaching of the present damaging agent such as combretastatin A4. (vii) an agent specification concerning the use of the compounds according used in antisense therapy, for example one directed to one of to formula (I) and its derivatives for the production of a the targets listed above, such as ISIS 2503, an anti-ras anti medicament for the prophylactic or therapeutic treatment US 2016/01 68090 A1 Jun. 16, 2016 48 and/or monitoring is considered as valid and applicable with modification of their overall condition or of the condition of out restrictions to the use of the compound for the antagonism particular regions of the organism could establish at least of P2X7 activity if expedient. temporarily. 0.195 The invention also relates to the use of compounds 0201 In another aspect, the invention provides for a kit according to formula (I) and/or physiologically acceptable consisting of separate packs of an effective amount of a com salts thereof for the prophylactic or therapeutic treatment pound according to the invention and/or pharmaceutically and/or monitoring of diseases that are caused, mediated and/ acceptable salts, derivatives, Solvates and stereoisomers or propagated by P2X7 activity. Furthermore, the invention thereof, including mixtures thereof in all ratios, and option relates to the use of compounds according to formula (I) ally, an effective amount of a further active ingredient. The kit and/or physiologically acceptable salts thereof for the pro comprises Suitable containers, such as boxes, individual duction of a medicament for the prophylactic or therapeutic bottles, bags orampoules. The kit may, for example, comprise treatment and/or monitoring of diseases that are caused, separate ampoules, each containing an effective amount of a mediated and/or propagated by P2X7 activity. In certain compound according to the invention and/or pharmaceuti embodiments, the invention provides the use of a compound cally acceptable salts, derivatives, Solvates and stereoisomers according to formula I or physiologically acceptable salts thereof, including mixtures thereof in all ratios, and an effec thereof, for the production of a medicament for the prophy tive amount of a further active ingredient in dissolved or lactic or therapeutic treatment of a P2X7-mediated disorder. lyophilized form. 0196) Compounds of formula (I) and/or a physiologically 0202 As used herein, the terms “treatment,” “treat, and acceptable salt thereof can furthermore be employed as inter “treating refer to reversing, alleviating, delaying the onset mediate for the preparation of further medicament active of or inhibiting the progress of a disease or disorder, or one or ingredients. The medicament is preferably prepared in a non more symptoms thereof, as described herein. In some chemical manner, e.g. by combining the active ingredient embodiments, treatment is administered after one or more with at least one solid, fluid and/or semi-fluid carrier or symptoms have developed. In other embodiments, treatment excipient, and optionally in conjunction with a single or more is administered in the absence of symptoms. For example, other active Substances in an appropriate dosage form. treatment is administered to a susceptible individual prior to 0197) The compounds of formula (I) according to the the onset of symptoms (e.g., in light of a history of symptoms invention can be administered before or following an onset of and/or in light of genetic or other Susceptibility factors). disease once or several times acting as therapy. The afore Treatment is also continued after symptoms have resolved, mentioned compounds and medical products of the inventive for example to prevent or delay their recurrence. use are particularly used for the therapeutic treatment. A 0203 The compounds and compositions, according to the therapeutically relevant effect relieves to some extent one or method of the present invention, are administered using any more symptoms of a disorder, or returns to normality, either amount and any route of administration effective for treating partially or completely, one or more physiological or bio or lessening the severity of a disorder provided above. The chemical parameters associated with or causative of a disease exact amount required will vary from Subject to Subject, or pathological condition. Monitoring is considered as a kind depending on the species, age, and general condition of the of treatment provided that the compounds are administered in Subject, the severity of the infection, the particular agent, its distinct intervals, e.g. in order to booster the response and mode of administration, and the like. Compounds of the eradicate the pathogens and/or symptoms of the disease com invention are preferably formulated in dosage unit form for pletely. Either the identical compound or different com ease of administration and uniformity of dosage. The expres pounds can be applied. The methods of the invention can also sion “dosage unit form as used herein refers to a physically be used to reducing the likelihood of developing a disorder or discrete unit of agent appropriate for the patient to be treated. even prevent the initiation of disorders associated with P2X7 It will be understood, however, that the total daily usage of the activity in advance or to treat the arising and continuing compounds and compositions of the present invention will be symptoms. decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any 0198 In the meaning of the invention, prophylactic treat particular patient or organism will depend upon a variety of ment is advisable if the Subject possesses any preconditions factors including the disorder being treated and the severity of for the aforementioned physiological or pathological condi the disorder; the activity of the specific compound employed: tions, such as a familial disposition, a genetic defect, or a the specific composition employed; the age, body weight, previously passed disease. general health, sex and diet of the patient; the time of admin 0199 The invention furthermore relates to a medicament istration, route of administration, and rate of excretion of the comprising at least one compound according to the invention specific compound employed; the duration of the treatment; and/or pharmaceutically usable derivatives, salts, Solvates drugs used in combination or coincidental with the specific and stereoisomers thereof, including mixtures thereof in all compound employed, and like factors well known in the ratios. In certain embodiments, the invention relates to a medical arts. medicament comprising at least one compound according to 0204 Pharmaceutically acceptable compositions of this the invention and/or physiologically acceptable salts thereof. invention can be administered to humans and other animals 0200. A “medicament in the meaning of the invention is orally, rectally, parenterally, intracisternally, intravaginally, any agent in the field of medicine, which comprises one or intraperitoneally, topically (as by powders, ointments, or more compounds of formula (I) or preparations thereof (e.g. drops), bucally, as an oral or nasal spray, or the like, depend a pharmaceutical composition or pharmaceutical formula ing on the severity of the infection being treated. In certain tion) and can be used in prophylaxis, therapy, follow-up or embodiments, the compounds of the invention are adminis aftercare of patients who suffer from diseases, which are tered orally or parenterally at dosage levels of about 0.01 associated with P2X7 activity, in Such away that a pathogenic mg/kg to about 100 mg/kg and preferably from about 1 mg/kg US 2016/01 68090 A1 Jun. 16, 2016 49 to about 50 mg/kg, of Subject body weight per day, one or 0210 Solid dosage forms for oral administration include more times a day, to obtain the desired therapeutic effect. capsules, tablets, pills, powders, and granules. In such solid 0205 Liquid dosage forms for oral administration dosage forms, the active compound is mixed with at least one include, but are not limited to, pharmaceutically acceptable inert, pharmaceutically acceptable excipient or carrier Such as emulsions, microemulsions, Solutions, Suspensions, syrups Sodium citrate or dicalcium phosphate and/or a) fillers or and elixirs. In addition to the active compounds, the liquid extenders such as starches, lactose, Sucrose, glucose, manni dosage forms optionally contain inert diluents commonly tol, and silicic acid, b) binders such as, for example, car used in the art such as, for example, water or other solvents, boxymethylcellulose, alginates, gelatin, polyvinylpyrrolidi solubilizing agents and emulsifiers such as ethyl alcohol, none. Sucrose, and acacia, c) humectants such as glycerol. d) isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alco disintegrating agents such as agar-agar, calcium carbonate, hol, benzyl benzoate, propylene glycol. 1,3-butylene glycol, potato or tapioca starch, alginic acid, certain silicates, and dimethylformamide, oils (in particular, cottonseed, ground Sodium carbonate, e) solution retarding agents such as paraf nut, corn, germ, olive, castor, and sesame oils), glycerol, fin, f) absorption accelerators such as quaternary ammonium tetrahydrofurfuryl alcohol, polyethylene glycols and fatty compounds, g) wetting agents such as, for example, cetyl acid esters of sorbitan, and mixtures thereof. Besides inert alcohol and glycerol monostearate, h) absorbents such as diluents, the oral compositions can also include adjuvants kaolin and bentonite clay, and i) lubricants such as talc, cal Such as Wetting agents, emulsifying and Suspending agents, cium Stearate, magnesium Stearate, Solid polyethylene gly Sweetening, flavoring, and perfuming agents. cols, Sodium lauryl Sulfate, and mixtures thereof. In the case 0206. Injectable preparations, for example, sterile inject of capsules, tablets and pills, the dosage form also optionally able aqueous or oleaginous Suspensions are formulated comprises buffering agents. according to the known art using Suitable dispersing or wet 0211 Solid compositions of a similar type are also ting agents and Suspending agents. The sterile injectable employed as fillers in Soft and hard-filled gelatin capsules preparation are also a sterile injectable solution, Suspension using such excipients as lactose or milk Sugar as well as high or emulsion in a nontoxic parenterally acceptable diluent or molecular weight polyethylene glycols and the like. The solid Solvent, for example, as a solution in 1,3-butanediol. Among dosage forms of tablets, dragees, capsules, pills, and granules the acceptable vehicles and solvents that may be employed can be prepared with coatings and shells Such as enteric are water, Ringer's solution, U.S.P. and isotonic sodium chlo coatings and other coatings well known in the pharmaceutical ride solution. In addition, sterile, fixed oils are conventionally formulating art. They optionally contain opacifying agents employed as a solvent or suspending medium. For this pur and can also be of a composition that they release the active pose any bland fixed oil can be employed including synthetic ingredient(s) only, or preferentially, in a certain part of the mono- or diglycerides. In addition, fatty acids such as oleic intestinal tract, optionally, in a delayed manner. Examples of acid are used in the preparation of injectables. embedding compositions that can be used include polymeric 0207. Injectable formulations can be sterilized, for Substances and waxes. Solid compositions of a similar type example, by filtration through a bacterial-retaining filter, or are also employed as fillers in soft and hard-filled gelatin by incorporating sterilizing agents in the form of sterile Solid capsules using Such excipients as lactose or milk Sugar as well compositions which can be dissolved or dispersed in sterile as high molecular weight polethylene glycols and the like. water or other sterile injectable medium prior to use. 0212. The active compounds can also be in micro-encap 0208. In order to prolong the effect of a compound of the sulated form with one or more excipients as noted above. The present invention, it is often desirable to slow the absorption Solid dosage forms of tablets, dragees, capsules, pills, and of the compound from Subcutaneous or intramuscular injec granules can be prepared with coatings and shells Such as tion. This is accomplished by the use of a liquid Suspension of enteric coatings, release controlling coatings and other coat crystalline or amorphous material with poor water solubility. ings well known in the pharmaceutical formulating art. In The rate of absorption of the compound then depends upon its Such solid dosage forms the active compound may be rate of dissolution that, in turn, may depend upon crystal size admixed with at least one inert diluent Such as Sucrose, lac and crystalline form. Alternatively, delayed absorption of a tose or starch. Such dosage forms also comprise, as is normal parenterally administered compound form is accomplished practice, additional Substances other than inert diluents, e.g., by dissolving or Suspending the compound in an oil vehicle. tableting lubricants and other tableting aids Such a magne Injectable depot forms are made by forming microencapsule sium Stearate and microcrystalline cellulose. In the case of matrices of the compound in biodegradable polymers such as capsules, tablets and pills, the dosage forms optionally also polylactide-polyglycolide. Depending upon the ratio of com comprise buffering agents. They optionally contain opacify pound to polymer and the nature of the particular polymer ing agents and can also be of a composition that they release employed, the rate of compound release can be controlled. the active ingredient(s) only, or preferentially, in a certain part Examples of other biodegradable polymers include poly of the intestinal tract, optionally, in a delayed manner. (orthoesters) and poly(anhydrides). Depot injectable formu Examples of embedding compositions that can be used lations are also prepared by entrapping the compound in include polymeric Substances and waxes. liposomes or microemulsions that are compatible with body 0213 Dosage forms for topical or transdermal administra tissues. tion of a compound of this invention include ointments, 0209 Compositions for rectal or vaginal administration pastes, creams, lotions, gels, powders, solutions, sprays, are preferably Suppositories which can be prepared by mixing inhalants or patches. The active component is admixed under the compounds of this invention with Suitable non-irritating sterile conditions with a pharmaceutically acceptable carrier excipients or carriers such as cocoa butter, polyethylene gly and any needed preservatives or buffers as required. Oph color a Suppository wax which are solid at ambient tempera thalmic formulation, ear drops, and eye drops are also con ture but liquid at body temperature and therefore melt in the templated as being within the scope of this invention. Addi rectum or vaginal cavity and release the active compound. tionally, the present invention contemplates the use of US 2016/01 68090 A1 Jun. 16, 2016 50 transdermal patches, which have the added advantage of pro 0221) LCMS-Analysis was performed under the follow viding controlled delivery of a compound to the body. Such ing conditions: dosage forms can be made by dissolving or dispensing the 0222 Method A (Rapid LC): A Shimadzu Shim-pack XR compound in the proper medium. Absorption enhancers can ODS, 3.0x30 mm, 2.2 rpm, was used at a temperature of 50° also be used to increase the flux of the compound across the C. and at a flow rate of 1.5 mL/min, 2 ul injection, mobile skin. The rate can be controlled by either providing a rate phase: (A) water with 0.1% formic acid and 1% acetonitrile, controlling membrane or by dispersing the compound in a mobile phase (B) methanol with 0.1% formic acid; retention polymer matrix or gel. time given in minutes. Method details: (I) runs on a Binary 0214. The compounds of the invention can also be utilized Pump G1312Bwith UV/Vis diode array detector G1315C and as commercial research reagents for various medical research Agilent 6130 mass spectrometer in positive and negative ion and diagnostic uses. Such uses can include but are not limited electrospray mode with UV-detection at 220 and 254 nm with to: use as a calibration standard for quantifying the activities a gradient of 15-95% (B) in a 2.2 minlinear gradient (II) hold of candidate P2X7 antagonists in a variety of functional for 0.8 min at 95% (B) (III) decrease from 95-15% (B) in a 0.1 assays; use as blocking reagents in random compound screen min linear gradient (IV) hold fro 0.29 min at 15% (B). ing, i.e. in looking for new families of P2X7 receptor ligands, 0223 Method B: A: 0.1% TFA in HO, B:0.1% TFA in the compounds can be used to block recovery of the presently ACN: claimed P2X7 compounds; use in the co-crystallization with P2X7 receptor, i.e. the compounds of the present invention Runtime: 6.5 min will allow formation of crystals of the compound bound to P2X7, enabling the determination of receptor/compound 0224 Flow Rate: 1.0 mL/min structure by X-ray crystallography; other research and diag Gradient: 5-95% B in 4.5 min, wavelength 254 and 215 nM. nostic applications, etc.; use in assays as probes for determin Column: Waters Sunfire C18, 3.0x50mm, 3.5um, +ve mode ing the expression of P2X7 on the surface of cells; and devel oping assays for detecting compounds which bind to the same Mass Scan: 100-900 Da site as the P2X7 binding ligands. 0225 Chiral analysis/separation condition: 0215. The compounds of formula (I), their salts, isomers, Mobile Phase: Hexane:EtOH:DEA=70:30:0.1: Flow Rate: tautomers, enantiomeric forms, diastereomers, racemates, 1.0 mL/min: Runtime: 25 min derivatives, prodrugs and/or metabolites are characterized by a high specificity and stability, low manufacturing costs and Column: CHIRALPAKAY-H (250x4.6 mm, 5um). convenient handling. These features form the basis for a reproducible action, wherein the lack of cross-reactivity is 0226 Chiral analysis/separation condition: included, and for a reliable and safe interaction with the target Structure. Column: AS-H (250*4.6 mm 5um) 0216. The term “biological sample', as used herein, Mobile Phase: Hexane:ETOH:DEA=90:10:0.1 includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts 0227 Flow: 1 ml/min thereof, and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Temperature: 40 0217. Antagonism of P2X7 activity in a biological sample is useful for a variety of purposes that are known to one of skill Runtime: 30 min in the art. Examples of Such purposes include, but are not 0228. Chiral-HPLC conditions: limited to, blood transfusion, organ transplantation, biologi Co-Solvent: 30% MeOH: Column: AD-H (4.6*250 mm, 5 cal specimen storage, and biological assays. um); CO. Flow Rate: 2.1 mL/min Co-Solvent Flow Rate: 0.9 mL/min: Total Flow: 3 mL/min: EXEMPLIFICATION Runtime: 9 min 0218. As depicted in the Examples below, in certain exem Example 1 plary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, Preparation of 4-chloro-N-((4.4-difluorocyclohexyl) although the general methods depict the synthesis of certain methyl)-1-(2.2.2-trifluoroethyl)-1H-indole-3-car compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in boxamide (5) the art, can be applied to all compounds and Subclasses and 0229 species of each of these compounds, as described herein. 0219 Compound numbers utilized in the Examples below correspond to compound numbers set forth Supra. F 0220 "H NMR was recorded on a Bruker 400 uMHz spec O H F trometer, using residual signal of deuterated solvent as inter C -N nal reference. Chemical shifts (8) are reported in ppm relative to the residual solvent signal (8–2.49 ppm for 1H NMR in DMSO-de). 1H NMR data are reported as follows: chemical 120° C., 3 h microwave shift (multiplicity, coupling constants, and number of hydro N gens). Multiplicity is abbreviated as follows: s (singlet), d H (doublet), t (triplet), q (quartet), m (multiplet), br (broad). US 2016/01 68090 A1 Jun. 16, 2016

