SA08290382B1 - 1Cyanocyclopropyl Derivatives Comprising a Tricyclic Ring System and Their - Google Patents

Abstract

Abstract The present invention relates to compounds and formulations for the treatment of diseases related to cysteine protease activity. These compounds are reversible cysteine protease inhibitors and include cathepsins B, K, C, F, H, L, O, S, W and X. In particular, diseases related to cathepsins K.

Description

_ Y — Cyanocyclopropyl Derivatives Comprising a Tricyclic Ring System and Their Use in Treatment

Use in Therapy Full Description BACKGROUND: The present invention relates to compounds and formulations for the treatment of diseases related to cysteine protease activity. These compounds are reversible inhibitors of ccysteine protease enzymes and include cathepsins 8©; “Fs” agents Cy and 11; “Ly and ©; and 5; and 17 and 2. In particular diseases related to K cathepsins© In addition; This invention also discloses processes for the preparation of these inhibitors. K cathepsins are a member of the papain family of cysteine protease enzymes that also includes Cy B cathepsins, Hy, A, A, 0, 5, F/L1, and G. K cathepsins is a lysosomal collagenase-like enzyme that Las is highly expressed in costeoclast cells and plays a role as Lala in the inversion and degradation of organic bone matrix. bone organic matrix is involved in skeletal growth but also in diseases. In this regard, K cathepsin inhibitors can be useful agents in the treatment of, for example, but not limited to; osteoporosis, costeoarthritis, asthma, rheumatoid arthritis, and

metastatic bone disease, osteolytic bone cancer, and neuropathic pain related to bone. General description of the invention: Therefore, the present invention provides a compound of formula (1) 7 R o NR N= 0 R'R'N 1 m 0 0 where: A is an aliphatic ring in which © to 1 atoms optionally containing a double bond and optionally including an oxygen atom as a ring member and optionally substituting with up to three individually selected substitution groups of halogen 0 and the eloquence 0 and the success of his efforts 0; R is hydrogen or alkyl ©; R' and 182 with their attached nitrogen atom form a partially unsaturated heterocyclic or monocyclic ring having from © to 7 atoms; This ring shares one atom with the partially unsaturated or unsaturated Léa or second monocyclic saturated ring to form a 1 thicyclic ring system, and the bicyclic ring system participates in

—_— p_ at least one atom with a saturated third ring; or partially unsaturated or unsaturated to form a tricyclic ring system comprising up to 19 ring atoms » whereby the tricyclic ring system optionally includes up to five hetero-atoms each selected on sharpness of an atom©; or 5 or 7 and optional substituents with up to three 0 substituent groups individually selected from: “phenyl,” “benzyl,” “naphthyl,” “alkyl,” “C,”alkenyl, or “C,alkenyl” deaf money or “cyano” or “NO, J” OR® J “COOR' Jf halogen R OR' R “CONR'R® R NR'R® R heteroaryl 0 C, salkanesulfonyl- monocyclic with up to 7 ring atoms; Jl heteroaryl bicyclic rings include up to “carbon 33 11 0” and the cyclic system ok the rings optionally substituted on adjacent carbon atoms with the -0-008(0-0-) group; Cus 18 expresses a hydrogen atom or chalogen to form de gana -1,3 .dioxolo and where 0) is “phenyl de ganas” and “benzyl s Casalkynyl s 1 Cogalkenyl x Ci alkyl s cnaphthyl 1 optionally substituted with up to three individually selected substituent groups of «NR'R'; terrestrial halogen «CONR'R'; restoration (NSO,R' 5 “SONR'R*s OR'; 10083 and the Cis alkyl ic gana itself is optionally substituted by up to three individually selected substitution groups (NR'R' 5 «SO,R' 5 «cyano 3 «halogen «CONR'R® s NR'COR' 5 {NSO,R? 5 «SO,NR'R'

C(7) as monocyclic heteroaryl or bicyclic Al rings 17616 » optionally substituted with up to three individually selected substitution groups (NR'COR' 5 (NSO,R? 3 «<SO,NR*R' 5 (NR'R' 5 thalogen) RotCameron. “OR? 5 «cyano 5 «SO,R' and optionally substituted with phenyl itself with Up to three ©chalogen groups or SOR? or be with an alkyl group of is an optional substitution of up to three individually selected substitution groups of «SO,NR'R' 5 <SO,R' 5 “cyano s halogen (NR'R® 3 0106083 <(NSO,R') RAPPAROMEMBLED RACK 5 “CONR'R® 183 hydrogen and coronal heteroaryl 5 “phenyl 5 ¢ Cs. scarbocyclyl y monocyclic or a monocyclic saturated heterocyclic ring having from ; to V 0 atoms comprising up to three hetero-atoms each selected individually from 0; or 8 or “ISN where each of the alkyl mb heteroaryl s phenyl monocyclic 100068 can be optionally substituted by up to three individually selected groups of actuators and labels” 3 NSO;R? 5 «SO,NR'R' 5 ¢NR*R' 5 «CONR'R' 17 and 8 separately express hydrogen and abolites of 5 heteroaryl 5 «COR® monocyclic Vo comprising up to 7 ring atoms or bicyclic heteroaryl comprising up to 11 ring atoms or forming with its attached nitrogen atom a saturated monocyclic heterocyclic ring having from 1 to 1 © atoms optionally comprising up to three additional, individually selected hetero-rings from the © atoms; OR 5 OR 17 and has an optional substitution of a Crealkyl group which has an optional substitution of NRR” AREY:

85 and 17 separately express “Cis alkyl sf hydrogen or with nitrogen attached to a saturated heterocyclic monocyclic ring end having from © to 7 atoms optionally comprising up to three additional heteroatoms each selected separately from the © atoms; Or 5 or oN and salts thereof are pharmaceutically acceptable.

0 in the context of the current specification; unless otherwise indicated; The alkyl group or alkynyl i alkenyl or the alkenyl moiety can be “alkyl” or “alkynyl” in a linear or branched substituent group however references to individual alkyl groups such as 'propyl' is specific to the straight string version only; References to individual branched chain alkyl groups t= Jie butyl are specific to the branched chain version only. For example (JU) includes "annoldi," examples

methyl, ethyl, propyl and isopropyl 0 includes Crealkyl ibd 'Craalkyl examples' and additionally 'pentyl s' t-butyl and <2,3-dimethylpropyl and 3-methylbutyl hexyl Cy alkyl examples include Cre alkyl' and additionally: heptyl, 2,3-dimethylpentyl, 1-propylbutyl, and rah. Similar convention applies to gil expressions (eg “C,xalkenyl” includes vinyl, allyl, 1-propenyl , 2-butenyl, 3-butenyl, 3-methylbut-1- enyl, 1-pentenyl and 4-hexenyl and examples of “Casalkynyl” includes ethynyl, 1-propynyl, 3-butynyl, 2-pentynyl and 1-methylpent-2-ynyl. partially saturated loja or unsaturated containing between ?£5 cyclic carbon atoms;

The existence of a -CH substitution,— ic jana optionally = - )© —C The LAL examples for Cy scarbocyclyl " are cyclopropyl and .cyclobutyl ." A saturated, saturated, or partially unsaturated monocyclic ring containing between ?and no cyclic carbon atoms, where ° Jas can optionally have a —CH,— group with -C(0) 1-yl.jali phenyl groups «aryl and .naphthyl 0 monocyclic heteroaryl'' groups include rings with - or = atoms containing one or more heteroaryl atoms that Selected from ON, 5, or 0. Examples include: pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyridazinyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl and triazolyl. aryl heterocyclic pyridinyl ¢monocyclic particularly .pyridin-2-yl and pyridin-6-yl Examples of "monocyclic heterocyclic include saturated or partially saturated of © to 1 atoms:

_ A —_ pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, homo-morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,4-diazepanyl and homopiperazinyl. monocyclic saturated heterocyclic Special examples of a heterocyclic ring include atoms that optionally contain one or more © atoms; pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, 1,4-diazepanyl and especially pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl , homopiperazine-1-yl and 1,4-diazepan-1-yl. It has a monocyclic saturated heterocyclic saturated heterocyclic Ad Examples include: JE atoms of azetidinyl pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, homo- morpholinyl, thiomorpholinyl, 1,1- dioxothiomorpholinyl and homopiperazinyl. saturated heterocyclic Examples of a saturated heterocyclic ring include 0 or “O©” or 1 or 7 atoms optionally containing one or more monocyclic atoms : or 17 including azetidinyl, pyrrolidinyl , piperidinyl, piperazinyl, homopiperazinyl and especially azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl. Examples include "tricyclic ring system".

Yi4¢

—q- 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indolyl, 5,7,8,9-tetrahydro-6H-pyrrolo[2,3-b:4,5- ¢ 'dipyridinyl, 1,3,4,5-tetrahydro-2H-pyrrolo[2,3-c:4,5-c'[dipyridinyl, 1,3,4,5-tetrahydro- 2H-pyrrolo[3,2- c:4,5-¢'[dipyridinyl, 5,6,7,9-tetrahydro-8H-pyrido[3',4:4,5]pyrrolo[2,3-b]pyrazinyl, 5,6,7 ,9-tetrahydro-8H-pyrrolo[3,2-b:4,5-c"|dipyridinyl, 5,7,8,9-tetrahydro-6H-pyrrido[3',4":4,5]pyrrolo[ 2,3-c]pyridazinyl, 1,2,3,4-tetrahydro[ 1 Jbenzofuro[3,2-c]pyridinyl, 6,7,8,9-tetrahydrofuro[3,2-b:4,5-c '|dipyridinyl, 5,6,7,8-tetrahydrofuro[2,3-b:4,5-¢'|dipyridinyl, 5,6,7,8-tetrahydrothieno[2,3-b:4,5-c] ']dipyridinyl, 1,2,3,4-tetrahydro

[1]benzothieno|3,2-c]pyridinyl, 6,7,8,9-tetrahydrothieno[3,2-b:4,5-cdipyridinyl, 5,6,7, 8- tetrahydro-4H-[1, 3]thiazolo[4',5":4,5]pyrrolo[3,2-c]pyridinyl, 5,6,7,8-tetrahydro-4H-[1,3}thiazolo[5',4":4 ,5]pyrrolof3,2-c]pyridinyl, 5,6,7,8-tetrahydro-4H-thieno[2',3"4,5]pyrrolo[3,2-c]pyridinyl, 5,6,7, 8-tetrahydro-4H-thieno[3',2".4,5]pyrrolo[3,2-c]pyridinyl, 5,6,7,8-tetrahydro-4H-furo[2',3":4, 5]pyrrolo[3,2-c]pyridinyl, 5,6,7,8-tetrahydro-4H-furo [3',2"4,5]pyrrolo[3,2-c]pyridinyl , 5,6,7 ,8-tetrahydro-4H-[1,3]oxazolo[4',5":4,5]pyrrolo[3,2-c]pyridinyl, 5,6,7,8-tetrahydro-4H-[1,3] ]oxazolo[5',4":4,5]pyrrolo[3,2-c]pyridiny], 1,4,5,6,7,8-hexahydroimidazo[4',5"4,5]pyrrolo[3 ,2-c]pyridinyl, 3,4,5,6,7,8- hexahydroimidazo[4',5":4,5]pyrrolo[3,2-c]pyridinyl, 2,3,4,5-tetrahydro -1H-pyrido[4,3-b]- 7-azaindolyl, 2,3-dihydro-1H-spiro[isoquinoline-4,4'-piperidinyl], benzofuro[3,2-c]- 1,2,3 ,4-tetrahydropyridyl. Particular examples of a tricyclic ring system include a tricyclic ring system containing arbitrarily 0 on one or more atoms:

- 1and = 0, S or N atoms include 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indolyl, 5,7, 8,9-tetrahydro- 6H-pyrrolof2,3-b :4,5-c'ldipyridinyl, 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-7azaindolyl, 2, 3-dihydro-1H-spiro[isoquinoline-4,4'- piperidinyl], benzofuro[3,2-c]-1,2,3,4- tetrahydropyridyl and especially 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl and 5 ,7,8,9-tetrahydro-6H-pyrrolo[2,3-b:4,5-c'|dipyridin-6-yl, 2,3,4,5-tetrahydro-1H-pyrido[4,3-b] -7azaindol-2-yl, 2,3-dihydro-1H-spiro[isoquinoline-4,4'-piperidin-2-yl], benzofuro[3,2-c]-1,2,3,4-tetrahydropyrid- 2-yl.

The expression “halo” refers to “chloro y “fluoro and .iodo s bromo when selective groups are selected from groups of 'up to three'; it is understood that this definition 0 includes all substituent groups that are selected from One of the specified groups or substitution groups that are chosen from one or more of the specified groups

A corresponding convention on substitution groups chosen from the 1" or "Y" group.