-continued -continued F F O H F F C N O H N C N N OH N\\ F N F Sct, 0230. A mixture of 4-chloro-N-((4,4-difluorocyclohexyl) methyl)-1H-indole-3-carboxamide (0.163 g, 0.50 mmol), Step 1 2-bromo-1,1,1-trifluoroethane (0.204 g, 1.25 mmol) and CsCO (489 mg, 1.50 mmol) in anhydrous DMF (2 ml) was Preparation of 1-(4-chloro-1-(2.2.2-trifluoroethyl)- stirred at 120° C. for 30 minunder microwave irradiation. The 1H-indol-3-yl)-2.2.2-trifluoro-ethanone reaction mixture was diluted with EtOAc (20 mL) and washed with water (3x20 mL). The separated organic layer 0233 was dried over NaSO and concentrated in vacuo. The resi due was purified by Prep-HPLC to give 4-chloro-N-((4.4- O difluorocyclohexyl)methyl)-1-(2.2.2-trifluoroethyl)-1H-in C CF dole-3-carboxamide (0.067 g., 33%) as white solid. 0231 "H NMR (500 uMHz, DMSO-d) & 8.29-8.27 (m, N 1H), 7.73 (s, 1H), 7.68-7.66 (m. 1H), 728-7.20 (m, 2H), 5.32-5.27 (m, 2H), 3.17-3.15 (m, 2H), 2.04-2.02 (m, 2H), N 1.85-1.70 (m, 5H) 1.29-124 (m, 2H) ppm, M+H 409.1; LC-MS (254 nm) Purity: 97.98%; t—2.10 min: HPLC (254 Sct, nm.) Purity: >99%; t-10.10 min. 0234. A mixture of 1-(4-chloro-1H-indol-3-yl)-2.2.2-trif Example 2 luoroethanone (0.500g, 2.0 mmol), 2.2.2-trifluoroethyl trif luoromethanesulfonate (0.57 mL, 4.0 mmol), KCO (0.828 Preparation of 4-chloro-N-((4.4-difluoro-1-hydroxy g, 6.0 mmol) and DMF (2 mL) was stirred at 80°C. for 50 min cyclohexyl)methyl)-1-(2.2.2-trifluoroethyl)-1H under microwave condition. The mixture was cooled to room temperature, partitioned between water (30 mL) and EtOAc indole-3-carboxamide (4) (80 mL). The separated organic layer was dried over anhy 0232 drous NaSO filtered and concentrated to give the title com pound (0.600 g, 90%) as a green solid. V O CF Step 2 C O CF FC YN-"\, Preparation of 4-chloro-1-(2.2.2-trifluoroethyl)-1H 2 indole-3-carboxylic acid N K2CO3, DMF, 80° C. MW 0235 N H O O C OH C CF

N 10% NaOH -e- EtOH, 80° C. N N

CF Sct, F 0236. A mixture of 1-(4-chloro-1-(2.2.2-trifluoroethyl)- O NHHCI C OH F 1H-indol-3-yl)-2.2.2-trifluoroethanone (0.600 g, 1.8 mmol), EtOH (10 mL) and 10% NaOH (4 mL) was stirred at 80° C. for 2 h. The mixture was partitioned between water (50 mL) N OH and EtOAc (30 mL). The aqueous phase was adjusted to pH 5 EDCL, HOBt, EtN with 1 uM HCl and then extracted with EtOAc (100 mL). The separated organic layer was dried over anhydrous NaSO4, \ CHCN, r.t. filtered and concentrated to give 4-chloro-1-(2.2.2-trifluoro CF ethyl)-1H-indole-3-carboxylic acid (0.377 g, 75%) as a white solid.

US 2016/01 68090 A1 Jun. 16, 2016 53

-continued -continued F F O OH C HN

N HO EDCL, HOBt, DIPEA s DCM, r.t., 3 h F ON F O H C N F 0247 To a stirred solution of 4-Chloro-1-(2.2.2-trifluoro ethyl)-1H-indole-3-carboxylic acid (200.00 mg 0.72 mmol; N HO F 1.00 eq.), HATU (301.31 mg: 0.79 mmol; 1.10 eq) and 1-Aminomethyl-3,3-difluoro-5-methyl-cyclohexanol (142.01 mg; 0.79 mmol; 1.10 eq.) in DMF (3 ml) was added DIEA (0.38 ml, 2.16 mmol: 3.00 eq.). The mixture was stirred at room temperature overnight. Then the reaction was s O quenched with water (15 mL), and extracted with DCM/ methanol (10: 1, 30 mLX3). The combined organic layer was washed with water (20 mLx2), brine (20 mLX2), dried over Step 1 sodium sulfate, filtered and concentrated in vacuo. The resi due was purified by column chromatography on silica gel Preparation of (DCM:methanol=80:1) to obtain 4-chloro-N-((3.3-difluoro 1-(4-chloro-1H-indol-3-yl)-2.2.2-trifluoroethanone 1-hydroxy-5-methylcyclohexyl)methyl)-1-(2.2.2-trifluoro 0249 ethyl)-1H-indole-3-carboxamide (62.20%) as a white solid. M+H" 439. C CF Example 6 N Preparation of 4-chloro-N-((4,4-difluorocyclohexyl) N methyl)-1-(3,3,3-trifluoropropyl)-1H-indole-3-car H boxamide (37) 0250. To a solution of 4-chloro-1H-indole (10.0 g. 66.2 0248 mmol) in DMF (25 mL) was added 2.2.2-trifluoroacetic anhydride (14 ml, 100 mmol) at 0°C. The reaction was heated C to 40°C. for 5 h, then cooled to room temperature and water (50 mL) was added. The precipitate was collected by filtra N (CFCO)2O, DMF tion, dired in vacuo to give 1-(4-chloro-1H-indol-3-yl)-2.2.2- 40° C., 5 h trifluoroethanone (12.8 g., 78.8%), which was used in the next N run without further purification. LCMS m/z: 248.1 M+H". H O C CF Step 2 Preparation of 1-(4-chloro-1-(2-methoxyethyl)-1H N 1N1 O N indol-3-yl)-2.2.2-trifluoroethanone KOH, MeCN 0251 NH r.t., 6 h O 2 C CF O C CF

N aq. NaOH Hs reflux, 2h s s ON ON 0252) To a mixture of 1-(4-chloro-1H-indol-3-yl)-2.2.2- trifluoroethanone (5.00 g. 20.2 mmol), KOH (1.70 g, 29.8 US 2016/01 68090 A1 Jun. 16, 2016 54 mmol) in CHCN (20 mL) was added 1-bromo-2-methoxy (2-methoxyethyl)-1H-indole-3-carboxamide (0.044 g, ethane (4.2g, 30.4 mmol) at room temperature. The reaction 50.6%) as a light-yellow solid. was stirred at room temperature for 6 h, and then water (50 0257 "H NMR (500 uMHz, DMSO-d) & 7.91 (t, J=6.0 mL) was added. The precipitate was collected by filtration HZ, 1H), 7.80 (s, 1H), 7.57 (d. J=8.0 Hz, 1H), 7.19 (t, J=8.0 and dried in vacuo to give 1-(4-chloro-1-(2-methoxyethyl)- HZ, 1H), 7.15 (d. J=7.5 Hz, 1H), 4.69 (s, 1H), 4.39 (t, J=5.0 1H-indol-3-yl)-2.2.2-trifluoroethanone (6.4 g. 61.2%) as a Hz, 2H), 3.67 (t, J=5.0 Hz, 2H), 3.40-3.35 (m, 2H), 3.25 (s, white solid, which was used in the next step without further 3H), 2.02-1.89 (m,3H), 1.76-1.71 (m, 2H), 1.61-1.47 (m,3H) purification. LCMS m/z: 306.1 M+H". ppm, M+H" 401.1. Step 3 Example 7 Preparation of (R)-4-chloro-N-((3.3-difluoro-1-hydroxycyclohexyl) 4-chloro-1-(2-methoxyethyl)-1H-indole-3-carboxylic methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxam acid ide (21) 0253 0258

O C OH C

N HO

sO s 0254. A mixture of 1-(4-chloro-1-(2-methoxyethyl)-1H O indol-3-yl)-2.2.2-trifluoroethanone (0.100 g, 0.33 mmol) and / 30% aqueous NaOH (5.0 mL) was heated to 105° C. for 2 h, and then cooled to room temperature. The aqueous solution 130 mg of 4-chloro-N-((3.3-difluoro-1-hydroxycyclohexyl) was adjusted to pH 3 with concentrated HC1. The precipitate methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxamide was was collected, dried in vacuo to give 4-chloro-1-(2-methoxy separated to obtain 57 mg of the title compound. M+H" ethyl)-1H-indole-3-carboxylic acid (0.051 g, 61.0%) as a 4.01.1. Chiral-HPLC conditions: Co-Solvent: 30% MeOH: white solid, which was used in the next step without further Column: AD-H (4.6*250 mm, 5 um) CO, Flow Rate: 2.1 mL/min: Co-Solvent Flow Rate: 0.9 mL/min: Total Flow: 3 purification. LCMS m/z: 254.1 M+H". mL/min Runtime: 9 min. Step 4 Example 8 Preparation of 4-chloro-N-((3.3-difluoro-1-hydroxy cyclohexyl)methyl)-1-(2-methoxyethyl)-1H-indole (S)-4-chloro-N-((3.3-difluoro-1-hydroxycyclohexyl) 3-carboxamide methyl)-1-(2-methoxyethyl)-1H-indole-3-carboxam ide (20) 0255 0259

O H C N O F C N HO F

N Y. N 0256 The title compound was synthesized according to the procedure described in Example 2 using 4-chloro-1-(2- y methoxyethyl)-1H-indole-3-carboxylic acid (0.050 g, 0.198 mmol), EDCI (0.049 g, 0.257 mmol), HOBt (0.0347g, 0.257 0260 130 mg of 4-chloro-N-((3.3-difluoro-1-hydroxycy mmol), TEA (0.1 mL) and 1-(aminomethyl)-3,3-difluorocy clohexyl)methyl)-1-(2-methoxy ethyl)-1H-indole-3-car clohexanol (0.0354 g, 0.198 mmol) in DCM to provide boxamide was separated to obtain 56 mg of the title com 4-chloro-N-((3.3-difluoro-1-hydroxycyclohexyl)methyl)-1- pound. M+H 401. (For separation, see example 7)

US 2016/01 68090 A1 Jun. 16, 2016

0325 The title compound was synthesized according to -continued the procedure described in Example 2 using 4-Chloro-1-(2- methoxy-ethyl)-1H-indole-3-carboxylic acid (200 mg. 0.79 O mmol. 1.00 eq), 1-(2-Aminoethyl)-cyclopentanol (199 mg, C F 1.18 mmol, 1.50 eq), DIPEA (0.42 mL, 2.37 mmol. 3.00 eq), EDC (457 mg, 2.37 mmol. 3.00 eq) and Benzotriazol-1-ol (192 mg, 1.18 mmol, 1.50 eq) in dry DMF (5 mL, 25 V) to provide 4-Chloro-1-(2-methoxy-ethyl)-1H-indole-3-car boxylic acid 2-(1-hydroxy-cyclopentyl)-ethyl-amide (180 mg, 0.47 mmol, 60.2%) as a white solid. 0326 H NMR (400 uMHz, DMSO-d): 8 7.92 (t, J=5.48 HZ, 1H), 7.66 (s, 1H), 7.53 (dd, J=7.92, 1.16 Hz, 1H), 7.18 7.10 (m, 2H), 4.36 (t, J=5.20 Hz, 2H), 4.17 (s, 1H), 3.64 (t, J=5.12 Hz, 2H), 3.33-3.32 (m, 2H), 3.21 (s, 3H), 1.76-1.68 - 1 (m, 4H), 1.61-1.61 (m. 2H), 1.58-1.48 (m, 4H) ppm, M+H+ 365.2. Step 1 Example 31 Preparations of Preparation of 4-chloro-1-(2-cyclopropoxyethyl)-N- 4-chloro-1-(2-cyclopropoxyethyl)-1H-indole ((4.4-difluorocyclohexyl)methyl)-1H-indole-3-car 0328 boxamide (149) 0327 C C

N --B { NaH, THF s reflux, 6 h s OH - 1 C 0329. To a solution of 2-(4-chloro-1H-indol-1-yl)ethanol (1.95g, 10 mmol) in THF (13 mL) was added NaH(0.80g, 20 N (CFCO)2O -- mmol. 60% in mineral oil) and bromocyclopropane (1.82 g, MeCN, 45° C. 15 mmol) at 0°C. The resulting reaction mixture was refluxed for 6 h, and then concentracted to dryness in vacuo. The residue was redissolved in EtOAc (20 mL) and washed with water (20 mLx2) twice and brine (20 mL). The organic layer s 3 was dried over MgSO filtered and concentrated in vacuo. The residual oil was purified by column chromatography on - 1 silica gel (eluting with petroleum ether:ethyl acetate=5:1 to O 2:1) to give 4-chloro-1-(2-cyclopropoxyethyl)-1H-indole C CF (1.53 g. 65%) as a yellow solid. LC-MS Purity: >95%; t-1. 73 min: M+H 236. N aq. NaOH He Step 2 100° C., 18 h Preparation of 1-(4-chloro-1-(2-cyclopropoxyethyl)- 1H-indol-3-yl)-2.2.2-trifluoroethanone s 0330 S1 O C OH F HN F N Her EDCL, HOBt N TEA, DCM r.t., 3 h US 2016/01 68090 A1 Jun. 16, 2016 62