Compounds of formula (I) can exist in stereoisomeric forms. It will be understood that the invention includes all geometric and optical isomers, geometric and

.racemates and mixtures thereof including (I) for compounds of formula optical isomers Vo. It is understood that some of the compounds of formula [defined above] may exhibit igneous phenomena in particular; Sinusiness can affect any cyclic groups other than tautomerism. It is understood that the present invention is a homologous oxo bearing one or two substituent groups that includes in its definition any of the aforementioned forms of flinosis; or mixture thereof which are active

- 11 - i mentioned above and is not limited to any of the silt forms used in the forms of the formula or named in the examples. It is also understood that some compounds of formula (1) and salts thereof can exist in dissolved forms of hydrated “JU” hydrated forms together with undissolved forms for example 10 It is understood that the invention includes all of these dissolved forms. : as organic or inorganic hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric, para-toluenesulphonic, methanesulphonic, tartaric or maleic acid or, for example, the salt of a compound of formula (1) which is sufficiently acidic For example, or calcium such as alkaline salt, alkali earth metal salt Example is an alkaline earth metal salt (I) Another pharmaceutically acceptable salt of a compound of formula ammonium or “magnesium” is For example; a salt formed inside the human or animal body after a compound is administered to it .0) of the formula Yo The compounds of the invention are in the form of a prodrug and it is a compound that is broken down in a body c It can be administered to a human or animal body to release compound of the invention. A prodrug may be used to alter the pharmacokinetic and/or physical properties of a compound of the invention. A prodrug can form when the special compound contains 5

Yi4¢

— \ Y —

by the invention on a suitable replacement group or group; A property modification property can be attached to it. Examples of prodrugs include; ALE ester derivatives cleavable in vivo can form at a carboxy group or a hydroxy group in a compound of formula (1) and amide derivatives cleavable in vivo can form at a carboxy group or an amino group in

0 A compound having formula (1) Therefore, the present invention includes those compounds of formula (1) as previously defined in this patent when made available by organic synthesis and when made available inside the human body or animal body by the cleavage of a primary drug from it Hence, the present invention includes those compounds of formula (1) which are produced by an organic synthesis method and also such compounds which are produced in

0 human body or animal body by the metabolism of a produced compound; That is, a compound of formula (I) can be a synthetically produced compound or a metabolically produced compound, and the appropriate pharmaceutically acceptable prodrug of a compound of formula (I) is one that is based on a reasonable medical decision as appropriate For administration into the human or animal body without unwanted pharmacological activities and without undue toxicity.

0 A variant pen has been described for the prodrug; For example; In the following documents: 1 : ‎methods in enzymology, vol. 42, p. 309-396, edited by k. widder, et al. (academic press,

.) 1985 b. 11:8

1” -:

Design of Pro-Drugs, edited by 11. Bundgaard (Elsevier, 1985). (e a textbook of drug design and development, edited by krogsgaard-larsen and h. bundgaard, chapter 5 "design and application of pro-drugs", by h. bundgaard ed. 113-191 (1991).d): h. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992). kakeya, et al., chem. pharm. bull, 32, 692 (1984). 11: (5 t. higuchi and v. stella, "pro-drugs as novel delivery systems", 2.0.5. symposium series, volume 14. He 1 e. roche (editor), "bioreversible carriers in drug design", pergamon press, 1987.

—_ 1 $ —_

A pharmaceutically acceptable prodrug is a compound of formula (1) in which the carboxy group is

For example ¢ ester is divisible in the body of an organism. | A cleavable ester in a body

The organism of a compound of formula (I) containing a carboxy group is e.g.; ester

It is acceptable to catch a Lay where it is divided into the body of | of a human or animal because the z is the parent acid. include ester

Pharmaceutically acceptable for:

(1-6C)alkoxymethyl esters 5 st-butyl 5 ethyl s «methyl as (1-6C)alkyl esters «carboxy

: Jia (1-6C)alkanoyloxymethyl esters 3 cmethoxymethyl esters (Jie

(3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl and «3-phthalidyl esters s «pivaloyloxymethyl esters

2-0x0- 3 «1-cyclohexylcarbonyloxyethyl esters s cyclopentylcarbonyloxymethyl mcl esters 1 01

: 3-dioxolen-4-ylmethyl esters «5-methyl-2-ox0-1 Jie 3-dioxolenylmethyl esters

: Jie (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters

.1-methoxycarbonyloxyethyl ester and methoxycarbonyloxymethyl

A pharmaceutically acceptable prodrug of a compound of formula (1) is one that has a hydroxy group eg vo;

The organism or ether of a compound of formula (0) containing a hydroxy group is for example;

pharmaceutically acceptable ester or ether; Where it is broken down in the human or animal body to produce a compound

,. to pray | hydroxy

DM \ _ includes pharmaceutically acceptable ester constituent groups of inorganic hydroxy ester group such as phosphate esters (including phosphoramidic cyclic esters). More pharmaceutically acceptable ester constituent groups include hydroxy group (1-10C)alkanoyl groups such as <benzoyl 5 “acetyl” and “phenylacetyl” and phenylacetyl 5 benzoyl groups with “Jail©” and Jie (1-10C)alkoxycarbonyl groups cethoxycarbonyl groups and : <N,N-[di-(1-4C)alkyl]carbamoyl and .2-carboxyacetyl s 2-dialkylaminoacetyl Examples of ring-substituting groups on phenylacetyl and caminomethyl benzoyl groups include: N- alkylaminomethyl, ~N,N-dialkylaminomethyl, ~morpholinomethyl, piperazin-1- ylmethyl and 4-(1-4C)alkylpiperazin-1-ylmethyl. a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. A pharmaceutically acceptable prodrug for a compound of formula (1) having an amino group is, for example, an amide derivative that can be cleavable in the body of an organism from it . Pharmacologically acceptable amide compounds from the camino group include, but are not limited to; An amide formed using -1 (10C)alkanoyl 01 methyl cbenzoyl sl «acetyl or phenylacetyl groups and the benzoyl and phenylacetyl groups substituted. Examples of ring-substituting groups for phenylacetyl, benzoyl caminomethyl, <N-alkylaminomethyl, and 9N,N-dialkylaminomethyl groups include: <morpholinomethyl, piperazin-1-ylmethyl, and 4. -(1-4C)alkylpiperazine-1-ylmethyl

A - 11 - The effects in the body of a living organism of a compound of formula (1) can be partially exerted by one or more metabolites that are in the body J of a human or animal body after administration of a compound of formula (0). As decided above. The effects in the organism of a compound of formula (1) can also be exerted by the metabolism of the compound

Product (pro-drug) The new compounds of the invention, for example (Jal), include the compounds of formula (1); or salts thereof are acceptable fishing day where; unless otherwise decided » Ry A, O, O, and 18 have any of the meanings defined above in this patent or later in this patent:- Appropriately” A is an aliphatic ring with from © to 1 atoms Optionally containing a double bond and optionally including a suasSoxygen atom 0 ring and having optionally substituent aa, 1 or ¥ substituent groups separately selected from halogen and . C,4carbocyclyl double bond can be found in any convenient position on the A ring Atom 07860 can be found in any convenient position_ on the A ring plus a double bond if needed Conveniently; A is dds Aliphatic having from © to 1 atoms with an arbitrary substitution of number 101, 0?, or ¥ substituent groups selected separately from Caucarbocyclyl s halogen .More suitably; AS) was made of any of: “cyclopentane or 00108 or cycloheptane or more cyclohexane A dla Ble than cyclohexane . Ble Reade more than hydrogen or alkyl ben .

1 - : - in a more obsequious manner; R is <hydrogen or “methyl or ethyl or .propy! more appropriately; R is hydrogen in cafe form of 8 and 182 with a nitrogen atom attached to it a saturated heterocyclic or partially saturated monocyclic ring of m 0 to 1 atoms; This ring shares two atoms with a second saturated ring

Or unsaturated to form a bicyclic ring system where the bicyclic ring system shares one or two atoms with a third ol saturated unsaturated ring to form a three ring system containing contains a total of up to VA atom” and optionally a three-ring toroidal system can contain up to three

0 heteroatoms selected separately from © atoms; or 8 or 18 and may optionally have up to three substitution groups as defined earlier herein or later herein. appropriately The cyclic system contains a tricyclic consisting of 1 and 82 with a nitrogen atom J) deo Le lo Lez 035d £310

1 appropriately; The tricyclic system formed by R' and 182 with its itll nitrogen atom optionally can contain up to three heterocyclic atoms each Lesa selected separately from 0 or 17 atoms and can have Optionally replaceable with up to three replacement groups as defined earlier herein or later herein. more appropriately; The three-ring ring system can be optionally replaced by 1

0 or Y substitution groups as defined earlier herein or later herein.

—_ \ A —_ aptly»; The D0 ring system of A and 1682 rings with 5 nitrogen optionally bonded to it can contain up to three individually selected heteroatoms from © atoms; , 8, or N with optional substitution of up to three selectable substitution groups «COR? 5 and Tom ¢ halogen 3 “cyano 3 “ Cy elakynyl 5 “Cysalkenyl s” Crgalkyl separately from Croalkyl where it can be found in groups (NRR® 5 “CONR'R® 5 SR' and ¢ SOR? 5 RTM (NO, 5 0 “Cagalkynyly Coalkenyls) also optionally substituted by 1 or ¥ of individually selected substitution groups of <CONR'R® 5 < SO,R' 5 (NR 'R' 5 chalogen Rhythm Rhythm .Cy4carbocyclyl sf 10013 Rnata Taiyoi remcla in a disguised manner; it forms Lyr 2p with a nitrogen atom attached to it either : : or a 1,3,4,5- ring tetrahydro-2H-pyrido[4,3-blindolyl 0 5,7,8,9-tetrahydro-6H-pyrrolo[2,3-b:4,5-c'[dipyridinyl ring, 2,3,4,5- tetrahydro-1H-pyrido[4,3-b]-7azaindolyl, 2,3-dihydro-1H-spiro[isoquinoline-4,4'-piperidinyl], benzofuro[3,2-c]-1,2,3 ,4-tetrahydropyridyl, 5,6,7, 8-tetrahydrofuro[2,3-b:4,5-c']dipyridine.Sle gana from Y or Yo) with any of the rings optionally by number Sasi can have the aa substitution as defined earlier herein or later herein. (ale on the way

nrr

«cyano or <halogen optionally substituted with a Cig alkyl or hydrogen of R? (ale on the way

SOR' J NSOR' A SONRR” J is annihilated. Jf

1 — - more appropriately R* (dade is hydrogen ar arol © optionally substituted with halogen suitably; p1 is suitably hydrogen i.e. Crealkyl; 15 and 7 separately express hydrogen aranol Lm 0. It is understood that the convenient compounds of the invention include each compound shown; Each of the groups of compounds, any combination of compounds within each group, and pharmaceutically acceptable salts that can be hydrolyzed in vivo, expresses a separate feature of the invention: (1R2R)-N-(1- cyanocyclopropyl)-2-[(8-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3 -b]indol- 2-yl)carbonyl]cyclohexanecarboxamide (IR,2R)- 2-[(8-chloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b] indol-2-yl)carbonyl]-N-(1- cyanocyclopropyl)cyclohexanecarboxamide ( 1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)earbonyl ]cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-(1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2- ylcarbonyl)cyclohexanecarboxamide (1R,2R)-2-[(8-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]-N-(1- cyanocyclopropyl)cyclohexanecarboxamide (1R2R)-N-(1-cyanocyclopropyl)-2-[(6-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-bJindol-2] -yl)carbonyl]cyclohexanecarboxamide

l.(1R,2R)-N-(1-cyanocyclopropyl)-2-{[8 ~(trifluoromethyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b)indol -2-yl]carbonyl}cyclohexanec arboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-[(8-methoxy-1,3,4,5 -tetrahydro-2H-pyrido[4,3 - b]indol-2-yl)carbonyl]cyclohexanecarboxamide (IRZR)-N-(1-cyanocyclopropyl)-2-[(8-isopropyl-1,3,4,5 -tetrahydro-2H-pyrido[ 4,3- bJindol-2-yl)carbonyl]cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-[(9-fluoro-1,3 ,4,5-tetrahydro- 2H-pyrido[4,3-b]indol- 2-yl)carbonyl]cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-[(7-fluoro-1,3,4) ,5 -tetrahydro-2H-pyrido[4,3-bJindol- 2-ylyoarbonyl]cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-[(8-fluoro-5-methyl- 1,3,4,5 -tetrahydro-2H- pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide (1R,2R)-2-[(6-bromo-1, 3,4,5-tetrahydro-2H-pyrido[4,3-b] indol-2-yl)carbonyl]-N-(1- cyanocyclopropyl)cyclohexanecarboxamide (1R,2R)-N-(1- Cyanocyclopropyl)-2-[1,3,4,5-tetrahydro-1H-pyrido[4,3-B]-7-azaindol-2- yl)carbonyl]cyclohexanecarboxamide (1R2R)-N-( 1-cyanocyclopropyl)-2-({8-[(dimethylamino)methy 1]-1,3,4,5-tetrahydro- 2H-pyrido[4,3-b]indol-2-yl}carbonyl)cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-{[8-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-blindol-2-] yl]carbonyl} cyclohexanecarboxami de (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-methoxy-1,3,4,5 -tetrahydro-2H-pyrido[4,3-] b]indel-2-yl)carbonyl]cyclohexanecarboxamide