0331. A solution of 4-chloro-1-(2-cyclopropoxyethyl)- mmol), EDCI (0.800 g, 0.42 mmol) and HOBt (0.425 g, 3.1 1H-indole (1.50 g. 6.3 mmol) and 2.2.2-trifluoroacetic anhy mmol) in DCM (10 mL) were added EtN (0.525 g, 5.2 dride (2.10 g, 10 mmol) in MeCN (15 mL) was stirred at 45° mmol) and (4,4-difluorocyclohexyl)methanamine (0.298 g. C. for 3 h. Then the reaction mixture was concentracted in 2.0 mmol) at room temperature. After stirred at room tem vacuo and the residue was purified by column chromatogra perature for 3 h, the reaction was quenched with water (10 phy on silica gel (eluting with petroleum ether:ethyl mL) and extracted with DCM (20 mLX3). The combined acetate-2:1 to 1:2) to give 1-(4-chloro-1-(2-cyclopropoxy organic layers were washed with water (10 mL), brine (10 ethyl)-1H-indol-3-yl)-2.2.2-trifluoroethanone (1.35 g. 65%) mL), dried over Na2SO and concentrated to give a residue. as a yellow solid. LC-MS Purity (254 nm): >95%: M+H" The residue was purified by column chromatography on silica 332; t-1.24 min. gel (DCM: MeOH-20:1) to afford 4-chloro-1-(2-cyclopro poxyethyl)-N-((4,4-difluorocyclohexyl)methyl)-1H-indole Step 3 3-carboxamide (0.150 g. 18%) as a white solid. Preparation of 4-chloro-1-(2-cyclopropoxyethyl)- 0336 H NMR (500 uMHz, DMSO-d) & 8.09 (s, 1H), 1H-indole-3-carboxylic acid 7.69 (s, 1H), 7.53 (d. J–7.5 Hz, 1H), 7.17-7.12 (m, 2H), 4.35 (t, J=10.5 Hz, 2H), 3.76 (t, J=10.5 Hz, 2H), 3.30-3.27 (m. 1H), 0332 3.15 (t, J=6.5 Hz, 2H), 2.00 (s. 2H), 1.84-1.72 (m, 5H), 1.25-1.22 (m, 2H), 0.38-0.36 (m, 4H) ppm, M+Nat 433.

O C OH Example 32 Preparation of 4-chloro-N-((4.4-difluorocyclohexyl) methyl)-1-(2-(difluoromethoxy)ethyl)-1H-indole-3- carboxamide (95) s 0337 O st) C OH 0333. A mixture of 1-(4-chloro-1-(2-cyclopropoxyethyl)- N MeI, K2CO3 Her 1H-indol-3-yl)-2.2.2 trifluoroethanone (1.0 g, 3 mmol) and DMF, r.t., 4h 10% aqueous sodium hydroxide (10 mL) was stirred at 100° C. for 18 h, then cooled to room temperature. The mixture was adjusted to pH 2 with 1 NHCl and extricted with DCM (15 mLx2). The combined organic layers were dried over s OH MgSO filtered and concentracted in vacuo to give 4-chloro 1-(2-cyclopropoxyethyl)-1H-indole-3-carboxylic acid (0.560 g. 66%) as a yellow solied, which was used in the next O O O step without purification. O V/ C ON F1 S Step 4 OH, CuI Preparation of 4-chloro-1-(2-cyclopropoxyethyl)-N- N —F - ((4,4-difluorocyclohexyl) methyl)-1H-indole-3-car CHCN, 559 C., 3 h boxamide 0334 sOH O H F C N F O C N N NaOH, MeOHVH2O 60 ae, overnight s N st? 0335 To a stirred solution of 4-chloro-1-(2-cyclopro poxyethyl)-1H-indole-3-carboxylic acid (0.560 g, 2.0 US 2016/01 68090 A1 Jun. 16, 2016 63

-continued Step 2

C OH HN Preparation of methyl 4-chloro-1-(2-(difluo 2 F romethoxy)ethyl)-1H-indole-3-carboxylate F -> 0340 HoBt, EDCI, TEA DCM, r.t., 2h -

0341 To a stirred solution of methyl 4-chloro-1-(2-hy droxyethyl)-1H-indole-3-carboxylate (0.500 g, 1.98 mmol) ... O in acetonitrie (100 mL) was added copper(I) iodide (0.075 g, 0.4 mmol). The system was stirred at 55° C. under nitrogen atmosphere for a few minutes, then a solution of 2,2-difluoro S. F 2-(fluorosulfonyl)acetic acid (1.407 g., 7.90 mmol) in aceto nitrie (20 mL) was added dropwise thereto. The reaction was F stirred at 55° C. for 3 hunder nitrogen atmosphere, then the solvent was removed in vacuo. The residue was redissolved in dichloromethane (10 mL). The precipitate was filtered and washed with dichloromethane (10 mLX3). The filtrate was Step 1 evaporated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=5:1) to afford methyl 4-chloro-1-(2-(difluoromethoxy)ethyl)-1H Preparation of methyl 4-chloro-1-(2-hydroxyethyl)- indole-3-carboxylate (0.120g, 20%) as colorless oil. M+H" 1H-indole-3-carboxylate 3O41. 0338 Step 3 Preparation of 4-chloro-1-(2-(difluoromethoxy) O C O ethyl)-1H-indole-3-carboxylic acid N 0342

O C OH

s OH N 0339. To a stirred mixture of 4-chloro-1-(2-hydroxy ethyl)-1H-indole-3-carboxylic acid (2.00 g, 8.37 mmol) and potassium carbonate (4.62g, 33.47 mmol) in anhydrous DMF s F (20 mL) was added iodomethane (1.18 g, 8.37 mmol) at room -, temperature and stirred for 4 h. The reaction mixture was F quenched with brine (25 mL), extracted with ether (30 mLX3), the combined organic layer was washed with brine 0343 To a stirred solution of methyl 4-chloro-1-(2-(dif (20 mL), dried over anhydrous sodium sulfate, filtered and luoromethoxy)ethyl)-1H-indole-3-carboxylate (0.100 g, concentrated in vacuo. The reside was purified by column 0.33 mmol) in methanol (50 mL) was added sodium hydrox chromatography on silica gel (petroleum ether:EtOAc=4:1) ide (10%, 5 mL). The mixture was stirred at 60°C. overnight, to afford methyl 4-chloro-1-(2-hydroxyethyl)-1H-indole-3- cooled to room temperature, the solvent was removed in carboxylate (1.50 g, 73%) as a white solid. M+H 254.2. vacuo. The pH value of the residue was adjusted to 1 with US 2016/01 68090 A1 Jun. 16, 2016 64 addition of hydrochloric acid (1N), and extracted with EtOAc -continued (20 mLX3). The combined extracts was washed with brine (10 O Ti(OiPr)4, EtMgBr mL), dried over anhydrous sodium Sulfate, filtered and con He centrated in vacuo. The residue was purified by column col 1N O luori umn chromatography on silica gel (petroleum ether: PhCOCl, TEA EtOAc=2:1) to afford 4-chloro-1-(2-(difluoromethoxy) He ethyl)-1H-indole-3-carboxylic acid (0.090 g, 98%) as a HO yellow solid. M+H" 290.1. PPTS, MeOH -e- Step 4 BZO F O H F Preparation of 4-chloro-N-((4,4-difluorocyclohexyl) C -N methyl)-1-(2-(difluoromethoxy) ethyl)-1H-indole-3- carboxamide 0344 N O H F H CMTP, toluene, 110° C. C -NN-O< F Xu Sri

N NaOH He S. F EtOH, 50° C. -, ... O F \-A OBZ 0345. A mixture of 4-chloro-1-(2-(difluoromethoxy) ethyl)-1H-indole-3-carboxylic acid (0.09 g, 0.31 mmol), (4,4-difluorocyclohexyl)methanamine (0.046 g., 0.31 mmol), HOBt (0.126 g., 0.93 mmol), EDCI (0.090 g, 0.47 mmol) and triethylamine (0.063 g, 0.62 mmol) in DCM (5 mL) was stirred at room temperature for 2 h, then quenched with water (10 mL), and extracted with EtOAc (20 mLX3). The com ... O bined extract was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. \-> The residue was purified by column chromatography on silica OH gel (hexane:EtOAc=2:1) to afford 4-chloro-N-((4.4-difluoro cyclohexyl) methyl)-1-(2-(difluoromethoxy)ethyl)-1H-in dole-3-carboxamide (0.050 g., 38%) as a white solid. Step 1 (0346) 1H NMR (500 uMHz, DMSO-d) 88.12 (t, J=6.0 HZ, 1H), 7.74 (s, 1H), 7.58 (d. J=8.0 Hz, 1H), 7.20 (t, J–7.5 HZ, 1H), 7.15 (d. J=7.5 Hz, 1H), 6.79-6.49 (m, 1H), 4.50 (t, Preparation of ethyl J=5.0 Hz, 2H), 4.18 (t, J=5.0 Hz, 2H), 3.16 (t, J=6.5 Hz, 2H), 2-(tetrahydro-2H-pyran-2-yloxy)acetate 2.06-2.00 (m, 2H), 1.85-1.70 (m, 5H), 1.30-1.21 (m, 2H) ppm, M+H 421.0. 0348 Example 33 O

Preparation of 4-chloro-N-((4,4-difluorocyclohexyl) OTHP methyl)-1-((1-hydroxycyclopropyl)methyl)-1H-in --- dole-3-carboxamide (117) CMTP reaction example 0347 0349. A mixture of 3,4-dihydro-2H-pyran (20.4g, 242.3 O mmol), ethyl 2-hydroxyacetate (24.0 g, 230.8 mmol) and TsOH (0.794g, 4.6 mmol) in toluene (150 mL) was stirred at O room temperature overnight. The resulting mixture was con centrated in vacuo and the residue was purified by column HeO les-s-s p-TSA, tol. chromatography on silica gel (2% EtOAC in petroleum ether) r.t., overnight to afford ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (25.2 g, 58%) as a colorless oil. US 2016/01 68090 A1 Jun. 16, 2016 65

Step 2 raphy on silica gel (0-10% EtOAc in petroleum ether) to afford 1-(hydroxymethyl)cyclopropyl benzoate (0.200 g, Preparation of 1-((tetrahydro-2H-pyran-2-yloxy) 47%) as a colorless oil. methyl)cyclopropanol Step 5 0350 Preparation of 1-((4-chloro-3-((4.4-difluorocyclo hexyl)methylcarbamoyl)-1H-indol-1-yl)methyl)cy sus-X clopropylbenzoate. (CMTP-Example) C OH 0356 O H F 0351. To a stirred solution of ethyl 2-(tetrahydro-2H-py F ran-2-yloxy)acetate (1.0 g, 5.32 mmol) in anhydrous Et2O C -NN-O< (30 mL) was added Ti(Oi-Pr). (0.997 g, 3.51 mmol) and ethylmagnesium bromide (13.1 mmol. 1 uM in EtO) drop wise at 0°C. After being stirred at room temperature for 2 h, the resulting mixture was quenched with water (10 mL) at 0° C. and extracted with EtOAc (50 mLX3). The combined organic layers were dried over Na2SO, filtered and concen AO trated in vacuo. The residue was purified by silica gel column chromatography (4% EtOAc in petroleum ether) to afford 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol O (0.5g, 54%) as a colorless oil. 0357. A mixture of 1-(hydroxymethyl)cyclopropyl ben Zoate (0.100 g, 0.52 mmol), 4-chloro-N-((4.4-difluorocyclo Step 3 hexyl)methyl)-1H-indole-3-carboxamide (0.085 g, 0.26 mmol) and cyanomethylenetributylphosphorane (CMTP) Preparation of (0.188 g., 0.78 mmol) in anhydrous toluene (4 mL) was stirred 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropyl at 110° C. for 4 hour under nitrogen. The resulting mixture benzoate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0-5% MeOH in DCM) O352 to afford 1-((4-chloro-3-((4,4-difluorocyclohexyl)methyl O carbamoyl)-1H-indol-1-yl)methyl)-cyclopropyl benzoate (0.050 g., 38%) as a white solid. sus-X Step 6 C O Preparation of 4-chloro-N-((4.4-difluorocyclohexyl) methyl)-1-((1-hydroxycyclopropyl)methyl)-1H-in 0353 To a stirred solution of 1-((tetrahydro-2H-pyran-2- dole-3-carboxamide yloxy)methyl)cyclopropanol (0.500 g, 2.9 mmol) in anhy drous DCM (15 mL) was added benzoyl chloride (0.494g, 3.5 0358 mmol) and TEA (0.879 g, 8.7 mmol) dropwise at 0°C. After F being stirred at room temperature overnight, the resulting O H F mixture was concentrated in vacuo and the residue was puri C N fied by column chromatography on silica gel (0-20% EtOAc in petroleum ether) to afford 1-((tetrahydro-2H-pyran-2- yloxy)methyl)cyclopropylbenzoate (0.6 g., 75%) as a yellow oil. Step 4 Preparation of 1-(hydroxymethyl)cyclopropyl AOH benzoate 0359 A solution of 1-((4-chloro-3-((4,4-difluorocyclo 0354) hexyl)methylcarbamoyl)-1H-indol-1-yl) methyl)cyclopro O pyl benzoate (0.044 g., 0.088 mmol) and NaOH (1.0 mL, 2 uM) in ethanol (2.0 mL) was stirred at 50° C. for 2 h. The resulting mixture was concentrated in vacuo and the residue roux O was purified by column chromatography on silica gel purified by prep-HPLC to afford 4-chloro-N-((4,4-difluorocyclo hexyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-1H-in dole-3-carboxamide (0.006 g, 17%) as a white solid. 0355. A mixture of 1-((tetrahydro-2H-pyran-2-yloxy)me 0360 "H NMR (500 uMHz, CDC1) & 7.98 (s, 1H), 7.45 thyl)cyclopropyl benzoate (0.6 g. 2.17 mmol) and PPTS 7.42 (m. 1H), 7.25-7.20 (m, 2H), 6.87-6.85 (m, 1H), 4.29 (s. (0.055 g, 0.22 mmol) in methanol (50 mL) was stirred at room 2H), 3.43 (t, J=8.3 Hz, 2H), 2.24-2.14 (m,3H), 1.94-1.92 (m, temperature for 2 h. The resulting mixture was concentrated 2H) 1.82-1.70 (m,3H), 1.47-128 (m, 2H), 1.00-0.98 (m, 2H), in vacuo and the residue was purified by column chromatog 0.86-0.83 (m, 2H) ppm, M+H" 397.2. US 2016/01 68090 A1 Jun. 16, 2016 66