(1R,2R)-N-(1-cyanocyclopropyl)-2-(1H-spiro[isoquinoline-4,4'-piperidin]-2(3H)- ylcarbonyl)cyclohexanecarboxamide (1R,2R)-2-[(6) -chloro-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]-N-(1- cyanocyclopropyl)cyclohexanecarboxamide (IRZR)-N-(1-cyanocyclopropyl) )-2-[(6-cyano-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indol- 2-yl)carbonyl]cyclohexanecarboxamide (1R,2R)-N-(1- cyanocyclopropyl)-2-[(9-methyl-5,7,8, 9-tetrahydro-6H-pyrrolo[2,3-b:4,5-¢']dipyridin-6-yl)carbonyl]cyclohexanecarboxamide (1R, 2R)-N-(1-cyanocyclopropyl)-2-{ [6-(methylthio)-1,3,4,5-tetrahydro-2H-pyrido[4,3- blindel-2-yl]carbonyl} cyclohexanecarboxamide (1R) ,2R)-N-(1-cyanocyclopropyl)-2-[(benzofuro[3,2-c]-1 ,2,3,4-tetrahydropyridyl)carbonyl]cyclohexanecarboxamide

(1R,2R)-N-(1-cyanocyclopropyl)-2-{ [6-(trifluoromethoxy)-1,3,4,5-tetrahydro-2H-pyrido[4,3-blindol-2-yl]carbonyl} cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-ethoxy-1,3 ,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl) carbonyl]cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-[(5 -methoxycarbonylmethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl )carbonyl]cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-[(5-hydroxycarbonylmethyl-1,3,4,5 -tetrahydro-2H-pyride[4,3-b]indol-2 -yl)carbonyl]cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-{(5 -cyclopropylmethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol- 2-yl)carbonyl]cyclohexanecarboxami de

- YY - (1R,2R)-N-(1-cyanocyclopropyl)-2- [(5-methoxyethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3- bJindol-2-yl) carbonyl]cyclohexanec arboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-{[6-(tr ifluoromethyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-blindol-2] - yl]carbony1}cyclohexanecarboxamide. (IR€R)-N-(1-cyanocyclopropyl)-2-{[6-(m ethylsulfonyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl ]carbonyl}cyclohexanecarboxamide (1R,2R)-2-{[6-(benzyloxy)-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indol-2-yl]carbony 1} -N-(1-cyanocyclopropyl)cyclohexanec arboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6 -hydroxy-1,3,4,5-tetrahydro-2H-pyrido[4,3 - b]indel-2-yl)carbonyl]cyclohexanecarboxamide. (IR,2R)-N-(1-cyanocyclopropyl)-2-[(6-propoxy- 1,3,4,5-tetrahydro-2H-pyrido[4,3- bindol-2-yl)carbonyl]cyclohexanecarboxamide ( 1R,2R)-N-(1-cyanocyclopropyl)-2-{[6-(cyano ethoxy)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl] carbonyl}cyclohexanec arboxamide (1R2R)-N-(1-cyanocyclopropyl)-2-(6-(2- (dimethylamino)ethoxy)-2,3,4,5 -tetrahydro- 1H-pyrido[4,3-b] indole-2-carbonyl)cyclohexanec arboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-morp holinoethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4, 3-b]indole-2-carbonyl)cyclohexanec arboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-(pyrroli din-1-yl)ethoxy)-2,3,4 ,5-tetrahydro- 1H-pyrido[4,3-b]indole-2-carbonyl)cyclohexane carboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-(piperi din-1) -yl)ethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2- [(5-methanesu Iphonyl-1,3,4,5-tetrahydro-2H- pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanec arboxamide

_ Y Y — (1R,2R)-2-(7,8-Dihydro-5SH-furo[2,3-b:4,5 -¢']dipyridine-6-carbonyl)- cyclohexanecarboxylic acid (1-cyano-cyclopropyl) )-amide (1R,2R)-2-(7-Methanesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b] indole-2-carbonyl)-cyclohexanecarboxylic acid (1-cyano-cyclopropyl) -amide (1R2R)-2-(9-Methanesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b] indole-2-carbonyl)-cyclohexanecarboxylic acid (1-cyano-cyclopropyl)-amide ( 1R,2R)-N-(1-cyanocyclopropyl)-2-(2,2-difluoro-7,8,9,10-tetrahydro-6H-[1,3]dioxolo[4,5-g]pyrido[4] ,3-b]indole-7-carbonyl)cyclohexanecarboxamide (1R,2R)-N-(1-cyanocyclopropyl)-2-(8-fluoro-6-methoxy-2,3,4,5-tetrahydro-1H- pyride [4,3-b]indole-2-carbonyl)cyclohexanecarboxamide

Compounds of formula (1) can be prepared by any of the following methods: Method A Rub 0 Ri N + “on <<] =x Ri except for L2: 1-7 HH, — NTs | 8 + C2 A J R RZ £ A 3 / A A Se (IL) (XI) 0 Method B Apa 2 S—=n R1 0 © <1 __y 9 0 HX FN + "N—H RY Co R rR? —_— RY 5 £ n 5 l m LA fa) RN _ (IV) (V} {0 \o

These methods are also illustrated by the following diagrams: Scheme 1 [< B 9 Pd B 7 R1 JO Q K RI Holy AB 4 1 Ha 7 + 4 + 04011 BH RY p ) “0 p 1 La) > Pp, - p iV} OE (II) 10 0 Compounds of type (I) can be synthesized by combining three building blocks as shown illustration above. A secondary amine of the type shown in the general structure (V) is conjugated with Lie isomers of 018010 -1,2cyclic of type (VI) and then conjugated: 1-aminocyclopropylcarbonitrile (III) with the remaining acid .remaining acid 0 chart? Yi4¢

Yo - - 0 = 3 name OH Ce / Nah 0 HO-- 5 Dekbydrating > nam agent {a | | M A SL SS 1 ! No /_ R,R cnantiomer i i 81 for 1 HZ Vv) > 0 : Bach 0 Rola 1 Asi 8 Yah... << N Coupling No P secret Ri 4 yi 2m ot cm cursed RY 2 0. R A p LA Se eo” (hi (i) 0 in more detail; 40 can be dehydrated from Cyclic 1,2-diacid of type (VI) using a suitable reactant such as: acetic anhydride, acetyl chloride, dicyclohexylcarbodiimide (DCC), thionylchloride. © and so on. Acetic anhydride is preferred at a temperature ranging from chamber and (2Y ee) thereafter; removal of the excess dehydration agent produces a (VID)-type bi-cyclic-anhydride and the (VII) anhydride reacts towards secondary amines of type (V) in the presence or absence of a suitable base such as: triethylamine, diethylisopropylamine, 1,8-diazabicyclo[5.4.0Jundec-7-ene (DBU) 13% 0 or potassium carbonate Jie ionic bases bases in a suitable aprotic solvent such as: dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene.

The following acid is combined with an appropriately substituted 1-aminocyclopropylcarbonitrile using a Jie coupling agent: O-(7-azabenzotriazol-1-y1)-N,N,N' N'-tetramethyluronium hexafluorophosphate ( HATU), dicyclohexylcarbodiimide (DCC) / hydroxylbenzotriazole (HOB), 1 -benzotriazolyoxy- tris-dimethylamino-phosphonium hexafluorophosphate (BOP), benzotriazolyoxy-tris- pyrrolidino-phosphonium hexafluorophosphate (PyBOP), N,N- dimethylaminoethylcyclohexylcarbodiimide (EDC), 4-(4,6-dimethoxy-1,3 ,5-triazin-2-yl)- 4-methylmorpholinium chloride (DMTMM), trichloroacety! chloride, by forming one in the presence of suitable bases such as triethylamine “diethylisopropylamine s 0 and [031; etc. or potassium Je ionic bases 76; In the presence or absence of an activating base such as: N,N-dimethyl-4-amino-pyridine (DMAP) in an appropriate solvent suitable solvent: dichloromethane (DCM), tetrahydrofuran (THF) , diethylether, dimethylformamide (DME), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene at a temperature between 0 * C and 10 to give compounds of type (1). Preferably a mixture of SHATU PyBOP in either DMF or DCM at a temperature between room temperature and 5 mM. 1,2-diacid cyclo(VI) can be produced by the methods as described in References 2002, 2002 Eur.

J.

Org.

Chem. which includes

Chiral resolution and chiral separation by chromatographic and symmetry removal methods using cesterase enzymes such as pig liver esterase, as will be explained in general below. oR 9 2 “mila YN oH Ro - i l 0 i R, mla Regd resolving enzyme 7 2 J 2 3 ala + > l pam {a (A) ( Ha RN RNs Ne” racemic R.R-enmantiomer )-/~{ o 9 0 300 4- um Re 1) Sait formation + 0 no ol for 2 re-crystaltisation (2 Arf Acid (3 spray {+i-) racemic chiral amine R.R-enantiomer o: z can be produced preferred R,R-cyclohexyl-1,2-dicarboxylic acid by analyzing the acid zc) yua aan racemic diacid commercially available by hydrolytic process using chiral amines bases to form diastereomeric salts and return Lal 0 from single enantiomers As described in: ‎Eur)}. Org.

Chem. 2002, 2948-2952. The plot?

EN 1 2 > 0 [>| clear them w= _r=° Solve CTL A No '3 B {VH) vil) | iy a 9 pI c 4 “FN ON e Zn 8 mk er . HO Ns Re oc 81 A 1 P 83 ~~ B 1/0 = 2 9 81 N- FN Re N= 8 fa) A Alternative synthesis of compounds of type 1) is possible. ) by the method shown in schematic ? above. The previously described chiral 1,2-diacid can react with xe alcohol such as “benzyl alcohol 5 benzyl alcohol has a substituent (eg:” :( 4-methoxybenzyl alcohol ethanol, methanol, propan-1-ol, isopropanol, butan-1-ol 0 at room temperature to 1 8 C in a suitable unreacted solvent “DCM STH Jie or DMF etc. In addition, to produce an ester-acid of type (VII), it is preferable to react with benzyl and 21600015 with benzyl substituted.The ester group has now been expressed by the (PG) group, as it morphologically expresses a protecting group that hides A description of the appropriate protective groups in organic synthesis can be found: Green and wuts protective groups in organic synthesis, 1991, john wiley. with :

coupling Using a 1-aminocyclopropylcarbonitrile coupling agent such as: A 1

DMTMM EDC R PyBOP R R HOB/DCC R <EDC “PyBOP” or (HATU suitable bases) is active in the presence of suitable bases ester by formation of ctrichloroacetyl chloride or ionic 5 DBU 4 “diethylisopropylamine y “triethylamine Jie oo : appropriate solvent in potassium carbonate Jie immersed in dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformaide (DMF), dimethylacetamide (DMA) , tert-butylmethylether (TBME), toluene There is an alternative method (IX) at a temperature between 0 * C and 100 then to produce compounds of the type or coxalylchloride using a suitable reagent such as (ass chloride) represented in Convert to 0

Jie in the presence of (V) secondary amine bases and so on and then the secondary amine cthionylchloride is added between the temperature of DCM or DMF in any of the PYBOP or HATU shown above. Prefer a combination of an acid detector from (IX) chamber and 1 Tum. The protection group can be removed from vehicles of type: by the methods described in (Iv) g sill

Green and Wuts, Protective groups in Organic synthesis, 1991, John Wiley. They can be removed by ¢ (phenyl=CH, = PG) a benzyl group in the preferred state of a carbon group on a palladium such as a suitable catalyst isa hydrogen treated with transferred gas and so on or By transfer hydrogenation cpalladium hydroxide 5” (701 to 0) loading in ammonium formate and palladium (II) acetate solvent using systems such as 0 00

An appropriate solvent such as ethylacetate 5 ethanol 5 “methanol and so on. The heating temperature ranges from 0 * C to 100 C. The appropriate coupling secondary amine can then be coupled using a coupling agent (IV) with (HNR1R2) secondary amine (V) EDC (PyBOP) Ar (BOP) Ar ¢HOBt [DCC sf (EDC) Ar PyBOP Ar (HATU) as agent triethylamine suitable bases Active in the presence of ester by the formation of ODMTMM or © potassium (Jie appropriate jonic bases) and so on or ionic bases DBU “diethylisopropylamine s : appropriate solvent in ccarbonate dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformaide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene

HATU pe preferably (I) combination temperature between 0 "C and 100 * C to produce compounds of type dap at 0 or PYBOP in either DMF or DCM between room temperature and +090 Many of the secondary amines (HNRIR2) used in the synthesis of the examples below are from commercially available sources or from methods previously described in the references.In general, the compounds can be prepared by the methods described below.