Example 34 afford tert-butyl 2-(4-chloro-3-((4.4-difluorocyclohexyl)me thylcarbamoyl)-1H-indol-1-yl)ethylcarbamate (0.200 g, Preparation of 1-(2-aminoethyl)-4-chloro-N-((4.4- 80%) as a white solid. difluorocyclo-hexyl) methyl)-1H-indole-3-carboxa Step 2 mide (6) Preparation of 1-(2-aminoethyl)-4-chloro-N-((4.4- difluorocyclohexyl)methyl)-1H-indole-3-carboxam 0361 ide F O H 0364 F O H C NuOf C N F N HO N1NNHBoe CMTP, toluene N reflux, 4h F O H C N F

N TFA s -as NH2 DCM 0365. To a solution of tert-butyl 2-(4-chloro-3-((4.4-dif luorocyclohexyl)methylcarbamoyl)-1H-indol-1-yl)ethylcar bamate (0.200 g, 0.43 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction mixture was stirred at room tem s NHBOc perature for 2 h. The Volume was reduced in vacuo to approxi mately 2 mL. The residual liquid was partitioned between saturated aqueous NaHCO (10 mL) and DCM (30 mL). The organic layer was dried over anhydrous Na2SO4, concen trated and purified by Prep-HPLC to provide 1-(2-aminoet hyl)-4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-in dole-3-carboxamide (0.080 g, 51%) as a white solid. 0366 "H NMR (500 uMHz, DMSO-d) 8.07 (t, J=5.5 Hz, ... O 1H), 7.72 (s, 1H), 7.54 (d. J=7.5 Hz, 1H), 7.16 (t, J–7.5 Hz, 1H), 7.12 (d. J–7.0 Hz, 1H), 4.16 (t, J=6.5 Hz, 2H), 3.15 (t, S. J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H), 2.05-1.99 (m, 2H), 1.85-1.68 (m, 5H), 1.57-1.34 (m, 2H), 1.28-1.20 (m, 2H) ppm, M+H" 370.1. Example 35 Step 1 4-chloro-N-((3, 3-difluoro-1-hydroxycyclohexyl) Preparation of tert-butyl 2-(4-chloro-3-((4.4-difluo methyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole-3- rocyclohexyl)methyl carbamoyl)-1H-indol-1-yl) carboxamide (178) ethylcarbamate 0367 0362 F O H C C N F N HO

NHBOc 0363 A solution of 4-chloro-N-((4,4-difluorocyclohexyl) methyl)-1H-indole-3-carboxamide (0.15g, 0.46 mmol), tert 0368. The title compound was synthesized according to butyl 2-hydroxyethylcarbamate (0.148 g. 0.92 mmol) and the procedure described in Example 33 using 4-chloro-N-((3. cyanomethylenetributylphosphorane (CMTP) (0.443 g, 1.84 3-difluoro-1-hydroxycyclohexyl)methyl)-1H-indole-3-car mmol) in toluene (2 mL) was heated at 110°C. under nitrogen boxamide (70.00 mg 0.28 mmol: 1.00 eq.), 2-(pyrrolidin-1- for 4 h. The mixture was quenched with water (10 mL) and yl)ethanol (35.28 mg; 0.31 mmol; 2.50 eq.) and (Tributyl extracted with EtOAc (10 mLX3). The organic layers were lambda5-phosphanylidene)-acetonitrile (147.72 mg 0.61 washed with brine, dried over NaSO filtrated and concen mmol; 4.00 eq.) in Toluene (3 mL) by heating at 110°C. for trated to give a residue, which was purified by Prep-TLC to 4 hours.

US 2016/01 68090 A1 Jun. 16, 2016 70

-continued 0407. A mixture of 1-(4-chloro-1H-indol-3-yl)-2.2.2-trif O luoroethanone (0.5g, 2 mmol), CsCO (2.6 g., 8 mmol) and C CF 3,3,3-trifluoropropyl trifluoromethanesulfonate (0.74 g. 3 mmol) in DMF (10 mL) was heated at 80° C. for 1 h under N 10% NaOH ad microwave condition. The reaction was diluted with water (10 reflux mL), extracted with EtOAc (10 mLX3), dried over anhydrous N NaSO filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=20:1) to give 1-(4-chloro-1-(3,3,3-trifluoropro pyl)-1H-indol-3-yl)-2.2.2-trifluoro-ethanone (1.20 g, 71%) CF O as a light yellow solid. C OH F HCI Step 3 F N NH2 Preparation of 4-chloro-1-(3,3,3-trifluoropropyl)-1H EDCL, HOBT, TEA, DCM, rt indole-3-carboxylic acid 04.08 O s C OH CF F O H

C -NuO< N

CF s 04.09. A mixture of 1-(4-chloro-1-(3,3,3-trifluoropropyl)- CF 1H-indol-3-yl)-2.2.2-trifluoroethanone (0.650 g, 1.9 mmol) and 10% aqueous NaOH (6 mL) was refluxed for 1 h. Then the Step 1 reaction was cooled to room temperature and the pH value was adjusted to 3 with conc. HC1. The formed precipitate was Preparation of 3,3,3-trifluoropropyl collected by filtration and dired to give 4-chloro-1-(3,3,3- trifluoromethanesulfonate trifluoropropyl)-1H-indole-3-carboxylic acid (0.320 g, 58%) as a white Solid. 04.04 CF Step 4 To1N1 3 Preparation of 4-chloro-N-((4.4-difluorocyclohexyl) 04.05 To a solution of 3,3,3-trifluoropropan-1-ol (0.684g, methyl)-1-(3,3,3-trifluoropropyl)-1H-indole-3-car 6 mmol) and pyridine (0.48 g. 6 mmol) in dry DCM (5 mL) at boxamide 0°C. was added trifluoromethanesulfonic anhydride (1.86 g. 6.6 mmol) dropwise. The reaction was stirred at 0°C. for 1 h, 0410 and then ice water (10 mL) was added. The pH value was F adjusted to 7 with saturated aqueous NaHCO, and the solu O H tion was extracted with DCM (10 mLX3), dried over anhy C N F drous NaSO, filtered and concentrated to give 3,3,3-trifluo ropropyl trifluoromethanesulfonate (0.98 g. 66%) as pale yellow oil. Step 2 Preparation of 1-(4-chlorë (3,3,3-trifluoropropyl)- s 1H-indol-3-yl)-2.2.2-fifluoro-ethanone CF 0406 0411. A mixture of 4-chloro-1-(3,3,3-trifluoropropyl)- 1H-indole-3-carboxylic acid (0.050 g., 0.17 mmol), EDCI (0.043 g, 0.22 mmol), HOBt (0.023 g, 0.22 mmol) and TEA (0.1 mL, 0.7 mmol) in DCM (1.0 mL) was stirred at room temperature for 1 h. Then cyclohexylmethanamine hydro chloride (0.032g, 0.17 mmol) was added and the reaction was stirred at room temperature for 3 h. The mixture was diluted with DCM (10 mL) and washed with water (3 mLX3). The US 2016/01 68090 A1 Jun. 16, 2016 71 organic layer was dried over NaSO4, filtered, concentrated to 0415) To a solution of 4-Chloro-1H-indole (1.50 g, 9.70 dryness, and the residue was purified by Prep-HPLC to give mmol. 1.00 eq) and 3-Bromo-1,1-dimethoxy-propane (3.75 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1-(3,3,3-trif. g, 18.42 mmol, 1.90 eq) in dry DMF (15 mL, 10.00 V) was luoropropyl)-1H-indole-3-carboxamide (0.020 g, 38%) as a added KOH (2.56 g. 38.79 mmol. 4.00 eq) at room tempera white solid. ture. The mixture was stirred at 50° C. for 5h, The completion 0412 H NMR (500 uMHz, DMSO-d): 8 8.09 (t, J=6.0 of the reaction was confirmed by TLC and then quenched HZ, 1H), 7.81 (s, 1H), 7.55 (d. J=8.0 Hz, 1H), 7.21 (t, J=8.0 HZ, 1H), 7.16 (d. J=8.0 Hz, 1H), 4.49 (t, J=7.0 Hz, 2H), 3.31 with water (1x50 mL) and extracted with EtOAc (1x100 mL). (t, J=6.0 Hz, 2H), 2.83-2.89 (m, 2H), 2.01-2.04 (m, 2H), The combined extracts were washed with water (50 mL) and 1.69-1.85 (m, 5H), 1.26-1.28 (m, 2H) ppm, M+H" 423.1. brine solution (50 mL), dried over NaSO, filtered and evaporated to afford the crude product. The crude product was Example 48 further purified using column chromatography 15% ethyl acetate in petroleum ether to afford 4-Chloro-1-(3.3- Preparation of 4-Chloro-1-(3.3-difluoro-propyl)-1H dimethoxy-propyl)-1H-indole (2.45 g, 9.60 mmol. 99.0%) as indole-3-carboxylic acid (4,4-difluoro-cyclohexyl a yellow liquid. "H NMR (400 uMHz, DMSO-d): 8 7.49-7. methyl)-amide (11) 43 (m, 2H), 7.15-7.07 (m, 2H), 6.47 (s. 2H), 4.26-4.19 (m, 0413 3H), 3.20 (s, 6H), 2.03-1.98 (m, 2H) ppm.

O O C C O O C CF C CF N KOH, DMF N ---, N HCI N Br DMF N N N N

H O \--" / O Diethylamino / / / Sulfur trifluoride

F O H O O C N F C OH C CF

N EDC, HOBT N KOH N F c F F N N N F F F

Step 1 Step 2

4-Chloro-1-(3.3-dimethoxy-propyl)-1H-indolePreparation of Pries,pyl)-1H-indol-3-yl)-2.2.2-trifluoro-ethanone grip 0416 0414

O C C CF

N N

/ / US 2016/01 68090 A1 Jun. 16, 2016 72

0417. To a solution of 4-Chloro-1-(3.3-dimethoxy-pro 0421. To a stirred solution of 3-4-Chloro-3-(2.2.2-trif pyl)-1H-indole (2.45 g, 9.60 mmol. 1.00 eq) in DMF (20 mL) luoro-acetyl)-indol-1-yl)-propionaldehyde (1.80 g, 5.74 was added Trifluoroacetic anhydride (2.75 mL, 19.20 mmol. mmol. 1.00 eq) in DCM (20 mL) at -78° C. was added 2.00 eq) at room temperature. The reaction mixture was Diethylaminosulfur trifluoride (1.69 mL, 11.48 mmol. 2.00 stirred at 45° C. for overnight. After the completion of the eq) and allowed to stir for 3 h. After the completion of the reaction as evidenced by TLC, the reaction mixture was reaction as evidenced by TLC, the reaction mixture was quenched with water (1x50 mL) and extracted with EtOAc diluted with DCM (120 mL) and extracted with water (1x20 (1x100 mL). The combined extracts were washed with water mL) and brine solution (1x20 mL). The separated organic (1x50 mL) and brine solution (lx 50 mL), dried over NaSO layer was dried over NaSO and concentrated under vacuum filtered and evaporated to afford the crude product. 1-4- to get the crude product. which was further purified by col Chloro-1-(3.3-dimethoxy-propyl)-1H-indol-3-yl)-2.2.2-trif umn chromatography using silica gel (9:1) DCM and Metha luoro-ethanone (3.10 g. 6.16 mmol. 64.2%) as a pale yellow nol to afford 1-4-Chloro-1-(3.3-difluoro-propyl)-1H-indol liquid. The crude product was used as such for the next step 3-yl)-2.2.2-trifluoro-ethanone (1.40 g, 4.30 mmol. 75%) as a without further purification. M+H" 350.0. yellow brown solid. "H NMR (400 MHz, DMSO-d): 88.67 (s, 1H), 7.74-7.72 (m. 1H), 7.42-7.37 (m, 2H), 6.37-6.07 (m, Step 3 1H), 4.58 (t, J=7.00 Hz, 2H), 2.50-2.41 (m, 2H) ppm. Preparation of 3-4-Chloro-3-(2.2.2-trifluoro-acetyl)- Step 5 indol-1-yl-propionaldehyde Preparation of 4-Chloro-1-(3.3-difluoro-propyl)-1H 0418 indole-3-carboxylic acid 0422 O C CF O C OH

N F \lvio N F 0419. To a solution of 1-4-Chloro-1-(3.3-dimethoxy-pro pyl)-1H-indol-3-yl)-2.2.2-trifluoro-ethanone (3.10 g. 6.16 0423. A suspension of 1-4-Chloro-1-(3.3-difluoro-pro mmol. 1.00 eq) in dry THF (20 mL) was added drop wise 1.5 pyl)-1H-indol-3-yl)-2.2.2-trifluoro-ethanone (1.40 g, 4.30 uM aqueous solution of hydrochloric acid (25 mL, 37.50 mmol. 1.00 eq) and KOH1N solution (20 mL) was stirred at mmol. 6.09 eq). After stirred at 80 OC for 30 min, the reaction 100° C. overnight. After the completion of the reaction as mixture was allowed to reach to RT, sat. aq. NaHCO solution evidenced by TLC, the reaction mixture was acidified with was added to the reaction mixture and solvent was removed aqueous hydrochloric acid (1.5 N, 10 mL) to pH 1-3. The under reduced pressure. The remaining aqueous layer was formed precipitate was collected by filtration and dried to extracted with EtOAc (2x50 mL). The combined organic afford 4-Chloro-1-(3.3-difluoro-propyl)-1H-indole-3-car layers were dried over NaSO filtered and the solvent was removed under reduced pressure to yield 3-4-Chloro-3-(2.2, boxylic acid (0.90 g, 3.24 mmol. 75.4%) as an off-white solid. 2-trifluoro-acetyl)-indol-1-yl)-propionaldehyde (1.80g, 5.74 M+HI 274.0; LC-MS Purity (254 nm): 98.5%; t3.37 min. mmol. 93.2%) as a pale yellow solid, which was used in the Step 6 next step without further purification. M+H 322.2. Preparation of 4-Chloro-1-(3.3-difluoro-propyl)-1H Step 4 indole-3-carboxylic acid (4,4-difluoro-cyclohexyl methyl)-amide Preparation of 1-4-Chloro-1-(3.3-difluoro-propyl)- 1H-indol-3-yl)-2.2.2-trifluoro-ethanone 0424 0420 F O H C N F C CF

F N F F

Us 0425 To a solution of 4-Chloro-1-(3.3-difluoro-propyl)- 1H-indole-3-carboxylic acid (0.20g, 0.72 mmol. 1.00 eq) and US 2016/01 68090 A1 Jun. 16, 2016