X—NH. Kee rrr - 0: a dL

R R

X=0.NR

X) (XI) (XI)

Yi4¢

— and tricyclic compounds of type (XII) can be synthesized by the fischer indole spigma-promoter realignment reaction [; ]0 equivalent using (XI) piperidone (Reaction Scheme 4). An aromatic compound having a suitable substitution (X) is condensed using piperidone to form an intermediate hydrozone by mixing in a suitable inert solvent Jala 0 such as “dichloromethane and absorbent” 5 ethanol And so on ; in the presence or absence of acid; such as <hydrochloric acid, sulphuric acid or TFA. The intermediate hydrozone can be separated and sorted or taken directly to the cyclicization step; either by heating in a solvent with a suitable high boiling point xylene sf «BuOH sl ctoluene Jie + or acetic acid possibly using microwave technology the reaction can also be carried out by the presence of a strong acid Jie poly phosphoric acid or <hydrochloric acid or csulphuric sulfuric acid or by lewis acid such as zine boron trifluoride etherate s <chloride and so on usually in combination with heating at a temperature of 52 00 ° Yer based on the solvent in this way; Manner tricyclic compounds can be separated directly. : 10 Scheme o x —NH 5 X a —~ Os — I. © A 1 7 of RNs Nagy Lan I A 0 Lee” Po Soden d

R R

X=, NR (X) (XH (XIV)

Kemer m

R-4 IC bin R X=0, NR {XID Protection for the conversion reaction to take place. piperidone nitrogen In some cases required “appropriate protecting groups” protection groups Masked: and removed in 80801

Greene and Wut Green and Wuts Protective groups in Organic synthesis, 1991, John

Wiley. For example, “benzyl 4 trifluoroacetyl” and “tert-butyl carbamate 5” benzyl carbamate synthesis uses the PG conditions expressed above in reaction diagram © as group (XIV) to produce the compounds of the type of ccyclisation described above for conversion to cyclic compounds -(X1I) desired secondary amine and then removal of the protecting group to yield secondary amine 0 For a further feature of the invention a compound of formula (1) is provided; or a pharmaceutically acceptable salt thereof; ai, for use as a therapeutic agent

Ahem According to another feature of the invention a compound of formula (1) is provided; or a pharmaceutically acceptable salt thereof; for use as a therapeutic agent; Where it is preferable to achieve inhibition of cathepsins K According to another feature of the present invention, a method for producing inhibition of Soysteine protease is provided from a warm-blooded animal Jie cwarm blooded animal human; would need such dal which comprises giving said organism an effective amount of a compound of the present invention; Or a pharmaceutically acceptable salt thereof. The invention also provides a compound of formula (1); or a pharmaceutically acceptable ate salt; for use as a medicine; use of a compound of formula (a) of the present invention; or a pharmaceutically acceptable salt thereof; In the manufacture of a drug for use in inhibiting the protease P51610 of a warm-blooded animal like a human. In particular ang 1 the compounds of the invention are useful in the treatment of inflammation and immune disorders, for example but not limited to; osteoporosis, rheumatoid arthritis, costeoarthritis, metastatic bone disease, osteolytic disease, and neuropathic pain related to bone. 1 on aay in particular; Jig The use of a compound of formula (I) of the present invention; or a pharmaceutically acceptable salt thereof; In the manufacture of a drug for use in the inhibition of cathepsin K in warm-blooded organisms » such as humans. for the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof for the medical treatment of mammals including humans; Particularly in inhibiting cysteine protease, it is naturally formulated according to standard pharmaceutical procedure as a pharmaceutical formulation.

- Ye =

For this in the coil feature the present invention provides a pharmaceutical composition; They contain a compound of formula (1) or

A salt thereof is an acceptable Lysed fish and a pharmaceutically acceptable diluent or carrier.

The pharmaceutical composition of the present invention may be administered in a standardized manner for the desired disease condition

treatment, for example.” Oral, rectal, or intravenous administration

© parenteral for these purposes » The compounds of the present invention may be formulated by

a known method to domain to an image; For example (Jal tablets, cttablets, capsules

or aqueous or oily coily solutions or sf suspensions emulsions

lipid, ALE dispersible powders, suppositories, or

ointments, creams, or drops; Or sterile injectable aqueous or oily solutions or suspensions. :

The appropriate pharmaceutical composition of the present invention is that suitable for intravenous administration

Oral route as a unit dose; For example a tablet or capsule containing between 1

mg and 1 g of the compound of the present invention.

In the coal aspect the pharmaceutical composition of the invention is that LDL for administration by intravenous “intravenous,” subcutaneous, intramuscular, or injection into

.intra-articular injection joints

can receive every patient; For example; into a vein; or subcutaneous or intramuscular dose

ranging from 0000 mg aS to 100 mg kg” of the compound; Preferably in the range of 100 mg kg '

to 01 mg kg ' of the present invention; The formula is given from once to; times a day. © _ The dose may be given intravenously; Subcutaneously and intramuscularly by continuous infusion by injection

— Yo —

large doses at once. in an alternative way The dose may be given intravenously by continuous infusion

over a period of time. in an alternative way Each patient receives an equivalent daily oral dose

approximately daily dose by non-enteric route; The formula is given from once to; times a day.

The invention also relates to combination therapies; Where a special compound of the invention is given; or a salt thereof is acceptable

0 pharmacist; or a pharmaceutical composition or formula comprising a compound of the invention; at one time or

successively or as a combination preparation with other therapeutic agent or agents” for one or more treatments

More than one circumstance listed.

in particular; To treat (but not limited to) bone porosity, costeoporosis

rheumatoid arthritis osteoarthritis 0 and metastatic bone disease 01612512116 and osteolytic disease ~Nlpsteolytic bone

neuropathic pain related to bones; The compounds of the invention can be combined

using the above factors.

Non-steroidal anti-inflammatory agents (hereinafter referred to as NSAIDs)

These include non-selective cyclo-oxygenase inhibitors (COX-2/COX~) that are used topically or systemically (such as diclofenac 3 piroxicam and propionic acids such as

‎«ibuprofen s ketoprofen s fenoprofen s flurbiprofen y naproxen [r#flamsu] as acid

sulindac s indomethacin y mefenamic and cazapropazone and methylated pyrazolones

meloxicam and selective 0764-2 inhibitors (such as ¢(aspirin J-ie salicylates 5” phenylbutazone)

: ¢(etoricoxib 5 parecoxib s lumarocoxib 5 valdecoxib s rofecoxib s celecoxib s

name and donors of nitric oxide (and) 0140 tcyclo-oxygenase inhibitors and glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or orgasmic routes); 5 ¢ leflunomide 5 émethotrexate auranofin y ¢ d-penicillamine s hydroxychloroquine or other gold preparations taken by mouth Gla 0 oral gold by injection ¢ and analgesics ¢ diacerein ¢ analgesics and treatments taken into the joint such as derivatives hyaluronic acid and nutritional supplements such as glucosamine. The present invention also relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof with a cytokine or an adjuvant or antagonist of cytokine function (these include 0 agents that act on cytokine signaling pathways such as SOCS modifiers and include talpha-, beta-, and gamma-interferons, insulin-like growth factor type 1¢ (IGF-1), interleukins (IL) compounds including 11.1 to 11.17', antagonists or inhibitors of interleukins such as 08; and inhibitors of Jules necroptosis Tumor | alpha TNF- tumor necrosis (e.g. Jie) Anti-TNF monoclonal antibodies (such as adalimumab s infliximab 0 and CDP-870 and TNF receptor antagonists) alfa includes immunoglobulin (etanercept Ji) and low weight agents (aad) such as -pentoxyfylline Further to the foregoing; the invention relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; with an antibody A monoclonal antibody that targets cells

- L: lymphocytes (MRA - aIL16R (rituximab) CD20 Jie) B-Lymphocytes » or lymphocytes (HuMax 11-15 5 CTLA4-Ig Jie) T-Lymphocytes. As the present invention relates to a combination containing one of the compounds of the invention ; or a pharmaceutically acceptable salt thereof; With one of the modifiers of the function of the Jia chemokine receptor (CCR2A 5 “CCR2 3 < CCR1” “CCR2By 0” 5 “CCR8 4” CCR7 3 “CCRO” CCR5 5 “CCR4 LEVEL 5 CCR10 CCR 5 (And for the family of CXCR1 ¢ {(C-C) and CXCRS5 3 CXCR4 5 CXCR3 5 CXCR2 for the family of CX3CR1 5 (C-X-C) for the family of C-X3-C As the present invention relates to a mixture containing One of the compounds of the invention; or an acceptable salt Wana thereof; with a reticulum metalloprotein (MMPs) enzyme inhibitor “metalloproteases (MMPs) i.e. 01 ¢stromelysins, 85 enzymes” and 5 mM enzymes, a taggrecanase enzyme and in particular an enzyme “collagenase-1 (MMP-1) and collagenase-3 (MMP-”collagenase-2 (MMP-8) ra and stromelysin-3 (MMP-11) 5 ¢ stromelysin-2 (MMP-10) ¢stromelysin-1 (MMP-3) and Lay » MMP-12 5 MMP-9 agents including doxycycline Jie. The present invention also relates to a combination containing one of the compounds of the invention; or an acceptable salt thereof Waa Vo with a leukotriene biosynthesis inhibitor or a 5-lipoxygenase (5-LO) inhibitor or an anti-protein 8 of 5-lipoxygenase such as ?; ¢zileuton and ABT - tabbott-85761 5 tabbott-79175 5 ¢tepoxalin_s ¢fenleuton ¢761 and : N-(5-substituted)-thiophene-2-alkylsulfonamide : 2,6-di-tert- butylphenolhydrazones; a methoxytetrahydropyrans

VA - — such as Zeneca 71-2138, ¢SB-210661, and pyridinyl-substituted in position Jie 2-cyanophthalene 1-739,010; Jie 2-cyanoquinoline 1-746,530; or compound indole or MK-591 Jie quinoline or MK-886 and 1005 x preservative as the present invention relates to a combination containing one of the compounds of the invention” or a pharmaceutically acceptable salt ° cada and an antagonist to the receptor of 4 compounds leukotrienes (LT), 1104, LTD4, and (LTE4) selected from the group consisting of Jie phenothiazin-3-1 1-651,392; amidino methazole moieties P065-25019; and 5-challenged tontazolast and benzenecarboximidamides such as 284/260 ¢BIIL and compounds such as ablukast s zafirlukast verlukast (MK-679) s pranlukast s montelukast 5 and iralukast s Ro — 245913 5 RG-12525 BAY x 71955 (CGP 45715A)0 : The present invention also relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; arias of a phosphodiesterase (PDE) enzyme such as methylxanthanine including aminophylline 5 theophylline and a selective inhibitor of the coenzyme PDE includes a PDE4 inhibitor and an enantiomer 0 inhibitor or a PDE5 inhibitor J vo. As the present invention relates to a combination containing one of the compounds of the invention” or a pharmaceutically acceptable salt thereof; and a histamine receptor antagonist of cetirizine Jie 1 gil} or loratadine or desloratadine or fexofenadine or acrivastine or terfenadine or astemizole or azelastine or levocabastine and chlorpheniramine Or promethazine, cyclizine, or ¢mizolastine, which is used topically, orally, or by injection.

q — 7 — The present invention also relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type Y receptor antagonist. The present invention also relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; or an antagonist type 4 histamine receptor. The present invention also relates to a combination containing one of the compounds of the invention” or a pharmaceutically acceptable salt thereof; and a sympathomimetic vasoconstrictor propylhexedrine (Jie calpha-1/alpha-2 adrenoceptor). or phenylephrine or phenylpropanolamine or ephedrine or pseudoephedrine or naphazoline or hydrochloride or oxymetazoline hydrochloride or tetrahydrozoline hydrochloride or xylometazoline hydrochloride or tramazoline hydrochloride or ethylnorepinephrine hydrochloride as the present invention relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; and anticholinergic agents of action, including muscarinic (M1) receptor antagonist and atropine Jie (M35 M2 i.e. hyoscine). or ipratropium sl glycopyrrrolate bromide 0 or tiotropium bromide or oxitropium bromide or pirenzepine or telenzepine. The invention [Mall] still relates to a combination of one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; and the beta-adrenoceptor helper (including the receptor subtypes 1-4 Jie (subtypes): isoprenaline and corciprenaline 5 terbutaline 5 ¢salmeterol s formoterol 5 salbutamol bitolterol mesylate or epirbuterol or chiral isoforms thereof.

As the present invention relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt called “chromone jy” such as sodium cromoglycate i.e. nedocromil sodium, as the present invention relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; WITH : A glucocorticoid© such as flunisolide or triamcinolone acetonide or beclomethasone mometasone or ciclesonide or fluticasone propionate or budesonide or dipropionate-furoate as the present invention relates to a combination containing one of the special compounds by invention; or a pharmaceutically acceptable salt of PPARs fis nuclear hormone thereof; With an operator who modifies the receiver

0 The present invention also relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; with an immunoglobulin (Ig), an Ig preparation, an antagonist, or an antibody that modifies the function of the Jie Ig with an anti-IgE (such as omalizumab). The present invention also relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; and another anti-inflammatory agent for systemic use.

\o or topically, such as thalidomide or one of its derivatives. or “retinoid,” “dithranol,” or “calcipotriol.” As the present invention relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; And a combination of sulfapyridine 5 aminosalicylates such as mesalazine s sulfasalazine

gy = - balsalazide s and olsalazine and immunomodulatory factors such as compounds ::; budesonide Jie corticosteroids “US yy The present invention also relates to a combination containing one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; With Jie antibacterial agent a derivative of ¢penicillin “metronidazole s” ¢fluoroquinolone s “beta-lactam 5” macrolide 5 “tetracyclines © aminoglycoside taken by | for inhalation tinhaled and antiviral agent “amantadine s” cidofovir s “ganciclovir s” valaciclovir s “famciclovir s” acyclovir ded < zanamavir s “ribavirin y < rimantadine 5” and “Amsamah? and a protease inhibitor such as nelfinavir y < indinavir and ¢ritonavir 20011817?; and a nucleoside 0 reverse transcriptase inhibitor such as lamivudine s, didanosine, sstavudine, zalcitabine, zidovudine, or an efavirenz inhibitor. nevirapine Jie non-nucleoside usSaall transcriptase All of the invention relates to a combination containing one of the compounds of the invention” or a pharmaceutically acceptable salt Jules cate Cardiovascular as one of the calcium channel blockers “channel blocker” a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE)10 inhibitor, an antagonist for the tangiotensin-2 receptor, and a lipid lowering agent such as a statin or 16H:5F ; And a modifier for blood cell morphology such as ¢pentoxyfylline and an anti-Saal thrombolytic factor or anticoagulant such as day ie for platelet aggregation. aggregation inhibitor

The present invention also relates to a mixture containing one of the compounds of the invention” or a pharmaceutically acceptable salt thereof; Jie ONS antidepressant agent (such as sertraline), anti-Parkinsonian 8 anti-parkinsonian drug (such as L-dopa, ropinirole s (deprenyl cpramipexole) and an inhibitor of MAOB such as crasagiline 5 selegine and an inhibitor of Jie comP antagonism, an inhibitor of L-2, a dopamine reuptake inhibitor, an NMDA antagonist, an anicotine cofactor, a dopamine cofactor, or a nitric oxide synthase inhibitor, i.e. anti-alzheimer's Jie such as “donepezil” or “tacrine crivastigmine” or “COX - 2 dha” or “propentofylline” or “metrifonate” as the present invention relates to a combination containing one of the compounds of the invention” or an acceptable salt 0 pharmacologically; an agent for the treatment of acute or chronic pain; such as an analgesic agent acting centrally or peripherally (such as an opioid or one of its derivatives); or “carbamazepine,” “phenytoin,” “sodium valproate,” or camitryptiline or any other canti-depressant agent(s) or cparacetamol or a non-steroidal anti-inflammatory agent as the present invention relates to a combination containing one of the compounds of the invention ; or an acceptable salt Waa 00 thereof; with a local anesthetic agent used parenterally or topically (including by inhalation) such as lignocaine or one of its derivatives. A compound of the present invention or a pharmaceutically acceptable salt thereof may also be used; In combination with an anti-osteoporosis agent including any hormonal agent craloxifene Jie or alendronate (fie biphosphonate)

blood

The present invention also relates to a combination containing one of the compounds of the invention; or acceptable salt

pharmacist from him; With A: (1) a stryptase enzyme inhibitor (7) an anti-platelet activation factor

(Y) platelet activating factor (PAF) inhibitor of interleukin-4 (ICE) converting enzyme (£)

1 (°) adhesion molecule inhibitors including ¢VLA-4 antagonist (1)

(V) ¢cathepsins 0 A kinase inhibitor such as a tyrosine kinase inhibitor (such as 806, chlorine, or

threonine kinase [serine and enzyme ¢ (imatinib mesylate) or gefitinib Jae (MAP) or JaK3

hfe Jia) for INK «P38 Jie MPA kinase or protein kinase A or 8 or Se (IKK) enzyme

6 that contributes to the regulation of the cell cycle (eg, coenzyme 6 dependent on (A)¢(cylin)

¢glucose-6 phosphate dehydrogenase (9) antagonist ¢glucose-6 phosphate dehydrogenase receptor antagonist ¢B2-81 or ¢B2 (V4) 0 anti-gout agent (VV) tcolchicine Jie canti-gout xanthine inhibitor oxidase (VY) allopurinol Jia an agent that promotes the secretion of curicosuric acid such as probenecid or sulfinpyrazone or (VY) tbenzbromarone secreting growth hormone; (VE) transforming growth factor (TGFp) (10) platelet-derived growth factor (PDGF) (11) fibroblast Jie growth factor 0 basic fibroblast growth factor ¢ (bFGF) except 1 macrophage colony (VA) stimulating factor (GM-CSF) and cream (V4) capsaicin antagonist of tachykinin 11161 or NK3 receptor such as NKP - 608C or 233412 (talnetant) SB- or 08 (14) inhibitor of UT-77 Js elastase or (Y + ) ¢ZD-0892 inhibitor of TNF-alpha (Y) converting enzyme (TACE) 0 inhibitor of induced nitric oxide synthase (iNOS); (YY) molecule homologue of the chemoattractive receptor expressed on cells 1112 Jie) antagonist (YY)¢ (CRTH2)

- tt - |

daria of (VY) P28 is a modulator of function of TOLL-like receptors (a type of

receptors) (Yo) ¢ (TLR) factor that modulates the activity of allogenic receptors Je 5277; (Y1) activation inhibitor

Cloning parameter such as NFKB, API, or .STATS

It is also possible to use one of the compounds of the invention; or a pharmaceutically acceptable salt thereof; in combination with a factor

0 therapeutic already existing used in the treatment of cancer cancer eg agents include

Appropriate on:

)(/( Anti-proliferative [antiproliferative] antineoplastic anti-tumor growth drug or

a combination thereof; As used in the field of oncology; Jia is an alkylation agent cis Jw) alkylating agent

taddam, carboplatin, cyclophosphamide, nitrogen mustard containing mustard 0, melphalan, chlorambucil, busulphan, 008); and antifungal agent

for metabolites 16a (eg antifolate, fluoropyrimidine, 5-fluorouracil or

8 or craltitrexed any “methotrexate” or “cytosine arabinoside” or hydroxyurea or

gemcitabine or (paclitaxel; AAA antitumor antibiotic (such as

anthracycline such as adriamycin or bleomycin or doxorubicin or daunomycin or idarubicin 0 cepirubicin 00 or mitomycin-C or dactinomycin or ¢ (mithramycin) and factor

antimitotic agent (such as cvincristine Jie vinca alkaloid “vinblastine” or

vindesine or vinorelbine or taxol J——3 taxoid or (taxotere); or an enzyme inhibitor

“etoposide (fis epipodophyllotoxin Jia) topoisomerase or 160100506 or camsacrine or

¢ (camptothecin or topotecan

E: 14

(Y) antioestrogen Jie cytostatic agent (such as tamoxifen, ctoremifene, droloxifene sl raloxifene, iodoxyfene, or an uncontrolled regulator of the receptor (fulvestrant Js) oestrogen or “flutamide sl” (bicalutamide Js) antiandrogen (cyproterone acetate or antagonist 111811 or LHRH adjuvant (such as goserelin or coenzyme 10 or (megestrol acetate Jie) progestogen 0') buserelin and an aromatase é inhibitor (such as anastrozole, detrozole, vorazole, exemestane, or a reductase 4 inhibitor such as finasteride (Y) is an agent that inhibits the invasion of cancer cells cancer cell (e.g. a metalloproteinase inhibitor e.g. marimastat or an inhibitor of urokinase activated receptor function ¢(plasminogen ~~ \: (£) cgrowth factor function inhibitor e.g. antibody For the growth factor sail (Jie) antibody, the canti-erbb2 antibody ~~ trastuzumab or the antibody (cetuximab [0225] canti-erbbl; or Jase for the enzyme “farnesyl transferase” or an enzyme inhibitor tyrosine kinase or serine/threonine kinase inhibitor; Or a Jalal inhibitor of epidermal growth factor 10 family (such as an inhibitor of the tyrosine kinase enzyme of the EGFR family such as: N-(3-chloro-4-fluorophenyl)-7-methoxy- 6-(3 -morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)quinazolin-4-amine (erlotinib, 051- 774( or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033))

Or laste of the platelet-derived growth factor family “family” or related to the shepatocyte growth factor family 0 Antiangiogenic agent Jie is one of the factors that Inhibits vascular endothelial growth factor 0 (eg anti-vascular endothelial cell growth factor antibody). L, 7, or 4 14/177) or a compound acting by another mechanism (such as 1100106, an inhibitor of integrin ovB3 function, or ¢(angiostatin 0(1)), a vascular damaging agent such as combretastatin A4 or a compound then disclosed in international applications 44/07137 or 0/0874 or 4TAR or 4R Tadhart); 791 (agent used as an antisense agent Jie cantisense an agent that is directed at one of the aforementioned targets sf ISIS 2503 Jie canti-ras antisense (A)1 agent used in the study of gene therapy, such as studies to replace abnormal P53 aberrant genes or BRCALI or abnormal BRCA2 or 7 (treatment with a pro-drug for a genetically directed enzyme (gene-directed enzyme) and studies (Jie) that are conducted using the enzyme cytosine deaminase or the enzyme thymidine kinase or the enzyme “bacterial nitroreductase”

And studies that are being conducted to increase the patient’s tolerance for chemotherapy or radiation therapy, Jie radiotherapy, “resistance gen” [21] drugs, ¢multi-drug, or Jule (1) used in the study of immunotherapy; such as ex-vivo or in-vivo studies to increase the immunogenicity of tumor cells in a patient; Jie WAY infection with interleukin 4 of “interleukin 2” Jie cytokine or factor inducing phagocytic cell reproduction of the granulosa cell and studies that are conducted to reduce the energy of the “T” cell and studies that are conducted using infected immune cells such as infected branching cells with cytokine infection and studies using cytokine-infected tumor cell lines and studies using | to alld antibodies. Antibodies genetic factors. 1. Detailed Description: The invention will now be explained by the following examples; where the standard techniques are known to an experienced chemist in the art; 1 Similar techniques (Sh) described by these examples are used where appropriate: H NMR spectra of 1 were recorded with a Bruker DPX300 FT spectra or of 1 during a Flow NMR process Using an AVANCE 500 FT spectrometer and using chloroform sl d6-dimethylsulphoxide (06-01450) treated with (CDCl) deuterated with data expressed as chemical shifts in parts per million by TMS internal standard Jalal on scale 6 and with multiplicity =b) wide; =s odd; =d double =1t triple; =q quad; =qn quintile; 8X = hexagonal; =h seven) 4 and integration.

M - The mass spectra were obtained at a low resolution mass spectra using the mass spectrometry system ALS liquid chromatography Cua Waters. Purity is determined by UV absorption with a length of 358 Yot ily wavelength nanometer and mass ion determined by electrospray ionisation 0 (Micromass tool) The reverse phase column used was 4.76 mm 8 mm A+ Phenomenex Synergi Max-RP Angeptrum and the solvent system was water containing Le acetonitrile 5 formic acid 7001, not otherwise specified.typical run was 0.0 min with a 5.0 min scale from 0 to £30 of .acetonitrile microwave reactions were performed in a 0 W Smith synthesiser (AEF) on either normal or high settings using appropriate tubes suggested by the manufacturer. Column chromatography was carried out typically using silica gel (grade 4 (Merck) and solvent mixtures and gradients were visualized in this context. Purification was performed by high-performance reverse phase chromatography VO typically using Perkin Elmer SLA using UV detection at Yost 18 nm and 18 1900 X 71.7 mm column. 001 A Phenomenex. Acidic conditions (from 110 to 70.8 formic or ammonia) basic conditions to pH 01 were used using graded solvent mixtures of acetonitrile and water.

— $9 - Scx columns are supplied from international sorbent technology and used as described in this specification. Aldrich's high purity dry solvents are supplied and used as is. 0 The following abbreviations are used in this patent: hexafluorophosphate hexafluorophosphate chloride hexafluorophosphate performance liquid chromatraphy mass spectrometry

a — 0 _ sodium hexamethyldisylamide dimethylacetamide diethylazodicarboxylate meta-chloroperbenzioc acid mCPBA dimethylsulphoxide DMSO 1,8-diazabicyclo[5.4.0]Jundec-7-ene dichloromethane substrate 0.1 | 10 molar of hydrochloric acid in methanol Example 1 (1R,2R)-N-(1-cyanocyclopropyl)-2-{(8-fluoro- 1,3,4,5-tetrahydro-) 2H-pyrido[4,3-b]indol- 2-yl)carbonyl]cyclohexanecarboxamide as Noe 23 L | ee Aa for Nes A the NT 0 & .> © comment 0 ) (IR,2R)-Cyclohexane-1,2-dicarboxylic acid mg; AY mmol) in (Je Y) acetic anhydride and stirred at 80°C for one hour. The mixture was cooled, concentrated in cfte medium, separated once with toluene, and dried under reduced pressure to yield 3aR,7aR)-hexahydro-2-benzofuran-1,3-dione as a white solid - white solid 0 was absorbed in (Je 5) DMF ¢ and:

_— 3 0 _- Vit) 8-fluoro-2,3,4,5-tetrahydropyrido[4,3-B]indole mg .1 mmol) and the solution was stirred at room temperature for * hours. Add: 14 (1-Aminocyclopropanecarbonitrile hydrochloride mg; 1971 mmol) then 1 07 (triethylamine 1.10 mmol) and : PyBOP) benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate 0 » £44 mg 195 mmol) and the mixture was stirred overnight. DMF is removed in vacuo and the remainder divided between 1 x DCM (ml) and 1215 brine (dw V+) brine The combined organics were treated with saturated aqueous sodium bicarbonate (Ja 01( aqueous and brine V+) brine ml); “(magnesium sulphate) and concentration 0. were dried in vacuo and adsorbed on silica for purification by flash chromatography (from zero Ihe acetate / isohexane primer). for more piety; The sample was pulverized twice with diethyl ether la-mai (Jeo x ¥) » filtered and dried under reduced pressure. This produces: (1IR,2R)-N-(1 -cyanocyclopropyl)-2- [(8-fluoro-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indol- 2-yl)carbonyl]cyclohexanecarboxamide 1 as Y£.4) white solid mg (IV MS (+ve ESI): 408.9 (M+H)" 'H{ NMR (400 MHz, DMSO) 6 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 1H), (m, 3H), 3.8 (m, 2H), 4.5-4.7 (m, 2H), 9.9 (m, 1H), 7.2 (m, 1H), 7.3 (s, 1H), 8.65 2.7-3.0 (s, TH), 11.0(s, 1H) ) 0 Example Y Y14¢