C-(4,4-Difluoro-cyclohexyl)-methylamine hydrochloride Example 50 (0.16 g. 0.86 mmol. 1.20 eq) in THF (10 mL) were added EtN (0.30 mL, 2.16 mmol. 3.00 eq), EDC (0.28 g, 1.44 Preparation of 4-Chloro-1-(3.3-difluoro-propyl)-1H mmol. 2.00 eq) and Benzotriazol-1-ol (0.18 g, 1.08 mmol. indole-3-carboxylic acid (4,4-difluoro-1-hydroxy 1.50 eq) at 0°C. The reaction mixture was stirred at RT for cyclohexylmethyl)-amide (10) overnight. After the completion of the reaction as evidenced by TLC, the reaction mixture was diluted with ethyl acetate 0429 F (1x10 mL) then washed with aq.NaHCO solution (10%, O H 1x10 mL), and washed with water and brine solution, dried C N F over NaSO and concentrated under vacuum. The crude product was further purified using Column chromatography 45% ethyl acetate in petroleum ether to afford 4-Chloro-1-(3. N HO 3-difluoro-propyl)-1H-indole-3-carboxylic acid (4,4-dif F luoro-cyclohexylmethyl)-amide (0.15g, 0.35 mmol, 49.0%) N as a off-white solid. "H NMR (400 uMHz, DMSO-d): 88.10 F (t, J=5.9 HZ, 1H), 7.76 (d. J–74 Hz, 1H), 7.53 (d. J=7.7 Hz, 1H), 7.19 (t, J=8.0 Hz, 1H), 7.14 (d. J=7.1 Hz, 1H), 6.28-5.98 0430. The title compound was synthesized according to (m. 1H), 4.37 (t, J=7.4 Hz, 2H), 3.13 (t, J=6.2 Hz, 2H), the procedure described in Example 2 using 4-Chloro-1-(3. 2.38-2.32 (m, 2H), 2.01 (t, J–3.4 Hz, 2H), 1.84-1.67 (m, 5H), 3-difluoro-propyl)-1H-indole-3-carboxylic acid (0.20 g, 0.72 1.27-1.18 (m, 2H), ppm, M+H" 405.1. mmol. 1.00 eq), 1-Aminomethyl-4,4-difluoro-cyclohexanol (0.14g, 0.86 mmol. 1.20 eq), EtN (0.30 mL, 2.16 mmol. 3.00 eq), EDC (0.28 gm 1.44 mmol. 2.00 eq) and Benzotriazol-1- Example 49 ol (0.18 g, 1.08 mmol. 1.50 eq) to afford 4-Chloro-1-(3.3- difluoro-propyl)-1H-indole-3-carboxylic acid (4,4-difluoro Preparation of 4-Chloro-1-(3.3-difluoro-propyl)-1H 1-hydroxy-cyclohexyl methyl)-amide (0.25 mL, 0.59 mmol. indole-3-carboxylic acid (3.3-difluoro-cyclohexylm 81.9%) as a white solid. ethyl)-amide (9) 0431 H NMR (400 uMHz, DMSO-d): 8 7.96 (t, J=6.12 HZ, 1H), 7.83 (s, 1H), 7.56-7.54 (m, 1H), 7.23-7.14 (m, 2H), 0426 6.29-5.99 (m, 1H), 4.72 (s, 1H), 4.38 (t, J=7.28 Hz, 2H), 3.30 (t, J=6.20 Hz, 2H), 2.40-2.32 (m, 2H), 2.08 (t, J=6.80 Hz, 2H), 2.05-193 (m, 2H), 1.89-1.62 (m, 4H) ppm, M+H" 421.0. F F Example 51 O H C N Preparation of 4-Chloro-1-(3.3-difluoro-propyl)-1H indole-3-carboxylic acid (1S,3S)-1-hydroxy-3-me thyl-cyclohexylmethyl)-amide (79 uMSC2526161)

N 0432

F F

0427. The title compound was synthesized according to the procedure described in Example 2 using 4-Chloro-1-(3. 3-difluoro-propyl)-1H-indole-3-carboxylic acid (0.20 g, 0.72 mmol. 1.00 eq), C-(3.3-Difluoro-cyclohexyl)-methylamine hydrochloride (0.16 g. 0.86 mmol. 1.20 eq), Et N (0.30 mL. 2.16 mmol. 3.00 eq), EDC (0.28g, 1.44 mmol. 2.00 eq) and F Benzotriazol-1-ol (0.18 g, 1.08 mmol. 1.50 eq) to afford 4-Chloro-1-(3.3-difluoro-propyl)-1H-indole-3-carboxylic 0433. The title compound was synthesized according to acid (3,3-difluoro-cyclohexylmethyl)-amide (0.09 g, 0.22 the procedure described in Example 2 using 4-Chloro-1-(3. 3-difluoro-propyl)-1H-indole-3-carboxylic acid (150 mg. mmol. 30.6%) as a white solid. 0.54 mmol. 1.00 eq), (1S,3S)-1-Aminomethyl-3-methyl-cy 0428 H NMR (400 uMHz, DMSO-d): 8 8.11 (t, J=5.84 clohexanol (77.41 mg 0.54 mmol. 1.00 eq), Et N (0.23 mL, HZ, 1H), 7.78 (s, 1H), 7.55-7.53 (m. 1H), 7.22-7.13 (m, 2H), 1.62 mmol. 3.00 eq), HOBt (109.54 mg. 0.81 mmol, 1.50 eq), 6.29-5.98 (m, 1H), 4.37 (d. J=7.36 Hz, 2H), 3.21-3.10 (m, EDC (209.30 mg, 1.08 mmol. 2.00 eq) in dry THF to afford 2H), 2.50-2.31 (m, 2H), 2.14 (d. J=9.08 Hz, 1H), 1.97 (s, 1H), 4-Chloro-1-(3.3-difluoro-propyl)-1H-indole-3-carboxylic 1.80-1.74 (m, 3H), 1.55-1.37 (m, 3H), 1.12-0.86 (m. 1H) acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)- ppm, M+H+ 405.2. amide (65 mg, 0.19 mmol. 34.4%) as a white solid.

US 2016/01 68090 A1 Jun. 16, 2016 75

-continued Step 2 Preparation of 4-Chloro-1-dimethylcarbamoylm ethyl-1H-indole-3-carboxylic acid

C NH 0445 F HO F

O C NH N\- / NN Step 1 0446 o-(7-azabenzotriazol-1-yl)-N.N.N',N'-tetramethy luronium hexafluoro-phosphate (84.66 mg; 0.22 mmol; 1.25 eq.) (HATU) was added to a solution of 4-Chloro-1-dimeth Preparation of 4-Chloro-1-dimethylcarbamoylm ylcarbamoylmethyl-1H-indole-3-carboxylic acid (50.00 mg: ethyl-1H-indole-3-carboxylic acid 0.18 mmol; 1.00 eq.), 1-Aminomethyl-4,4-difluoro-cyclo hexanol (32.36 mg; 0.20 mmol; 1.10 eq.) and n,n-diisopro pylethylamine (0.12 ml, 0.71 mmol; 4.00 eq.) in DMF (1.81 ml; 23.54 mmol; 132.13 eq.) at 25°C. The reaction mixture 0442 was stirred overnight and evaporated to dryness under high vacuum. The residue was dissolved in Methanol (8 ml) and water (2 ml) and this solution was submitted to Medium Pressure Liquid Chromatography purification (Yamazen, O Interchim 150 g polymeric Reverse Phase column, basic C OH buffer) to afford the desired product 4-Chloro-1-dimethylcar bamoylmethyl-1H-indole-3-carboxylic acid (4,4-difluoro-1- hydroxy-cyclohexylmethyl)-amide (30.00 mg; 0.07 mmol). "H NMRIM+H 428.1. LC-MS (254 nm) to 3.94 min: N HPLC (254 nm) Purity: >99%; to 3.40 min. \- Example 55 NN Preparation of 4-Chloro-1-diethylcarbamoylmethyl / 1H-indole-3-carboxylic acid (4,4-difluoro-cyclo hexylmethyl)-amide (207) 0447 F

0443 2-chloro-N,N-dimethylacetamide (0.19 ml, 1.84 F mmol; 1.20 eq.) was added to a solution of 4-Chloro-1H indole-3-carboxylic acid (300.00 mg; 1.53 mmol; 1.00 eq.) O and barium hydroxide octahydrate (967.67 mg; 3.07 mmol; C NH 2.00 eq.) in DMF (15.63 ml;202.65 mmol; 132.13 eq) at 50° C. The reaction mixture was stirred overnight. The reaction mixture was diluted with DMSO (1 ml) and water (1 ml) then submitted to MPLC purification (Yamazen, Interchim 100 g N polymeric Reverse Phase column, basic buffer) to afford the desired product 4-Chloro-1-dimethylcarbamoylmethyl-1H \- indole-3-carboxylic acid (426.00 mg, 1.52 mmol) as a white N solid. N/ Y 0444 H NMR (400 uMHz, MeOD) & 7.42 (s, 1H), 6.89 0448. The title compound was synthesized according to 6.79 (m. 1H), 6.78-6.64 (m, 2H), 4.73 (s. 2H), 2.73 (s, 3H), the procedure described in Example 53 using a N,N-diethyl 2.57-2.49 (m, 4H) ppm, M+H" 281.1. LC-MS (254 nm) chloroacetamide (41.21 mg 0.28 mmol; 1.20 eq.) and t=3.47 min: HPLC (254 nm) Purity: >99%; t2.68 min. 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-indole-3- US 2016/01 68090 A1 Jun. 16, 2016 76 carboxamide (75.00 mg; 0.23 mmol; 1.00 eq.) to afford mmol; 1.20 eq.), 4-Chloro-1H-indole-3-carboxylic acid (4.4- 4-Chloro-1-diethylcarbamoylmethyl-1H-indole-3-carboxy difluoro-cyclohexylmethyl)-amide (100.00 mg; 0.31 mmol; lic acid (4,4-difluoro-cyclohexylmethyl)-amide (100.80 mg: 1.00 eq.) and barium hydroxide octahydrate (193.08 mg; 0.61 0.23 mmol) as a white amorphous solid. mmol; 2.00 eq.) in DMF (10 mL) at 50° C. to provide the 0449 H NMR (400 uMHz, CDC1) & 7.72 (s, 1H), 7.31 desired product as a white solid. 7.05 (m, 3H), 6.76 (s, 1H), 4.88 (s. 2H), 3.52-3.29 (m, 5H), 0454 H NMR (400 uMHz, DMSO-d) 8 ppm 8.10 (1H), 2.20-2.01 (m, 2H), 1.97-1.50 (m, 6H), 1.38 (dd, J=23.7, 11.1 7.72 (s, 1H), 7.53 (1H), 7.19 (m, 2H), 5.85 (1H), 3.15 (1H), Hz, 2H), 1.27 (t, J–7.2 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H) ppm: 3.04 (3H), 2.86 (3H), 2.03 (2H), 1.85 (2H), 1.71 (m, 1H), 1.60 M+H" 440.1. LC-MS (254 nm) to 4.77 min: HPLC (254 (2H), 1.25 (m, 2H), m/z: 426 M+H nm.) Purity: 98% Example 58 Example 56 Preparation of 1-(2-AZetidin-1-yl-2-oxo-ethyl)-4- Preparation of 4-Chloro-1-(isopropyl-methyl-car chloro-1H-indole-3-carboxylic acid (4,4-difluoro bamoyl)-methyl)-1H-indole-3-carboxylic acid (4.4- cyclohexylmethyl)-amide (201) difluoro-cyclohexylmethyl)-amide (203) 0455 0450 F F F F O O C NH C NH

N N \- C s 0456. The title compound was synthesized according to 0451. The title compound was synthesized according to the procedure described in Example 54 using 1-azetidin-1- the procedure described in Example 54 using a mixture of yl-2-chloro-ethanone (33.72 mg 0.25 mmol; 1.10 eq.) and 2-chloro-N-isopropyl-n-methylacetamide (41.21 mg; 0.28 (4,4-difluorocyclohexyl)methanamine (75.00 mg 0.23 mmol; 1.20 eq.) and (4.4-difluorocyclohexyl) methanamine mmol; 1.00 eq.) to afford the desired product 1-(2-AZetidin (75.00 mg; 0.23 mmol; 1.00 eq.) to afford the desired product 1-yl-2-oxo-ethyl)-4-chloro-1H-indole-3-carboxylic acid 4-Chloro-1-(isopropyl-methyl-carbamoyl)-methyl)-1H-in (4,4-difluoro-cyclohexylmethyl)-amide (34.50 mg; 0.08 dole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)- mmol). M+H" 424.1 LC-MS (254 nm) to 3.54 min: HPLC amide (35.00 mg; 0.08 mmol). M+H" 440.2 LC-MS (254 (254 nm) Purity: 99.4%; t3.97 min. nm) to 3.94 min: HPLC (254 nm) Purity: 99.0%; to 4.46 1. Example 59 Example 57 Preparation of 4-Chloro-1-(2-oxo-2-pyrrolidin-1-yl ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro Preparation of 4-chloro-N-((4, 4-difluorocyclohexyl) cyclohexylmethyl)-amide (185) methyl)-1-(1-(dimethylamino)-1-oxopropan-2-yl)- 1H-indole-3-carboxamide (200) 0457 0452 F O C N F C NH 2N / NN 0453 The title compound was synthesized according to the procedure described in example 53 using a mixture of 2-Bromo-N,N-dimethyl-propionamide (60.61 mg; 0.37 US 2016/01 68090 A1 Jun. 16, 2016 77

0458. The title compound was synthesized according to 0462. The title compound was synthesized according to the procedure described in Example 54 using a mixture of the procedure described in example 54 using a mixture of 2-chloro-1-pyrrolidin-1-yl-ethanone (37.27 mg; 0.25 mmol; 2-chloro-1-piperidin-1-yl-ethanone (40.81 mg 0.25 mmol; 1.10 eq) and (4,4-difluorocyclohexyl)methanamine (75.00 1.10 eq.) and (4,4-difluorocyclohexyl)methanamine (75.00 mg; 0.23 mmol; 1.00 eq.) to afford the desired product mg; 0.23 mmol; 1.00 eq.) to afford the desired product 4-Chloro-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-1H-indole-3- 4-Chloro-1-(2-oxo-2-piperidin-1-yl-ethyl)-1H-indole-3-car carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (65. boxylic acid (4,4-difluoro-cyclohexylmethyl)-amide (95.00 00 mg. 0.15 mmol). M+H" 438.1. LC-MS (254 nm) to 3.74 mg 0.21 mmol). M+H" 452.1 LC-MS (254 nm) to 4.83 min: HPLC (254 nm) Purity: 99.5%; to 4.18 min. min: HPLC (254 nm) Purity: 99.2%; to 4.53 min. Example 60 Preparation of 4-Chloro-1-(2-morpholin-4-yl-2-oxo Example 62 ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro Preparation of 4-chloro-1-(2-methoxyethyl)-N-((1- cyclohexylmethyl)-amide (190) phenylcyclohexyl) methyl)-1H-indole-3-carboxam 0459 ide (39) F 0463 F