—- 0 Y — (1R,2R)-2-[(8-chloro-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b] indol-2-yl)carbonyl]-N- (1-cyanocyclopropyl)cyclohexanecarboxamide

Now with 1 1

JN ~My 90 AH 1 J 1 34 7 2 J 1 As ct r >:

Sa 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-blindole] following example 1a but starting with compound (separation by silica gel chromatography mmol) and purification by 1 44. came 0 0 The aforementioned compound is produced in (ethyl acetate/isohexane / 790010- sequentially using from zero the title in the form of a white solid 17.01 (white solid VY 7 product). MS (-ve ESI) : 426 (M+H)" "NMR (400 MHz, DMSO) 8 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H),2.4 ( m, 1H), (m, 3H), 3.8 (m, 2H), 4.5-4.7 (m, 2H), 7.0 (m, 1H), 7.2 (m, 1H), 7.5 (m, 1H), 8.6 2.7-3.0 (m, 1H), 11.1 (s, 1H) Example?(1IR,2R)-N-(1 -cyanocyclopropyl)-2-[(6-fluoro-1,3,4, 5 -tetrahydro-2H-pyrido[4,3-b]indol- 2-yl)carbonyl] cyclohexanecarboxamide E 7 N Te m I a at la pour J 7 [1 Ba rr 1 N Ey p \o

oy — _ following example 1; but starting with 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 1) mg AY mmol) The compound mentioned in the title is produced in the form of a white solid

(p21) 4) white solid 74 7 output). MS(-veESI):410(M+H)" 'H NMR (400 MHz, DMSO) 6 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 1H), (m, 3H), 3.8 (m, 2H), 4.5-4.7 (m, 2H), 6.85 (m, 1H), 7.3 (m, 2H), 8.5 (m, 1H) , 2.7-3.0 (s, IH) 11.0 Example ¢ (1R,2R)-N+(1 -cyanocyclopropyl)-2-(1,3,4,5 -tetrahydro-2H-pyrido[4,3- b]indol-2- ylcarbonyl)cyclohexanecarboxamide No. I 0 M AB A LY 1%, k “ 0 MS (-ve ESI) : 392 (M+H)” (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 1H), 0.8-1.1 E" HNMR (400 MHz, DMSO) (m, 3H), 3.8 (m, 2H), 4.5-4.7 (m, 2H), 7.0 (m, 2H), 7.4 (m, 2H), 8.5 (m, 1H), 11.0 2.7-3.0 (s, 1H) \o o Judi

— $ 0 -— ‎(1R,2R)-2-[(8-bromo-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b] indol-2-yl)carbonyl]-N Br ! SN 0 following example 1a but starting with a compound:

01 1) 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 0 mg; (147 mmol) the compound mentioned in the title is produced as a yellow solid (cane YY 717 yield).

MS (-ve ESI) : 470 (M+H)" 'H NMR (400 MHz, DMSO) 8 0.8-1.1 (m, 2H), 1 3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 1H), 2.7-3.0 (m, 3H), 3.8 (m, 2H), 4.5-4.7 (m, 2H), 7.1 (m, 1H), 7.3 (m, 1H), 7.6 (m, 1H ), 8.65 00 (s, 1H), 11.0(s, 1H) 1 Example (1IR,2R)-N-(1 -cyanocyclopropyl)-2-[(6-methyl-1,3 ,4,5 -tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide

AY

Yoo. yd b "ed 4 with LA ham na 9 l

O = A He A,

Ne NN

Co N 6-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole : following Example 1; But by starting with the white compound (6 mg .a mmol), the compound mentioned in the title is produced in the form of white foam (mg; 47 7 result). 17 1) Color foam

MS (+ve ESI): 425 (M+H)" ° "HNMR (400.132 MHz, CDCls) 6 0.85 - 1.96 (1 1H, m), 2.62 (1H, t), 2.87 (2H, m), 3.03 ( 2H, m), 3.61 - 4.40 (2H, m), 4.67 - 4.90 (2H, m), 6.63 (1H, d), 7.04 (1H, m), 7.16 (1H, t), 7.35 (1H, m) , 8.16 (1H, m) v Example (IR2R)-N-(1-cyanocyclopropyl)-2-{ [8-(trifluoromethyl)-1,3,4,5-tetrahydro-2H-pyrido[4, 3-blindol-2-yl]carbonyl}cyc lohexanecarboxamide © ccm ho NE, o 2 m' six Ht A 5 \ z= 0 0 1 > 7 and following the example 1; but starting with a boat:

_ 1 0 M YE) 8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-bJindole aggregate; 0001 mmol); The compound mentioned in the title is produced in the form of yellow gum (£4 cana Y).

ot 7 output). MS (+ve ESI): 459 (M+H)" HNMR (400.132 MHz, CDCls) 5 0.83 - 1.96 (12H, m), 2.59 - 3.10 (4H, m), 3.72 - 4.21 ° (2H, m), 4.52 - 5.06 (2H, m), 6.81 (1H, d), 7.33 (1H, m), 7.39 (1H, 5), 7.70 (1H, d), 8.45 (1H, d ) 8-(trifluoromethyl)-1,3 4 5-tetrahydro-2H-pyrido[4,3-b]indole was prepared by the following method: B F A Amer TS J 7 H “FN 0 Following the previous example but starting with (4-trifluoromethy!)phenylhydrazine hydrochloride 01 cp 7 mmol) the compound mentioned in the title is produced in the form of a yellow solid 0 0 Total 715 yield ). MS (+ve ESI): 240 (M+H)' 'HNMR(400.132MHz, DMSO) 2.75 (2H, 1),3.08 (2H, 1),3.94 (2H, 5),7.34 (1H, d),7.50 (1H, d),7.75 (1H, 5), 11.30 (1H, 5) vo Example A (1R,2R)-N-(1-cyanocyclopropyl)-2- [( 8-methoxy-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b] indol-2-yl)carbonylJcyclohexanecarboxamide

— 0 7 _ o

A

L.A

1 m ham

Ea

NS l b onan IN ¢ < 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole following Example 1; But by starting with a compound (mmol) the compound mentioned in the title is produced as a yellow solid (<7 mg; 101 mg YX) yield). 7

MS (+ve ESI): 421 (M+H)" °' HNMR (400.132 MHz, CDCl3) 6 0.82 - 1.91 (13H, m), 2.63 (1H, m), 2.82 (1H, m), 3.00 (1H , m), 3.61 and 4.38 (1H, m), 3.86 (3H, d), 3.86 (1H, m), 4.76 (2H, m), 6.68 (1H, d), 6.81 (1H, m), 6.90 ( 1H, m), 7.19 (1H, m), 7.82 (1H, d) 01, 8 Examples (IR2R)-N-(1 -cyanocyclopropyl)-2-[(9-fluoro-1,3 ,4 ,5-tetrahydro-2H-pyrido[4,3-b]indol- 2-yl)carbonyl]cyclohexanecarboxamide

Pree 7 E D A B N 1 No Sy, (1R,2R)-N-(1 -cyanocyclopropyl)-2-[(7-fluoro-1, 3 4,5-tetrahydro- 2H-pyrido[4,3-bJindol- 2-yl)carbonyl]cyclohexanecarboxamide

A _ qm m — for TR IL Mo 2C and x © 7 has the expression LN Na and “] following example 1; but starting with a mixture of: H-pyrido[4,3-bJindole-9- fluoro-2,3,4,5-tetrahydro and 1H-pyrido[4,3-blindole-7- 1 fluoro-2,3,4,5-tetrahydro (30:70) Ya. ) 0 mg; 0.10 mmol) and heating the reaction mixture 0 at + 22 for a period of YA hours. The compound mentioned in the title is produced in the form of a mixture of jsomers produced for purification using a column “(ethyl acetate / isohexane 7860 — ja) chromatography : (1R,2R)-N-(1 -cyanocyclopropyl)-2-[(9-fluoro- 1,3,4,5-tetrahydro-2H-pyrido[4,3-b] indol-2- yl)carbonyl]cyclohexanecarboxam ide 0 as a yellow solid (0.10 mg product) and: (1R,2R)-N-(1-cyanocyclopropyl)-2- [(7-fluoro-1) ,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indol- 2-yl)carbonyl]cyclohexanecarboxamide as yellow solid (.1 mg A product). (1R,2R)-N-(1-cyanocyclopropyl) -2-[(9-fluoro-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indol- 2-yl )earbonyi]cyclohexanecarboxamide MS (+ve ESI): 409 (M+H)"

— 0 q _— 'HNMR (400.132 MHz, DMSO) 8 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 1H), 2.7-3.0 (m, 3H), 3.8 (m, 2H), 4.5-4.7 (m, 2H), 6.7 (m, 1H), 7.0 (m, 1H), 7.1 (s, 1H), is 8.7 (s, 1H), 11.2 ( s, 1H) (1R,2R)-N-(1 -cyanocyclopropy!)-2-[(7-fluoro-1,3 ,4,5-tetrahydro-2H-pyrido[4,3-b]indol- 2 -yRycarbonyl]cyclohexanecarboxamide

MS (+ve ESI): 409 (M+H)" 'HNMR(400.132 MHz, DMSO) 5 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H),2.4 (m, 1H), 2.7-3.0 (m, 3H), 3.8 (m, 2H), 4.5-4.7 (m, 2H), 6.8 (m, 1H), 7.05 (m, 1H), 7.4 (m, 1H), 8.7 (s, 1H), 11.0(s, 1H).1H-pyrido[4,3-blindole-9-fluoro-2,3,4,5-tetrahydro and 1H-pyrido[4,3-blindole-7- fluoro-2,3,4,5-tetrahydro used as a starting material are as follows: ml.(A+) ethanol mmol) in YEA g; ¥.YV) piperidin-4-one hydrochloride is Dissolve 1.8 can £.+£) 3-fluorophenylhydrazine hydrochloride Water is added (? drops) then mmol) and the reaction mixture is heated on reflux for an hour. The mixture is left to cool down to a temperature Ve min. Repeated 01 into bubbles through the solution for about room hydrogen chloride and gas reflux for 0 hours. Suspension cooled to room temperature overnight; cooled to 0 mL). Residue is absorbed in Te water (compared to M ethanol and the product filtered and washed with tell sodium hydroxide using ¥ M made basic; made basic (Je)

aks The resulting precipitate was filtered and washed with water to produce the desired compounds in the form of a yellow solid consisting of a mixture of: isomers (9-fluoro-2,3,4,5-tetrahydropyrido[4,3-Blindole: 7- fluoro-2,3,4,5- tetrahydropyrido[4,3-BJindole (30:70)) VV) 0 717 g/product). The isomers were conjugated by column chromatography and Use the mixture directly in the next step. Example 11 : (1R,2R)-N-(1-cyanocyclopropyl)-2- [(8-isopropyl-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b] indol-2-yl)carbonyl]cyclohexanecarboxamide 1 mY AEN lo © 0 Nn whose core is “Y” J { NS \ . following JU 1; But starting with 8-isopropyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (ARA) mg 1 mmol (the compound mentioned in the title is produced as a yellow solid LEY cana YA) yellow solid output). MS (+ve ESI): 433 (M+H)" Y14¢

'HNMR (400.132 MHz, CDCl;) 8 0.83 - 1 92 (19H, m), 2.58 - 3.09 (SH, m), 3.59 and 4.40 (1H, m), 3.88 (1H, m), 4.65 - 4.92 (2H , m), 7.05 (1H, 0, 7.23 (1H, 1), 7.29 (1H, d), 7.85 (1H, d) 8-isopropyl-2,3,4,5-tetrahydro-1H-pyrido[4 ,3-b]indole 4-isopropylphenylhydrazine hydrochloride following Examples 5 and 10 but starting with compound oo mmol); The compound mentioned in the title is produced in the form of a solid with a yield of 10 mg A (product). 1/1 Cp V.0 (yellow color)

MS (+ve ESI): 215 (M+H)' "HNMR (400.132 MHz, CDCls) 8 1.29 (6H, d), 2.74 (2H, t), 2.99 (1H, m), 3.22 (2H, t) , 4.07 (2H, s), 7.02 (1H, m), 7.22 (2H, m), 7.69 (1H, s) 11 Example (1R,2R)-N-(1 -cyanocyclopropyl)-2- [ (8-fluoro-5-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide

Mee m 8 1 a i WN Mee ~~ ~ oo

No I } 1 a F ( yt “ l) following example 3 but starting with a compound: 1

Y —_ 7 _— YO ) 8-fluoro-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole mg 0.16 m ( Use and heat the reaction mixture, Pybop, when done overnight; the compound mentioned in the title is produced as a yellow solid (1.0 mg” 17/product). MS (+ve ESI): 423 (M) +H)' 'HNMR(400.132 MHz, DMSO) 5 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, ° 1H), -2.7 3.0 (m, 3H), 3.65 (d, 3H), 3.9 (m, 2H), 4.5-4.75 (m, 2H), 6.9 (m, 1H), 7.3 (m, 2H), 8.5 (m, 1H), then prepare: 8-fluoro-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride used 1 as a starting material as follows: bY No ~ [l (m FN AN p. 7 0 m / m) is dissolved: tert-Butyl-8-fluoro-5-methyl-1,3,4,5 -tetrahydro-2H-pyrido[4 ,3-b] indole-2-carboxylate®. 1) 1,4-dioxan and the solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo; separated azeotroped once with toluene and the Y14¢ brown solid dried under reduced pressure to yield The compound mentioned in the title as a brown solid (yield). ), 4.25 (s, 2H), 7.0 (t, 1H), 7.3(d, 1H), 7.5(m, 1H), 9.7 (s, 1H) * Ruediger, Edward H.; Deon, Daniel H.; Kadow, John F. Preparation of tetrahydrocarbolines for treatment of HIV infection and AIDS. U.S.A. Pat. Apple. Publ. (2005), 12 pp. CODEN:USXXCO US 2005267130 Al 20051201 CAN 144:22907

AN 2005:1262744 CAPLUS 11 Example (1R2R)-2-[(6-bromo-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b] indol-2-yl)carbonyl] -N-(1-cyanocyclopropyl)cyclohexanecarboxamide ! aT #1 8 Bach LLL: QN AKR 8H” iN mh

TN 2 4 6-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole by starting with hy by following the example at 0006C overnight » Pybop is produced in mmol ) and heating the reaction mixture 100 mg; YOO (yield). 7 5 cana Ye) white foam + the compound mentioned in the title as white foam

MS (+ve ESI): 469 (M+H)" Tah

- + 3 — 'HNMR (400.132 MHz, CDCls) 5 0.83 - 1.96 (13H, m), 2.62 (1H, t), 2.87 (1H, m), 3.03 (1H, m), 3.61 - 4.39 (2H, m) ), 4.77 (2H, m), 6.68 (1H, d), 6.99 (1H, m), 7.31 (1H, t), 7.38 (1H, t), 8.12 (1H, s): Prepared: as follows ced as 6-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 0 mL 10 g; (4 017) (2-bromophenylhydrazine) as follows Examples 9 and 10, but starting with a compound

VA (mol) The compound mentioned in the title is produced as a yellow solid mg; 7743 output).

MS (+ve ESI) : 251 (M+H)" "HNMR (400.132 MHz, DMSO) 8 2.70 (2H, t), 3.01 (2H, t), 3.84 (2H, s), 6.88 (1H, 1) , 01 7.20 (1H, d), 7.33 (1H, d), 10.88 (1H, s) ye Example (1R,2R)-N-(1-Cyanocyclopropyl)-2-[1,3,4, 5-tetrahydro-1H-pyrido[4,3-B]-7-azaindol-2-yl)carbonyl]cyclohexanecarboxamide

Boe” and “We I 0 2 p 0 0 a boe a l os pe j ahas: STN re” Vo: following example 1 but starting with a compound

Combine “” _ Yoo) 2.3,4,5-tetrahydro- 1 H-pyrido[4,3-b]-7-azaindole mg; 0.15 mmol) and heat the reaction mixture Pybop at +10 °C *m Overnight the compound mentioned in the title is produced as a yellow solid (m 846 mg yield). 1.75 (m, 4H), 2.4 (m, 0.8-1.1 HNMR(400.132 MHz, DMSO) 1H), 2.7-3.0 (m, 3H), 3.8 (m, 2H), 45-47 ( m, 2H), 7.0 (m, 1H), 7.85 (m, 1H), 8.13 (m, 1H), 8.65 (s, 1H), 11.4 (s, 1H) Then build up: 2,3. ,4,5-tetrahydro-1H-pyrido[4,3-b]-7azaindole 0 used as a starting material is as follows: sb p M~N «OL N= { commented 2 -Hydrazinopyridine dihydrochloride (© g; YV.O mmol) and: 1 A) 1-benzylpiperidin-4-one g; YV.0 mmol) in (Jw V+) ethanol is added (Je X) acetic acid, and the mixture is stirred at 1 for reflux for two hours, cooled to room temperature 1, and concentrated in an incubator medium. The remaining material is divided between aqueous sodium hydroxide (+1) Ja Vex ( dichloromethane 5 (Je) and the combined organics ¢ (sodium sulphate) were dried and concentrated in vacuo and adsorbed on silica for purification by

Chromatography and sequencing using zero —0)/ dichloromethane / interrupt. This yields: -benzylpiperidin-4-one pyridin-2-ylhydrazone 1 in the form of light yellow a3 gum Used as crude in the following reaction Vay) g; 001 output). 7 PS 3.5 (t, 2H), 24 (t, 2H), 2.6 (m, 2H), 2.3 HNMR (400.132 Miz, DMSO) (m, 1H), 7.05 (d, 1H), 7.35 (m, SH), 7.55 (t, 1H), 8.05 (d, 1H), 9.4 (s, 1H) Noe oe LOD NR after 1 b) polyphosphoric acid added ) + g) to : v.14) 1-benzylpiperidin-4-one pyridin-2-ylhydrazone g; 777.5 mmol) and 0 the mixture was stirred gently at V0 for 4 ? hour. The mixture is cooled to room temperature and ice (0 g) is added to break the polyphosphoric acid gum. The reaction mixture ed basic was made using ? Molar of 0 aqueous hydroxide and 1 was extracted using ethylacetate (7*1007ml). The combined organic extracts are treated with brine (+4 ml); It was dried (sodium sulphate) and concentrated in a medium of 1 in vacuo. It was adsorbed on silica for purification by “chromatography. The sequential separation was done using dichloromethane 7) += ja / 06108001. It was clarified that the mustard-colored solid VoA ) mustard colored solid g) obtained; By NMR it is not pure and therefore it was crushed using a small amount of dichloromethane and filtering and drying to produce

oy - the compound mentioned in the title in the form of a sand colored solid «a> Y.+ +) sand colored solid 2 results). HNMR (400.132 MHz, DMSO) 52.8 (s, 4H), 3.6 (s, 2H), 3.75 (s, 2H), 6.95 (m, 1H), (m, 5H), 7.7 (4, 1H) ), 8.1 (5, 1H), 11.35 (s, 1H) 7.35 N--.©. N _the- MN NJ 0 c) JS is suspended from Y. 4+)2,3,4,5-Tetrahydro-1 -benzyl-pyrido[4,3-B]-7-azaindole G 0 mmol) ¢ 100016 pa Y.VA) ammonium 54.0 mmol ) and 10 7 palladium (Y4+) carbon le hydroxide mg) in 0 (ethanol ml) and stirred on reflux. After 1 hour, more ammonium formate (140 mg; 1 equiv.) The reflux continues 0 for one dela.The catalyst is filtered by 6;washed with a small amount of dichloromethane and the combined filtrate is concentrated in vacuo and dried under reduced pressure to produce the compound mentioned in the title in the form of a solid tending to Yellow (1.40 c; 001 / n. MHz, DMSO) 62.7 (t, 2H), 3.05 (t, 2H), 3.85 (s, 2H), 6.9 (m, 1H), 77 400.132) 1711/1 (d, 1H), 8.05 (m, 1H), 11.2(s, 1H) Vo Ex. 11 (1IR,2R)-N-(1 -cyanocyclopropyl)-2-({ 8- [(dimethylamino)methyl]-1,3,4,5 -tetrahydro- 2H-pyrido[4,3-b]indol-2-y1} carbony!)cyclohexanecarboxamide

Neen or

TL i Nye oN Na B. : .

NTT

{ | SEN

Ne J : Following Example 1; But by starting with a compound of mg; YY) N,N-dimethyl-1 -(2,3,4,5-tetrahydro-1H-pyrido[4,3-blindol-8-yl)methanamine at 10 pm overnight; The aforementioned compound (Pybop mmol) is produced and the reaction mixture is heated (4 yield). / 16 mg; (017) in the title as a yellow solid 0

MS (+ve ESI): 448 (M+H)" "HNMR (400.132 MHz, DMSO) § 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.7 (m, 8H), 3.0 (m, 2H), 3.85 (m, 2H), 4.3 (m, 2H), 4.4-4.9 (m, 2H), 7.1 (m, 1H), 7.35 (m, 1H), 7.6 (m , 1H), 8.65 (m, 1H), 11.1 (s, 1H)

N,Nvdimethyl-1-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)methanamine

AN a 5

AN I NN

\ 7 . / 0 \

N-— : but starting with compound 1 following the example g; 9.771 mmol). Y.4+) dimethylaminomethylphenylhydrazine hydrochloride 72100 is cascaded using silica gel. The residue is purified by chromatography.

Yi4¢

J 90 aqueous ammonia Then an increasing polarization to © 7 dichloromethane The compound mentioned in the title is produced in the form of light brown gum dichloromethane | ethanol mg; 7797 output). 1H), 7.2 (m, 2H), 10.6 (s, 1H) 57. Moron, etc, J. Heterocyclic Chemistry, 1992, 29(6), 1573-1576 11 Example (1R,2R)-N- (1-cyanocyclopropyl)-2-{[8-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]carbonyl} cyclohexanecarboxamide

ST

5s

FAN and NI 1 } A the . 5, Co" * 3 p. 1 : following Example 1; but starting with milli tA mg Yeu) 8-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[ 4,3-bJindole at 0°C overnight; the compound mentioned in the title (Pybop mol) is produced and the reaction mixture is heated (product 01) (47 cpa) in the form of a yellow solid

MS (+ve ESI): 469 (M+H)" Vo

= wa MHz, DMSO) 5 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 11/11/8400.132!1H), 2.7-3.0 ( m, 3H), 3.15 (m, 3H), 3.85 (m, 2H), 4.4-4.9 (m, 2H), 7.45 (m, 1H), 7.55 (m, is 1H), 8.1 (m, 1H) ), 8.65 (s, 1H), 11.5 (s, 1H) 0H 8-(Methylsulfonyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-blindole] was prepared by the method — :a ull TN SAD is done a (Ha Rajah 7 b 0) can 0.01 (4-(Methylsulphonyl)phenylhydrazine 5.77 mmol) is suspended in ethanol (Ja V1) ele was added (¥ drops) then (4Y0) 4-piperidone dihydrochloride (mg 0.YY mmol) and (Je 1) acetic acid, and the mixture is stirred at reflux for one hour. The 0 is allowed to cool to Room temperature and concentration in the medium of pie and subjected to azeotroped separation once using toluene and drying under reduced pressure, resulting in: 4-methylsulfonyl-N-(4-piperidylideneamino)aniline hydrochloride as a yellow solid V .0V) yellow solid g #37( MS (+ve ESI) : 268 (M+H)" 2.7(m, 4H), 3.3(s, 3H), 3.6 (m, 4H), 7.25 ( d, 2H), 7.7 (d, vo e' H NMR (400 MHz, DMSO) 2H). Yi4¢

Pour N LAS 7M Ga 8 = 0 suspension of 4-methylsulfonyl-N-(4-piperidylideneamino)aniline hydrochloride (1.01 g 57 mmol) in acetic acid (0?mL) and stirred at Room temperature at an atmosphere of 0..001 "Je 1.YT) boron trifluoride diethyl etherate mmol) is added at a single 0 ratio, and the yellow suspension is stirred at 98°C for two hours, resulting in a dark yaad solution Cooled to room temperature and the acetic acid was removed in vacuo The remaining material was divided among aqueous sodium hydroxide (0 ml) 5 x Y) dichloromethane 100 ml The collected organic materials were dried and aged. (sodium sulphate) combined and the concentration is done in vacuo and adsorption is done at 42 °C for purification by flash silica chromatography (++) DCM to #2 ammonium 0 aqueous (DCM ethanol Jo. This produces: 8- methanesulphonyl-2,3,4,5-tetrahydropyrido[4,3-b]indole in pa (8" light yellow foam (9 mg $e%) (m, 2H), 3.05). m, 2H), 3.15 ) 3H), 3.9 (s, 2H), 7.5 2.7 'H NMR (400 MHz, DMSO) (m, 2H), 7.95 (s, 1H), 11.4 (s, 1H).Vo example in (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-methoxy-1,3,4,5 -tetrahydro-2H-pyrido[4,3- b] ‎indol-2-yl)carbonyl]cyclohexanecarboxamide Tech

S fi 5 A ~ { ~ A, = 0 m To NUN TAN CZ _ n - 3 { mk by following example 1a but starting with compound: (Yo X) 6-methoxy-2 ,3,4,5-tetrahydro- 1 H-pyrido[4,3-b]indole mg; 1 mmol); The compound mentioned in the title is produced as yellow gum (YY) mg; 710 output). MS (+ve ESI): 421 (M+H)" o (12H, m), 2.59 - 3.08 (4H, m), 3.56 (1H, 1.97 - 0.82 E' HNMR (400.132 MHz, CDCls) ) (OH, m), 4.65 - 4.90 (2H, m), 6.64 (1H, 1), 6.89 (1H, 4.42 K m), 3.86 (1H, m), 3.94 (3H, (2H,m), 8.17 (1H,d) 7.04 ,5) 6-methoxy-2,3,4,5-tetrahydro- 1H-pyrido[4,3-blindole ~~ 0 used as starting material is prepared As follows: ~N 0 gl