O C NH

1) Raney Ni, H2, MeOH, r.t. N 2) HCl, dioxane C. -e- O \- C OH C. 0460. The title compound was synthesized according to the procedure described in example 53 using a mixture of 4-(bromoacetyl)morpholine (57.30 mg; 0.28 mmol; 1.20 eq.) s and 4-chloro-N-((4,4-difluorocyclohexyl)methyl)-1H-in ON dole-3-carboxamide (75.00 mg; 0.23 mmol: 1.00 eq.) to NHHC - S > afford 4-Chloro-1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-in HATU, DIPEA, DMF dole-3-carboxylic acid (4,4-difluoro-cyclohexylmethyl)- amide (54.00 mg 0.12 mmol) as a white amorphous solid. "H NMR (400 uMHz, CDC1) & 7.69-7.46 (m, 1H), 7.23 (t, J=34.2 Hz, 1H), 4.95 (s, 1H), 3.89-2.96 (m. 1H), 2.13 (s, 1H), 1.83 (d. J–72.4 Hz, 1H), 1.40 (s, 1H), 0.12-0.11 (m, 1H) ppm, M+H" 454.1. LC-MS (254 nm) to 4.35 min: HPLC (254 nm) Purity: 98.7%; t 3.97 min. Example 61 Preparation of 4-Chloro-1-(2-oxo-2-piperidin-1-yl ethyl)-1H-indole-3-carboxylic acid (4,4-difluoro cyclohexylmethyl)-amide (195) ca, 0461) s ON

Step 1 C NH Preparation of (1-phenylcyclohexyl)methanamine hydrochloride 0464

NHHCI US 2016/01 68090 A1 Jun. 16, 2016

0465. To a stirred solution of 1-phenylcyclohexanecarbo F -continued nitrile (0.500g, 2.70 mmol) in methanol (10 mL) was added F Raney Ni (0.100 g). The resulting mixture was stirred at room N temperature under hydrogen atmosphere for 16 h, and then F f| LAH, THF filtered through celite. To the filtrate was added hydrochloric acid (5 mL. 20 mmol. 4LM in dioxane), and the mixture was 60° C., 2h stirred at room temperature for 30 min, then concentrated in vacuo. The residue was triturated by EtOAc (20 mL) and the precipitate was filtered to afford (1-phenylcyclohexyl) O methanamine hydrochloride (0.400 g. 65.8%) as white solid. O C OH Step 2 Preparation of 4-chloro-1-(2-methoxyethyl)-N-((1- F / N phenylcyclohexyl) methyl)-1H-indole-3-carboxam ide N 0466 F NH2 S. o HATU, DIPEA O DMF, r.t., overnight O H C N O

O H C N

F y F / F 0467. The title compound was synthesized according to the procedure described in Example 5 using 4-chloro-1-(2- methoxyethyl)-1H-indole-3-carboxylic acid (0.100 g, 0.40 Step 1 mmol), HATU (0.225 g, 0.59 mmol) and (1-phenylcyclo hexyl) methanamine hydrochloride (0.116 g. 0.51 mmol) in Preparation of 4-(4-(trifluoromethyl) phenyl)-tet DMF (5 mL) to afford 4-chloro-1-(2-methoxyethyl)-N-((1- rahydro-2H-pyran-4-carbonitrile phenylcyclohexyl)methyl)-1H-indole-3-carboxamide (0.130 g, 77%) as a white solid. 0470 0468 H NMR (500 uMHz, DMSO-d): 87.63 (s, 1H), 7.52 (d. J=8.0 Hz, 1H), 7.47 (t, J=6.0 Hz, 1H), 7.43-7.41 (d. F J=8.0 Hz, 2H), 7.34 (t, J–7.5 Hz, 2H), 7.19 (t, J–7.5 Hz, 1H), F 7.15 (t, J=7.5 Hz, 1H), 7.09 (d. J=7.5 Hz, 1H), 4.35 (t, J=5.0 Hz, 2H), 3.64 (t, J=5.5 Hz, 2H), 3.33 (d. J=6.5 Hz, 2H), 3.22 F (s.3H), 2.13-2.10 (m, 2H), 1.73-1.69 (m, 2H), 1.58-1.55 (m, 2H), 1.44 (brs, 1H), 1.36-1.23 (m, 3H) ppm, M+H 425.1. aN Example 63 Preparation of 4-chloro-1-(2-methoxyethyl)-N-(4- (4-(trifluoromethyl) phenyl)-tetrahydro-2H-pyran-4- yl) methyl)-1H-indole-3-carboxamide (80) O 0469 0471 To a stirred solution of 2-(4-(trifluoromethyl)phe nyl)acetonitrile (2.0 g, 10.8 mmol) in DMF (10 mL) was slowly added a suspension of NaH (60%, 0.95g, 23.7 mmol) in DMF (10 mL) at 0°C. under N atmosphere over 10 min, the reaction was allowed to warm to room temperature and "N-1-1- Br stirred for 0.5 h. Then the reaction was cooled to 0°C. and NaH, DMF 2,2'-dibromodiethyl ether (1.5 mL, 11.8 mmol) in DMF (20 mL) was added dropwise over 60 min. The reaction was allowed to warm to room temperature and stirred for 1 h. The US 2016/01 68090 A1 Jun. 16, 2016 79 mixture was quenched with water (30 mL) and extracted with 0.59 mmol), HATU (0.247 g. 0.65 mmol), (4-(4-(trifluorom EtOAc (30 mLX3). The combined organic layer was washed ethyl) phenyl)-tetrahydro-2H-pyran-4-yl) methanamine with water (10 mL) and brine (10 mL), dried over sodium (0.168g, 0.65 mmol), DIPEA (0.3 mL, 1.77 mmol), to afford sulfate, filtered and concentrated in vacuo. The residue was 4-chloro-1-(2-methoxyethyl)-N-(4-(4-(trifluoromethyl) purified with column chromatography on silica gel (petro phenyl)-tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3- leum ether:EtOAc=100:1) to afford 4-(4-(trifluoromethyl) carboxamide (0.205 g, 70%) as an off white solid. phenyl)-tetrahydro-2H-pyran-4-carbonitrile (2.30 g, 83%) as 0476 H NMR (500 uMHz, DMSO-d) & 7.77 (t, J=6.0 red oil. GC-MS: MI" 255; t-10.39 min. HZ, 1H), 7.70-7.68 (m, 2H), 7.65-7.64 (m, 2H), 7.59 (s, 1H), 7.52 (d. J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.09 (t, J=8.0 Step 2 HZ, 1H), 4.35 (t, J=5.0 Hz, 2H), 3.81-3.77 (m, 2H), 3.65 (t, J=5.0 Hz, 2H), 3.52 (d. J=6.0 Hz, 2H), 3.42 (t, J=8.5 Hz, 2H), Preparation of (4-(4-(trifluoromethyl) phenyl)-tet 3.22 (s, 3H), 2.10-2.07 (m, 2H), 2.03-1.96 (m, 2H) ppm: rahydro-2H-pyran-4-yl) methanamine M+H" 495.1. 0472 Example 64 Preparation of 4-chloro-N-((4.4-difluorocyclohexyl) methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (94) 0477

Br O C 0473. To a stirred solution of 4-(4-(trifluoromethyl)phe nyl)-tetrahydro-2H-pyran-4-carbonitrile (1.0g, 3.9 mmol) in N O THF (20 mL) was added lithium aluminium hydride (0.3 g, KOH, DMF 7.8 mmol) in proportions at 0°C., then the reaction was NH 50°() C., overnight stirred at 60° C. for 2 h. After the mixture was cooled to 0°C., methanol (2 mL) was added slowly to quench the reaction. C Magnesium sulfate (0.500 g) was added and the system was stirred at room temperature for 0.5h. The mixture was filtered off through celite and the filtrate was concentrated to afford N (CFCO)2O (4-(4-(trifluoromethyl) phenyl)-tetrahydro-2H-pyran-4-yl) DMF, 50° C., 3 h methanamine (0.55g, 48%) as red oil. M+H" 260.1; LC-MS N Purity (254 nm): >99%; t-1.16 min.

Step 3 O

Preparation of 4-chloro-1-(2-methoxyethyl)-N-(4- F

(4-(trifluoromethyl) phenyl)-tetrahydro-2H-pyran-4- O yl) methyl)-1H-indole-3-carboxamide C F

0474) aq. KOH, EtOH 100° C., overnight O N O H C N 2) O C OH N

F N HOBt, EDCI, DIPEA F DCM, r.t., overnight O-N- F N

0475. The title compound was synthesized according to the procedure described in Example 5 using of 4-chloro-1- 2) (2-methoxyethyl)-1H-indole-3-carboxylic acid (0.150 g, US 2016/01 68090 A1 Jun. 16, 2016 80

-continued 0481 To a stirred solution of 4-chloro-1-(oxetan-3-yl)- O 1H-indole (0.70 g, 3.37 mmol) in DMF (10.0 mL) was added C trifluoroacetic anhydride (1.06 g, 5.05 mmol) at room tem perature. The mixture was stirred at 50° C. for 3 h. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mLX3). The combined extracts were washed with water (10 mL) and brine (10 mL), dried over NaSO concentrated in vacuo to give 1-(4-chloro-1-(oxetan-3-yl)-1H-indol-3-yl)-2, 2.2-trifluoroethanone (0.90 g, 87%) as a purple oil, which was used to next step without further purification. M+H 304.0. Step 3 Step 1 Preparation of 4-chloro-1-(oxetan-3-yl)-1H-indole-3- carboxylic acid Preparation of 4-chloro-1-(oxetan-3-yl)-1H-indole 0482 0478

O C C OH

0483 To a stirred solution of 1-(4-chloro-1-(oxetan-3-yl)- 0479. To a stirred solution of 4-chloro-1H-indole (0.90 g, 1H-indol-3-yl)-2.2.2-trifluoroethanone (0.90 g, 2.96 mmol) 5.93 mmol) and compound 3-bromooxetane (1.22 g, 8.90 in ethanol (5.0 mL) was added 20% aqueous potassium mmol) in DMF (10.0 mL) was added potassium hydroxide hydroxide (10 mL) at room temperature. The mixture was (1.00 g, 17.81 mmol) at room temperature. The mixture was stirred at 100° C. overnight. After being cooled to room stirred at 50° C. overnight. Water (30 mL) was added and the temperature, the mixture was extracted with EtOAc (10 mixture was extracted with EtOAc (30 mLX3). The combined mLX2). The aqueous layer was acidified with concentrated extracts were collected and washed with water (10 mL) and hydrochloric acid (3.0 mL) to pH 2-3, and then extracted with brine (10 mL), dried over NaSO concentrated in vacuo to EtOAc (20 mLX3). The combined organic layer was washed give 4-chloro-1-(oxetan-3-yl)-1H-indole (0.70 g, 47%) as a with brine (10 mL), dried over NaSO concentrated in brown oil, which was used in the next step without further vacuo to give 4-chloro-1-(oxetan-3-yl)-1H-indole-3-car purification. M+H 208.0. boxylic acid (0.60 g, 80%) as a off-white solid, which was used to next step without further purification. M+H 252.0. Step 2 Step 4 Preparation of 1-(4-chloro-1-(oxetan-3-yl)-1H-indol Preparation of 4-chloro-N-((4.4-difluorocyclohexyl) 3-yl)-2.2.2-trifluoroethanone methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide 0480 0484

US 2016/01 68090 A1 Jun. 16, 2016

0485. A mixture of 4-chloro-1-(oxetan-3-yl)-1H-indole Example 66 3-carboxylic acid (0.120g, 0.47 mmol), HOBt (0.070 g., 0.52 mmol), EDCI (0.100 g, 0.52 mmol) and TEA (0.144g, 1.43 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- mmol) in DCM (20 mL) was stirred at room temperature for carboxylic acid (2,2-difluoro-ethyl)-amide (76) 1 h, and then (4.4-difluorocyclohexyl)methanamine (0.71 g, 0490 0.47 mmol) was added thereto. The mixture was stirred at room temperature overnight, and then the Volatiles were removed in vacuo. The residue was dispersed in HO (10 mL) F and extracted with DCM/MeOH (10:1, 30 mLX3). The com bined organic layers were washed with brine (10 mL), dried r-, over NaSO4, and concentrated in vacuo. The residue was C NH purified by column chromatography on silica gel (DCM: MeOH=100: 1) to afford 4-chloro-N-((4,4-difluorocy-clo N hexyl)methyl)-1-(oxetan-3-yl)-1H-indole-3-carboxamide (0.110 g. 60%) as a white solid. 0486 H NMR (500 uMHz, DMSO-d) & 8.18 (t, J=5.5 HZ, 1H), 8.10 (s, 1H), 7.56 (d. J=8.0 Hz, 1H), 7.22-7.16 (m, 2H), 5.83-5.77 (m, 1H), 5.05 (t, J=7.5 Hz, 2H), 4.92 (t, J–7.5 Hz, 2H), 3.16 (t, J=6.5 Hz, 2H), 2.05-1.98 (m, 2H), 1.86-1.69 0491. The title compound was synthesized according to (m, 5H), 1.29-1.17 (m, 2H) ppm, M+H" 383.1; LC-MS the procedure described in Example 5 using a mixture of Purity (254 nm): >99%; to 4.15 min: HPLC Purity (254 nm): 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 >99%; to 4.31 min. mg; 0.30 mmol; 1.00 eq.) and 2,2-difluoroethylamine hydro chloride (52.54 mg. 0.45 mmol; 1.5 eq.) to afford the desired Example 65 product 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2.2-difluoro-ethyl)-amide (89 mg; 0.28 mmol). M+H" 315.1 LC-MS (254 nm) to 3.22 min: HPLC (254 nm) Purity: 4-chloro-N-(cyclohexylmethyl)-1-(oxetan-3-yl)-1H >99%; t3.27 min. indole-3-carboxamide (48) Example 66 0487 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- carboxylic acid (3,3,3-trifluoro-propyl)-amide (77) O C H 0492 N

C NH O

0488. The title compound was synthesized according to the procedure described in Example 2 using 4-Chloro-1-ox etan-3-yl-1H-indole-3-carboxylic acid (200.00 mg 0.79 mmol; 1.00 eq.), C-Cyclohexyl-methylamine (103.46 mg: 0.91 mmol; 1.15 eq.), EDC (198.05 mg: 1.03 mmol: 1.30 eq.), Benzotriazol-1-ol (139.60 mg: 1.03 mmol: 1.30 eq.) and Ethyl-diisopropyl-amine (0.39 ml; 2.38 mmol: 3.00 eq.) in 0493. The title compound was synthesized according to DCM (20 mL) to provide 4-chloro-N-(cyclohexylmethyl)-1- the procedure described in Example 5 using a mixture of (oxetan-3-yl)-1H-indole-3-carboxamide (215, 78%). 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol: 1.00 eq) and 3,3,3-trifluoropropylamine (37. 0489 HNMR (400 uMHz, Chloroform-d) 88.11 (s, 1H), 07 mg; 0.33 mmol; 1.1 eq.) to afford the desired product 7.40 (d. J=8.0 Hz, 1H), 7.32-7.16 (m, 2H), 6.72 (s, 1H), 5.57 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (3,3,3- (p, J=6.9 Hz, 1H), 5.19 (t, J–74 Hz, 2H), 5.06 (t, J=6.7 Hz, trifluoro-propyl)-amide (10 mg; 0.03 mmol). M+H 347.1 2H), 3.38 (t, J=6.3 Hz, 2H), 1.89-1.59 (m, 6H), 1.37-1.14 (m, LC-MS (254 nm) to 3.52 min: HPLC (254 nm) Purity: 4H), 1.05 (qd, J=11.7, 3.1 Hz, 3H). M+H+: 347. 95.79%; t—3.76 min. US 2016/01 68090 A1 Jun. 16, 2016 82

Example 67 Example 69 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- Preparation of 4.4-Chloro-1-oxetan-3-yl-1H-indole carboxylic acid (4,4,4-trifluoro-butyl)-amide (73) 3-carboxylic acid (tetrahydro-pyran-3-ylmethyl)- amide (74) 0494 0498

O C NH C NH

0499. The title compound was synthesized according to 0495. The title compound was synthesized according to the procedure described in Example 5 using a mixture of the procedure described in Example 5 using a mixture of 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and C-(Tetrahydro-pyran-3-yl)- mg; 0.30 mmol; 1.00 eq.) and 4,4,4-trifluorobutylamine (45. methylamine hydrochloride (54.23 mg; 0.36 mmol; 1.20 eq.) 46 mg; 0.36 mmol; 1.20 eq.) to afford the desired product to afford the desired product 4-Chloro-1-oxetan-3-yl-1H-in 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (4.4.4- dole-3-carboxylic acid (tetrahydro-pyran-3-ylmethyl)-amide trifluoro-butyl)-amide (59.0 mg 0.16 mmol). M+H 361.1 (72.0 mg 0.21 mmol). M+H"349.1 LC-MS (254 nm) to 3. LC-MS (254 nm) to 4.48 min: HPLC (254 nm) Purity: 83 min: HPLC (254 nm) Purity: >99%; to 3.18 min. 99.82%; to 4.03 min. Example 70 Example 68 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- carboxylic acid (1-hydroxy-cyclopentylmethyl)- carboxylic acid (2-ethoxy-propyl)-amide (78) amide (81) 0496 0500

O C C NH

0497. The title compound was synthesized according to 0501. The title compound was synthesized according to the procedure described in Example 5 using a mixture of the procedure described in Example 5 using a mixture of 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (100.00 mg; 0.40 mmol; 1.00 eq.) and 2-Ethoxy-propylamine (100.00 mg; 0.40 mmol; 1.00 eq.) and 1-(aminomethyl)cy hydrochloride (27.74 mg; 0.2 mmol: 0.5 eq.) to afford the clopentanol (22.88 mg; 0.2 mmol: 0.5 eq.) to afford the desired product 4-Chloro-1-oxetan-3-yl-1H-indole-3-car desired product 4-Chloro-1-oxetan-3-yl-1H-indole-3-car boxylic acid (2-ethoxy-propyl)-amide (8.00 mg; 0.02 mmol). boxylic acid (1-hydroxy-cyclopentylmethyl)-amide (40.0 M+H" 337.1 LC-MS (254 nm) to 4.14 min: HPLC (254 mg 0.11 mmol). M+H" 349.1 LC-MS (254 nm) to 3.12 nm.) Purity: 96.69%; t3.50 min. min: HPLC (254 nm) Purity: 97.70%; t3.20 min. US 2016/01 68090 A1 Jun. 16, 2016 83

Example 71 Example 73 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- Preparation of trans-4-Chloro-1-oxetan-3-yl-1H carboxylic acid 2-(2-methyl-dioxolan-2-yl)-ethyl indole-3-carboxylic acid-2-hydroxy-cyclohexylm amide (71) ethyl)-amide (87) 0502 0506

O O o, / t" O C NH C NH HO

N N

O O 0507. The title compound was synthesized according to 0503. The title compound was synthesized according to the procedure described in Example 5 using a mixture of the procedure described in Example 5 using a mixture of 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 (100.00 mg 0.40 mmol; 1.00 eq) and trans-2-aminomethyl mg; 0.30 mmol; 1.00 eq.) and 2-methyl-1,3-dioxolane-2- 1-cyclohexanol (61.61 mg; 0.48 mmol; 1.20 eq.) to afford the ethanamine (46.91 mg; 0.36 mmol; 1.20 eq.) to afford the desired product trans-4-Chloro-1-oxetan-3-yl-1H-indole-3- desired product 4-Chloro-1-oxetan-3-yl-1H-indole-3-car carboxylic acid-2-hydroxy-cyclohexylmethyl)-amide boxylic acid 2-(2-methyl-1,3dioxolan-2-yl)-ethyl-amide (121.50 mg. 0.33 mmol). H NMR (400 uMHz, DMSO) & (26.0 mg; 0.07 mmol). M+H"365.2 LC-MS (254 nm) to 3. 8.12 (s, 1H), 8.03 (t, J=5.8 Hz, 1H), 7.64-7.51 (m, 1H), 87 min: HPLC (254 nm) Purity: 98.94%; t3.22 min. 7.29-7.12 (m, 2H), 5.88-5.72 (m, 1H), 5.07 (t, J=7.3 Hz, 2H), 4.93 (td, J=6.6, 3.3 Hz, 2H), 4.75 (d. J–4.8 Hz, 1H), 3.43 (dt, Example 72 J=13.2, 4.6 Hz, 1H), 3.36-3.26 (m. 1H), 3.19 (dt, J=14.2, 4.7 HZ, 1H), 1.83 (m, 2H), 1.74-1.55 (m, 2H), 1.40 (m. 1H), Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- 1.28-0.92 (m, 4H); M+H" 363.1 LC-MS (254 nm) to 3.30 carboxylic acid (2-cyclopentyl-ethyl)-amide (82) min: HPLC (254 nm) Purity: >99%; t3.55 min. 0504 Example 74 Step 4 Preparation of cis-4-Chloro-1-oxetan-3-yl-1H-in dole-3-carboxylic acid (1R,2R)-2-hydroxy-cyclo hexylmethyl)-amide (88) C NH 0508

O C NH HO O

0505. The title compound was synthesized according to the procedure described in Example 5 using a mixture of N 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (100.00 mg; 0.40 mmol; 1.00 eq.) and 2-cyclopentyl-ethy lamine (22.49 mg; 0.2 mmol: 0.5 eq.) to afford the desired product 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic O acid (2-cyclopentyl-ethyl)-amide (35.0 mg; 0.1 mmol). 0509. The title compound was synthesized according to M+H" 347.2 LC-MS (254 nm) to 4.23 min: HPLC (254 the procedure described in Example 5 using 4-Chloro-1-ox nm.) Purity: 95.97%; to 4.65 min. etan-3-yl-1H-indole-3-carboxylic acid (100.00 mg 0.40 US 2016/01 68090 A1 Jun. 16, 2016 mmol; 1.00 eq.), cis-2-aminomethyl-cyclohexanol hydro 0513. The title compound was synthesized according to chloride (65.83 mg: 0.40 mmol; 1.00 eq) and HATU (188.86 the procedure described in Example 5 using a mixture of mg: 0.50 mmol; 1.25 eq.), and N,N-diisopropylethylamine 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 (0.20 ml, 1.19 mmol: 3.00 eq.) in DMF (4.05 ml:52.50 mmol; mg; 0.30 mmol; 1.00 eq) and 1-(aminomethyl)cyclohexanol 132.13 eq.) to afford the desired product cis-4-Chloro-1- (42.35 mg; 0.33 mmol; 1.10 eq.) to afford the desired product oxetan-3-yl-1H-indole-3-carboxylic acid (1R,2R)-2-hy 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-hy droxy-cyclohexylmethyl)-amide (86.50 mg 0.24 mmol). H droxy-cyclohexylmethyl)-amide (49.0 mg; 0.14 mmol). NMR (400 uMHz, DMSO) & 8.12 (s, 1H), 8.07 (t, J=5.9 Hz, M+H 363.2 LC-MS (254 nm) to 4.12 min: HPLC (254 1H), 7.64-7.52 (m. 1H), 7.28-7.12 (m, 2H), 5.87-5.72 (m, nm.) Purity: >99%; to 3.53 min. 1H), 5.06 (t, J=7.3 Hz, 2H), 4.93 (td, J=6.7, 1.7 Hz, 2H), 4.36 (t, J=7.3 Hz, 1H), 3.85 (s, 1H), 3.35-3.23 (m. 1H), 3.19-3.04 Example 77 (m. 1H), 1.77-1.48 (m, 4H), 1.46-1.29 (m, 4H), 1.27-109 (m, 1H); M+H" 363.1 LC-MS (254 nm) to 3.36 min: HPLC Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- (254 nm) Purity: 98.8%; t3.57 min carboxylic acid (1S,4R)-1-bicyclo[2.2.1]hept-2- ylmethyl)-amide (59) Example 75 0514 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- carboxylic acid (2-cyclopentyloxy-ethyl)-amide (72) O H C N 0510)

--> N O - C NH O 0515. The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 N mg; 0.30 mmol; 1.00 eq.) and c-bicyclo[2.2.1]hept-2-yl-me thylamine hydrobromide (67.57 mg; 0.33 mmol; 1.10 eq.) to afford the desired product 4-Chloro-1-oxetan-3-yl-1H-in O dole-3-carboxylic acid (1S,4R)-1-bicyclo[2.2.1]hept-2-yl methyl)-amide (65.0 mg. 0.18 mmol). M+H"360.2 LC-MS 0511. The title compound was synthesized according to (254 nm) to 5.14 min: HPLC (254 nm) Purity: >99%; to 4. the procedure described in Example 5 using a mixture of 67 min. 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 2-(cyclopentyloxy)ethylamine Example 78 (46.20 mg; 0.36 mmol; 1.20 eq.) to afford the desired product 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (2-cy Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- clopentyloxy-ethyl)-amide (37.0 mg 0.10 mmol). M+H" carboxylic acid (S)-1-cyclohexyl-2.2.2-trifluoro 363.2 LC-MS (254 nm) to 4.86 min: HPLC (254 nm) Purity: ethyl)-amide (52) >99%; to 4.11 min. 0516 Example 76 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- carboxylic acid (1-hydroxy-cyclohexylmethyl)-

amide (58) C 0512

O H C N N N HO

N O 0517. The title compound was synthesized according to the procedure described in Example 5 using a mixture of O 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq) and 1-(aminomethyl)cyclohexanol US 2016/01 68090 A1 Jun. 16, 2016

(56.70 mg; 0.31 mmol; 1.05 eq.) to afford the desired product dole-3-carboxylic acid (3-trifluoromethyl-cyclohexylm 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (S)-1- ethyl)-amide (93.3 mg; 0.22 mmol). M+H" 415.0 LC-MS cyclohexyl-2.2.2-trifluoro-ethyl)-amide (19.7 mg; 0.05 (254 nm) to 5.13 min: HPLC (254 nm) Purity: >99%; to 4. mmol). M+H" 415.0 LC-MS (254 nm) to 5.61 min: HPLC 01 min. (254 nm) Purity: >99%; t5.27 min. Example 81 Example 79 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- carboxylic acid ((R)-1-cyclohexyl-2-hydroxy-ethyl)- carboxylic acid (4-trifluoromethyl-cyclohexylm amide (63) ethyl)-amide (53) 0522 0518 F HO F O F C NH O C NH

O 0523 The title compound was synthesized according to 0519. The title compound was synthesized according to the procedure described in Example 5 using a mixture of the procedure described in Example 5 using a mixture of 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and d-cyclohexylglycinol (46.95 mg; 0.30 mmol; 1.00 eq.) and 1-aminomethyl-4-trifluorom mg; 0.33 mmol; 1.10 eq.) to afford the desired product ethylcyclohexane (56.70 mg 0.31 mmol: 1.05 eq.) to afford 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid ((R)-1- the desired product 4-Chloro-1-oxetan-3-yl-1H-indole-3- cyclohexyl-2-hydroxy-ethyl)-amide (75.0 mg; 0.20 mmol). carboxylic acid (4-trifluoromethyl-cyclohexylmethyl)-amide M+H 377.2 LC-MS (254 nm) t—4.39 min: HPLC (254 (85.5 mg:0.21 mmol). M+H 415.0 LC-MS (254 nm) to 5. nm.) Purity: >99%; to 3.94 min. 11 min: HPLC (254 nm) Purity: >99%; to 4.79 min Example 82 Example 80 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- carboxylic acid (2-cyclopentyl-2-hydroxy-propyl)- carboxylic acid (3-trifluoromethyl-cyclohexylm amide (49) ethyl)-amide (56) 0524 0520

O F C NH O F F C NH OH

N N

O 0521. The title compound was synthesized according to O the procedure described in Example 5 using a mixture of 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 0525. The title compound was synthesized according to mg; 0.30 mmol: 1.00 eq.) and 3-(trifluoromethyl)cyclo the procedure described in Example 5 using a mixture of hexylmethanamine (56.70 mg; 0.31 mmol: 1.05 eq.) to 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 afford the desired product 4-Chloro-1-oxetan-3-yl-1H-in mg; 0.30 mmol; 1.00 eq.) and 1-amino-2-cyclopentylpropan US 2016/01 68090 A1 Jun. 16, 2016

2-ol (42.68 mg; 0.30 mmol; 1.00 eq.) to afford the desired dole-3-carboxylic acid (1S,2S4S)-2-bicyclo[2.2.1]hept-5- product 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic en-2-yl-ethyl)-amide (53.0 mg; 0.14 mmol). M+H 371.2 acid (2-cyclopentyl-2-hydroxy-propyl)-amide (86.6 mg: LC-MS (254 nm) to 5.16 min: HPLC (254 nm) Purity: 0.23 mmol). M+H 377.1 LC-MS (254 nm) to 3.63 min: 97.14%; to 4.75 min. HPLC (254 nm) Purity: >99%; t3.90 min. Example 85 Example 83 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- carboxylic acid (2-cyclopentyl-2-methyl-propyl)- carboxylic acid (1-hydroxy-cycloheptylmethyl)- amide (50) amide (65) 0530 0526

O H C N

N HO O C NH N

O N 0527 The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.30 mmol; 1.00 eq.) and 1-Aminomethyl-cycloheptanol O hydrochloride (64.26 mg; 0.36 mmol; 1.20 eq.) to afford the 0531. The title compound was synthesized according to desired product 4-Chloro-1-oxetan-3-yl-1H-indole-3-car the procedure described in Example 5 using a mixture of boxylic acid (2-cyclopentyl-2-phenyl-ethyl)-amide (24.0 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.06 mmol). M+H" 377.1 LC-MS (254 nm) to 4.37 mg; 0.30 mmol: 1.00 eq.) and 2-cyclopentyl-2-methylpro min: HPLC (254 nm) Purity: >99%; t3.81 min. pan-1-amine (42.10 mg 0.30 mmol; 1.00 eq.) to afford the desired product 4-Chloro-1-oxetan-3-yl-1H-indole-3-car Example 84 boxylic acid (2-cyclopentyl-2-methyl-propyl)-amide (76.4 mg 0.20 mmol). M+H" 375.2 LC-MS (254 nm) to 4.69 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- min: HPLC (254 nm) Purity: >99%; to 5.21 min. carboxylic acid (1S,2S,4S)-2-bicyclo[2.2.1]hept-5- en-2-yl-ethyl)-amide (75) Example 86 0528 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- carboxylic acid (1-cyclohexyl-cyclopropyl)-amide (55) 0532

O A C NH O C NH

0529. The title compound was synthesized according to O the procedure described in Example 5 using a mixture of 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 0533. The title compound was synthesized according to mg; 0.30 mmol; 1.00 eq.) and 2-(1S,2S.4s)-bicyclo[2.2.1 the procedure described in Example 5 using a mixture of hept-5-en-2-yl)ethanamine (46.20 mg; 0.36 mmol; 1.20 eq.) 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 to afford the desired product 4-Chloro-1-oxetan-3-yl-1H-in mg; 0.30 mmol; 1.00 eq.) and 1-Cyclohexyl-cyclopropy US 2016/01 68090 A1 Jun. 16, 2016 lamine hydrochloride (57.6 mg 0.33 mmol; 1.10 eq.) to mantan-1-yl-ethyl)-amide (84.0 mg; 0.20 mmol). M+H" afford the desired product 4-Chloro-1-oxetan-3-yl-1H-in 413.2 LC-MS (254 nm) to 5.98 min: HPLC (254 nm) Purity: dole-3-carboxylic acid (1-cyclohexyl-cyclopropyl)-amide >99%; t5.45 min. (42.5 mg: 0.11 mmol). M+H 473.2 LC-MS (254 nm) to 5. 39 min: HPLC (254 nm) Purity: >99%; to 4.84 min. Example 89 Example 87 Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- carboxylic acid (3-hydroxy-adamantan-1-yl)-ethyl Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- amide (61) carboxylic acid (1-hydroxy-3,3-dimethyl-cyclohexy lmethyl)-amide (64) 0538

0534

O H C N

O N HO C

N O 0535 The title compound was synthesized according to the procedure described in Example 5 using a mixture of O 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 0539. The title compound was synthesized according to mg; 0.30 mmol; 1.00 eq.) and 1-Aminomethyl-3,3-dimethyl the procedure described in Example 5 using a mixture of cyclohexanol (56.24 mg. 0.36 mmol; 1.20 eq.) to afford the 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 desired product 4-Chloro-1-oxetan-3-yl-1H-indole-3-car mg; 0.30 mmol; 1.00 eq.) and (1S,3R,5R,7S)-3-(1-Amino boxylic acid (1-hydroxy-3,3-dimethyl-cyclohexylmethyl)- ethyl)-adamantan-1-olhydrochloride (75.98 mg; 0.33 mmol; amide (105.9 mg; 0.27 mmol). M+H" 391.2 LC-MS (254 1.10 eq.) to afford the desired product 4-Chloro-1-oxetan-3- nm) to 4.77 min: HPLC (254 nm) Purity: >99%; to 4.28 y1-1H-indole-3-carboxylic acid (3-hydroxy-adamantan-1- 1. yl)-ethyl-amide (96.0 mg; 0.22 mmol). M+H" 429.2 LC MS (254 nm) to 4.24 min: HPLC (254 nm) Purity: >99%; Example 88 t=3.75 min. Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- Example 90 carboxylic acid (1-adamantan-1-yl-ethyl)-amide (62) Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- 0536 carboxylic acid (1-adamantan-1-yl-1-methyl-ethyl)- amide (54) (0540 H H

O C NH

N O 0537. The title compound was synthesized according to the procedure described in Example 5 using a mixture of 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 O mg; 0.30 mmol; 1.00 eq.) and rimantadine hydrochloride 0541. The title compound was synthesized according to (70.73 mg; 0.33 mmol; 1.10 eq.) to afford the desired product the procedure described in Example 5 using a mixture of 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (1-ada 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 US 2016/01 68090 A1 Jun. 16, 2016 mg; 0.30 mmol; 1.00 eq.) and 1-Adamantan-1-yl-1-methyl 0545. The title compound was synthesized according to ethylamine hydrochloride (75.33 mg; 0.33 mmol; 1.1 eq.) to the procedure described in Example 5 using a mixture of afford the desired product 4-Chloro-1-oxetan-3-yl-1H-in 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 dole-3-carboxylic acid (1-adamantan-1-yl-1-methyl-ethyl)- mg; 0.30 mmol; 1.00 eq.) and (2-cyclopentyl-2-phenylethyl) amide (78.0 mg: 0.18 mmol). M+H" 427.2 LC-MS (254 amine (67.70 mg 0.36 mmol; 1.20 eq.) to afford the desired nm) to 5.30 min: HPLC (254 nm) Purity: >99%; to 5.84 product 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic 1. acid (2-cyclopentyl-2-phenyl-ethyl)-amide (24.0 mg; 0.06 mmol). M+H" 423.2 LC-MS (254 nm) to 5.71 min: HPLC Example 91 (254 nm) Purity: >99%; to 5.35 min. Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- Example 93 carboxylic acid (cyclohexyl-thiophen-2-yl-methyl)- amide (60) 4-chloro-N-(2-(1-hydroxycyclopentyl)ethyl)-1-(ox etan-3-yl)-1H-indole-3-carboxamide (45) 0542

(0546

O C H OH N

O 0547. The title compound was synthesized according to O the procedure described in Example 2 using 4-Chloro-1-ox 0543. The title compound was synthesized according to etan-3-yl-1H-indole-3-carboxylic acid (200.00 mg 0.79 the procedure described in Example 5 using a mixture of mmol; 1.00 eq.), 1-(2-Amino-ethyl)-cyclopentanol (118.08 4-Chloro-1-oxetan-3-yl-1H-indole-3-carboxylic acid (75.00 mg; 0.91 mmol; 1.15 eq.), 3-Dimethylamino-propyl)-ethyl mg; 0.30 mmol; 1.00 eq.) and C-Cyclohexyl-C-thiophen-2- carbodiimide hydrochloride (198.05 mg: 1.03 mmol; 1.30 yl-methylamine hydrochloride (75.98 mg; 0.33 mmol; 1.10 eq.), Benzotriazol-1-ol (139.60 mg, 1.03 mmol: 1.30 eq.) and eq.) to afford the desired product 4-Chloro-1-oxetan-3-yl Ethyl-diisopropyl-amine (0.39 ml; 2.38 mmol: 3.00 eq.) to 1H-indole-3-carboxylic acid (cyclohexyl-thiophen-2-yl-me obtain the title compound (230, 80%). thyl)-amide (98.0 mg; 0.23 mmol). M+H" 429.1 LC-MS (0548 H NMR (400 uMHz, DMSO-d) & 8.10 (s, 1H), (254 nm) to 5.69 min: HPLC (254 nm) Purity: >99%; t5. 8.01 (t, J=5.6 Hz, 1H), 7.56 (d. J–7.5 Hz, 1H), 7.35-7.07 (m, 32 min. 2H), 5.80 (p. J=6.9 Hz, 1H), 5.06 (t, J=7.2 Hz, 2H), 4.92 (t, J=6.6 Hz, 2H), 3.50-3.31 (m, 2H), 2.02-1.39 (m, 10H). Example 92 M+H+: 363. Preparation of 4-Chloro-1-oxetan-3-yl-1H-indole-3- Example 94 carboxylic acid (2-cyclopentyl-2-phenyl-ethyl)- amide (70) 4-chloro-N-(1-cyclopentyl-2.2.2-trifluoroethyl)-1- (oxetan-3-yl)-1H-indole-3-carboxamide (42) 0544 0549

O C N

C NH N F F F N

O 0550 The title compound was synthesized according to the procedure described in Example 2 using 4-Chloro-1-ox etan-3-yl-1H-indole-3-carboxylic acid (175.00 mg 0.70

US 2016/01 68090 A1 Jun. 16, 2016 97

0629. The title compound was synthesized according to 0633. The title compound was synthesized according to the procedure described in Example 5 using 4-Chloro-1-(tet the procedure described in Example 5 using a mixture of rahydro-furan-3-yl)-1H-indole-3-carboxylic acid (75.00 mg: 4-Chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic 0.28 mmol: 1.00 eq.), HATU (214.67 mg: 0.56 mmol; 2.00 acid 3 (75.00 mg; 0.28 mmol; 1.00 eq.) and n-(2-amino-1- eq.), 3-(trifluoromethyl)cyclohexylmethanamine (53.71 cyclohexylethyl)-n, n-dimethylamine (50.47 mg; 0.30 mmol; mg; 0.30 mmol: 1.05 eq.) and n,n-diisopropylethylamine (DI 1.05 eq.) to afford the desired product 4-Chloro-1-(tetrahy PEA) (0.19 ml: 1.13 mmol; 4.00 eq.) in DMF (2.88 ml:37.30 dro-furan-3-yl)-1H-indole-3-carboxylic acid (2-cyclohexyl mmol; 132.13 eq) to afford the desired product 4-Chloro-1- 2-dimethylamino-ethyl)-amide (51 mg; 0.12 mmol). M+H" (tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (3-trif. 418.1 LC-MS (254 nm) to 2.97 min: HPLC (254 nm) Purity: luoromethyl-cyclohexylmethyl)-amide (75.00 mg 0.17 96.30%; t3.37 min. mmol)). M+H" 429.2: LC-MS (254 nm) to 4.39 min: HPLC (254 nm) Purity: 97.53%; t-97.53 min. Example 123 Example 121 Preparation of 4-Chloro-1-(tetrahydro-furan-3-yl)- 1H-indole-3-carboxylic acid ((1R,4S)-1-bicyclo[2.2. Preparation of 4-Chloro-1-(tetrahydro-furan-3-yl)- 1 hept-2-yl-ethyl)-amide (109) 1H-indole-3-carboxylic acid (1-cyclohexyl-3-hy droxy-propyl)-amide (110) 0634)

0630

HO O C O C NH

N N

O O 0635. The title compound was synthesized according to 06.31 The title compound was synthesized according to the procedure described in Example 5 using a mixture of the procedure described in Example 5 using a mixture of 4-Chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic 4-Chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (75.00 mg; 0.28 mmol; 1.00 eq.) and 1-bicyclo[2.2.1 acid (75.00 mg; 0.28 mmol; 1.00 eq.) and 3-amino-3-cyclo hept-2-yl-ethylamine hydrochloride (52.08 mg; 0.30 mmol; hexyl-propan-1-ol (46.61 mg; 0.30 mmol; 1.05 eq.) to afford 1.05 eq.) to afford the desired product 4-Chloro-1-(tetrahy the desired product 4-Chloro-1-(tetrahydro-furan-3-yl)-1H dro-furan-3-yl)-1H-indole-3-carboxylic acid ((1R,4S)-1-bi indole-3-carboxylic acid (1-cyclohexyl-3-hydroxy-propyl)- cyclo[2.2.1]hept-2-yl-ethyl)-amide (52.0 mg; 0.13 mmol). amide (19.0 mg; 0.05 mmol). M+H" 405.3 LC-MS (254 M+H 387.1 LC-MS (254 nm) t—5.56 min: HPLC (254 nm) to 3.92 min: HPLC (254 nm) Purity: >99%; t 4.31 nm.) Purity: >99%; t5.10 min. 1. Example 124 Example 122 Preparation of 4-Chloro-1-(tetrahydro-furan-3-yl)- 1H-indole-3-carboxylic acid (2-cyclopentyl-ethyl)- Preparation of 4-Chloro-1-(tetrahydro-furan-3-yl)- 1H-indole-3-carboxylic acid (2-cyclohexyl-2-dim amide (108) ethylamino-ethyl)-amide (111) 0636 0632

C N C NH US 2016/01 68090 A1 Jun. 16, 2016

0637. The title compound was synthesized according to 0641. The title compound was synthesized according to the procedure described in Example 5 using a mixture of the procedure described in Example 5 using a mixture of 4-Chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic 4-Chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid 3 (75.00 mg; 0.28 mmol; 1.00 eq.) and 2-Cyclopentyl acid (75.00 mg; 0.28 mmol; 1.00 eq) and 1-Aminomethyl-3, ethylamine hydrochloride (46.47 mg; 0.31 mmol; 1.10 eq.) to 3-dimethyl-cyclohexanol hydrochloride (65.62 mg; 0.34 afford the desired product 4-Chloro-1-(tetrahydro-furan-3- mmol; 1.20 eq.) to afford the desired product 4-Chloro-1- yl)-1H-indole-3-carboxylic acid (2-cyclopentyl-ethyl)- (tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (4,4-di amide (40.0 mg: 0.11 mmol). M+H" 361.1 LC-MS (254 fluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide (58.0 nm) to 4.39 min: HPLC (254 nm) Purity: >99%; to 4.06 mg 0.14 mmol). M+H" 427.1 LC-MS (254 nm) to 3.72 1. min: HPLC (254 nm) Purity: 97.07%; to 4.09 min. Example 125 Example 127 Preparation of 4-Chloro-1-(tetrahydro-furan-3-yl)- Preparation of 4-Chloro-1-(tetrahydro-furan-3-yl)- 1H-indole-3-carboxylic acid (1-hydroxy-3,3-dim 1H-indole-3-carboxylic acid (4,4-difluoro-1-hy ethyl-cyclohexylmethyl)-amide (107) droxy-cyclohexylmethyl)-amide (104) 0638 0642

HO F HO F O C NH O C NH

N N

O O 0643. The title compound was synthesized according to 0639. The title compound was synthesized according to the procedure described in Example 5 using a mixture of the procedure described in Example 5 using a mixture of 4-Chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic 4-Chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid3 (75.00 mg; 0.28 mmol: 1.00 eq.) and 1-Aminomethyl acid3 (75.00 mg 0.28 mmol: 1.00 eq.) and 1-Aminomethyl 4,4-difluoro-cyclohexanol hydrochloride (68.30 mg 0.34 3.3-dimethyl-cyclohexanol hydrochloride (65.62 mg; 0.34 mmol; 1.20 eq.) to afford the desired product 4-Chloro-1- mmol; 1.20 eq.) to afford the desired product 4-Chloro-1- (tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (4,4-di (tetrahydro-furan-3-yl)-1H-indole-3-carboxylic acid (1-hy fluoro-1-hydroxy-cyclohexylmethyl)-amide (45.0 mg; 0.11 droxy-3,3-dimethyl-cyclohexylmethyl)-amide (51.0 mg: mmol). M+H" 413.1 LC-MS (254 nm) to 3.54 min: HPLC 0.13 mmol). M+H" 405.2 LC-MS (254 nm) to 4.10 min: (254 nm) Purity: 96.35%; to 3.82 min. HPLC (254 nm) Purity: 97.80%; to 4.50 min. Example 128 Example 126 Preparation of 4-Chloro-1-(tetrahydro-furan-3-yl)- Preparation of 4-Chloro-1-(tetrahydro-furan-3-yl)- 1H-indole-3-carboxylic acid (1S,4R)-1-bicyclo[2.2. 1H-indole-3-carboxylic acid (4,4-difluoro-1-hy 1 hept-2-ylmethyl)-amide (105) droxy-3-methyl-cyclohexylmethyl)-amide (106) 0644

0640

HO F O C F O C NH

N O 0645. The title compound was synthesized according to O the procedure described in Example 5 using a mixture of 4-Chloro-1-(tetrahydro-furan-3-yl)-1H-indole-3-carboxylic