Same as Example 11, but starting with (V.YA) compound (2-methoxyphenylhydrazine hydrochloride) gm 01 mm (Jse 'The compound mentioned in the title is produced as a solid with a color (Case VAY m product) that was used directly in the next step. HNMR (400.132 MHz, DMSO) § 2.65 (2H, 0, 3.01 (2H, 0, 3.83 (2H, 3), 3.89 (3H, s), 6.5%(1H, d), 6.84 (1H, t) ), 6.91 (1H, d), 10.71 (1H, s) Example YA (1R,2R)-N-(1-cyanocyclopropyl)-2-(1H-spiro[isoquinoline-4,4'- piperidin]-2(3H)- ylcarbonyl)cyclohexanecarboxamide AN 2 ls and ba ol bm © Y md jam I \ 4 eX SN " ] { 0 to solution From : tert-butyl 2-[((1R,2R)-2-{[(1-cyanocyclopropyl)amino]carbonyl} cyclohexyl)carbonyl]- 2,3-dihydro-1H, 1'H-spiro[ isoquinoline-4,4-piperidine]-1'-carboxylate 001 mg; 1% + mmol) in DCM (+ ¥ ml); added TFA (YY) mg; 09 mM ( Use drip and the reaction mixture is stirred for 2 hours.The reaction mixture is concentrated in an incubator and the residue is purified by basic HPLC (compound was diluted with acetonitrile /11.0; filtered; pH adjusted Greater than 9 using (NH;) and the injection is done on a 100 Waters mm column

1 x 4 mm XBridge C18 © Micron; flow 01 mL/min; the solvent INH; 7001 = f water; solvent B = } ¢"CH;CN nm) to produce the desired compound in the form of a white solid (0A) white solid (mg" 7977 yield). MS (+ve ESI): 421 (M+H)" HNMR (400.13 MHz, CDCl3) 81.04 1.13 (1H, m), 1.15- 1.21 (1H, m), 1.31-1.62 (6H, m), 1.86-1.92 (6H, m), 2.03 - 2.11 (1H, m), 2.61 (1H, m), 2.88-3.11 (SH, m), 3.48-4.34 (2H, m), -4.75 4.79 (2H, m), 7.06 (1H, s), 7.11 (1H, m), 7.19 (1H, m), 7.26 (1H, d), 7.45 (1H, m) tert-butyl 2- [((1R,2R)-2-{[(1 -cyanocyclopropyl)amino]carbonyl} cyclohexyl) carbonyl]- 2,3-dihydro-1H, 1'H-spiro[isoquinoline-4,4'-piperidine ]-1 '-carboxylate Oar ne! NL » ZT ml iv a a AS C 7 Sy following methyl 11 but starting with a compound: tert-butyl 2, 3-dihydro-1H,1'H-spiro[isoquinoline-4,4'-piperidine]-1 "-carboxylate (0 mg; 0.97 mmol) The compound mentioned in the title is produced as a colorless oil YAO) \o mg; 1 7 yield).MS(-veESI): 519(M-H)"

EM 7 _ Example 19 (1R,2R)-2-[(6-chloro-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b] indol-2-yl)carbonyl ]-N-(1- cyanocyclopropyl)cyclohexanecarboxam ide “Rg : 0# Sir N W Y -0 N ff \ — J Wy in N JS N \ 5 \ button” 01 2 2 :. b l” nka oo following example 1 but starting with compound Y +1 (6-chloro-2,3,4,5-tetrahydro-1 H-pyrido[4,3-blindole mg 6 mM) Use 'The compound mentioned in the title is produced as a white foam 175 ( foam mg ; 7 yield). 3-b]indole iY 0 ol FE 1 mL N “ WS 0 following Example 11 but starting with compound “a > 1.V4) (2-chlorophenyl) hydrazine hydrochloride (01 mmol) 'The compound in question (Ct gain) is produced as a yellow solid (04Y) as a YA aggregate). MS (+ve ESI): 207 (M+H)" 6 s

“HNMR (400.13 MHz, DMSO) 6 2.70 (2H, m), 3.02 (2H, m), 3.85 (2H, m), 6.93 (1H, m), 7.07 (1H, m), 7.23 - 7.38 (1H, m), 11.00 (1H, s)

Yo Example (1R,2R)-N-(1 -cyanocyclopropyl)-2-[(6-cyano-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indol- 2 -ylycarbonyl]cyclohexanecarboxamide 3 AN NN.AN

I.G

name | NN

AA LU

1 1 =

TN

N

: following example 1; But starting with [international patent application 2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole-6-carbonitrile mmol); The compound mentioned in the title is produced in 0.01 mg; 14 A) 1 ¢f 2.4 mg” 09 7 yield. (YEV) Fig. white solid 0

MS (+ve ESI) :416 (M+H)" "HNMR (400.132 MHz, DMSO) 0.69- 1.04 (m, 2H), 1.11 - 1.46 (m, 6H), 1.60- 1.88 (m, 4H), 2.40 - 2.48 (m, 1H), 2.55 - 3.07 (m, 3H), 3.68 - 3.94 (m, 2H), 4.61 (q, 1H), 4.78 (s, 1H), 7.09-7.19 (m, 1H), 7.53 (t, 1H), 7.85 (q, 1H), 8.71 (d, 1H), 11.86 (s, 1H)

Vo

Ex 71 (1R,2R)-N-(1-cyanocyclopropyl)-2-[(9-methyl-5,7, 8,9-tetrahydro-6H-pyrrolo[2,3-b:4,5) - ¢'|dipyridin-6-yl)carbonyl]cyclohexanecarboxamide N ee” 0 [ 4 Sach 7 0 Make No Ny & N A 0 Noms TREN 1 0 Dissolve: (1R,2R)-N-(1-Cyanocyclopropyl)-2-[1,3,4,5-tetrahydro-1H-pyrido[4,3-B]-7-azaindol-2- yl)carbonyl ]cyclohexanecarboxamide (Example 54 6.60 mg 101 mm (Use) in (Je ©) DMF and stirred at room temperature in an argon atmosphere (J 0.7) iodomethane is added then sodium hydride (4.4 mg; 1,100 mmol). one hour later; The reaction was quenched with saline (Je 01( brine) partitioned with Vo xY) ethylacetate _ml). The combined organic extraction products, 0 (sodium sulphate) combined organic, were dried and concentrated in vacuo, and adsorption was made on silica for purification by means of methanol 7 o— Sa) flash chromatography (s—= asa5 / (dichloromethane) This results : (1R2R)-N-(1-cyanocyclopropyl)-2-[1,3,4,5-tetrahydro-1H-pyridoj4,3-B]-7-N-methylazaindol-2-yl)carbonyl [cyclohexanecarboxamide (as white solid) .7 mg; ov %(

_YA—

MS (+ve ESI): 406 (M+H)" 'HNMR(400 MHz, DMSO) 8 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1 .75 (m, 4H), 2.4 ( m, 1H), 2.65-3.2 (m, 3H), 3.65 (m, 3H), 3.9 (m, 2H), 4.5-4.75 (m, 2H), 7.0 (m, 1H), 7.85 (m, 1H) , 8.15 (m, 1H), 8.65 (s, 1H).

Yy Example 0 (1R,2R)-N-(1-cyanocyclopropyl)-2- {[6-(methylthio)-1,3,4,5-tetrahydro-2H-pyrido[4,3- b] indol -2-yl]carbonyl} cyclohexanecarboxamide

TN oN i m A

Ne 3 0 by 1 liter? Hedhi eee / He A m 0 m a mn : but starting with compound 1 following the example m 0.01 mg | ) 6-methylsulfanyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole ~~ 0 mg; YY £) white solid mol); The compound mentioned in the title is produced as a white solid (product). 7 Ye

MS (+ve ESI): 454 (M+H)" 'HNMR(400.132MHz, DMSO) 5 0.70 - 1.05 (m, 2H), 1.22- 1.54 (m, 4H), 2.31 -2.47 (m, 1H), 2.65 - 2.75 (m, 1H), 2.85 (t, 2H), 2.91 - 3.07 (m, 2H), 3.20 (t, 1H), 3.34 (s, Vo 3H), 3.48-3.93 (m, 4H), 4.48 - 4.75 (m, 2H), 6.97 (q, 1H), 7.05 (q, 1H), 7.36 (q, 1H), 8.69 (s, 2H), 10.94 (s, 1H)

_— 9 7 b: 6-methylsulfanyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole is synthesized in the following way: [2-(methylthio)phenyl]hydrazine >N. _[ N_S o A partial solution of 01 (2-methylmercapto aniline mL; Av mM) was cooled in concentrated hydrochloric acid (01 mL) and (de 1 ) trifluoroacetic to about zero and then the Co remains that way during the addition of a solution of (TY) sodium nitrite g; 93.0 mmol) in water (Je YY) in 0 min. The reaction mixture was stirred at the same temperature for an additional 1 hour upon addition of tin chloride (¥ g 01 mmol) in (Jw © 1) hydrochloric acid during Yo min. The mixture was allowed to warm Reaction with stirring overnight. The resulting material was filtered, washed with TPA and dried (a>VV.A) MS (+ve ESI): 454 (M+H)” HNMR (400.132 MHz, DMSO) 8 2.43 (s, 3H), 7.03 (q, 2H), 7.21 - 7.28 (m, 1H), 7.35 (d, 1H), 7.74 (s, 1H), 10.23 (s, 2H) Vo Y14¢

Ae — - 6-(methylthio)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole IY hat . 7 N-Z L 0" N 0001 can 0.7Y) dissolved 2-(methylthio)phenyl hydrazine mmol) 5 4-piperidone £.0Y (g; 7006 mmol) Win in (Ja VO) ethanol and initially heated to reflux for 0 hr. A heavy precipitate forms from the almost pure solution. The reaction mixture is then treated with concentrated hydrochloric acid (0.0 mL) ) and diluted with more (Ja Y0) ethanol to aid stirring and continued heating for an additional hours. After cooling to room temperature overnight the solid was filtered and washed with (Yo)isopropanol ml). VV (t, 2H), 2.98 (s, 2H), 3.04 (t, 1H), 3.39 ) 3H), 1.90 V” HNMR (400.132 MHz, DMSO) (s, 1H), 7.02 ( t, 1H), 7.10 (d, 1H), 7.30 - 7.46 (m, 1H), 9.15 (s, 1H), 9.61 ( 1H), 427 (s, 1H). 11.17 YY Jedi ( IR,2R)-N-(1-cyanocyclopropyl)-2-[(benzofurof3,2-c]-1,2,3,4-tetrahydropyridyl) carbonyl]cyclohexanecarboxamide . Asl R ED 2 Np 9 tp? 2 Poe, \ L A == Ys

Following example 1a but starting with benzofuro[3,2-c]-1 2,3,4-tetrahydropyridine (017 mg soc mmol) ' the compound mentioned in the title is produced as a white solid (Cada vy zl 1 MS )+ESI) : 392 (M+H)" (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 1H), -0.8 1.1 TH NMR (400 MHz, DMSO) (m, 3H), 3.8 (m, 2H), 4.5-4.8 (m, 2H), 7.25 (m, 2H), 7.6 (m, 2H), 8.75 (m, 1H). Comment can 8 ) O-Phenylhydroxylamine hydrochloride (No.1 mmol) 0 AVY) 4-piperidone hydrochloride 5 g 17.1 mmol) in ethanol (10 mL) hydrochloric aes is added The concentrate (© Jae) and the mixture is stirred upon reflux sad? hours. It is left to cool to room temperature and then iced in an ice bath. The resulting precipitate is filtered and washed using a small amount of cold ethanol. It is then transformed into a slurry in water (Ja Ye) and 1 was extracted using 71*7 (00314 1 ml). The combined organics are washed with brine (Yo) brine ml); Sodium sulphate is dried and concentrated in vacuo, and adsorption is done on silica for purification by flash chromatography:

(ethanol / dichloromethane 750 imethanolic ammonia from fo ADCM ZY +) as a white solid benzofuro[3,2-c)-1,2,3,4-tetrahydropyridine<lld (154) is produced. gm V.YA)

MS (+ve ESI): 392 (M+H)"

TH NMR (400 MHz, DMSO) 8 2.7 (t, 2H), 3.05 (t, 2H), 3.8 (5, 2H), 6.9 (m, 1H), 7.2 (m, 5 2H), 7.5 (m, 2H ).

Ye Example (1R,2R)-N-(1-cyanocyclopropyl)-2-{ [6-(trifluoromethoxy)-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indol -2-yl]carbonyl} cyclohexanecarboxamide 0 SAFE N A 7 DY wy \ Se NT A eh 1) 5 ' Rala NTT - A 1 ~~

F

a 777 mg( 6-Trifluoromethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-blindole] 9724 mg NYY) (3aR,7aR)-hexahydro- 2-benzofuran-1,3-dione (mM) and +4 μM (+00) diisopropylethylamine using argon (ml) in an atmosphere of DCM (1© mol) in mmol) and stirred for one hour. The solvent is largely evaporated and replaced by 0 L 10109 mg; aminocyclopropanecarbonitrile hydrochloride (+0 ml) before adding DMF (0 µg) (©) diisopropylethylamine Lad (00+, mmol) 010 mg; £01 (HATU mmol).

liter TIT (mmol). The reaction mixture was stirred overnight. The reaction mixture was divided into two parts, diluted with aqueous acetonitrile, and purified by preparative HPLC (two injections of 5 M) (formic acid float peaks method, 1:01 1120 scale). Then the product fractions were collected and evaporated to produce a white powder (111 mg YY ( MS ) ESI): 475 (M+H)" °' HNMR (400.132 MHz, DMSO) § 0.68- 1.05 (m). , 2H), 1.11 - 1.47 (m, 6H), 1.58 - 1.87 (m, 4H), 2.64-3.09 (m, 4H), 3.66 - 3.94 (m, 2H), 4.60 (q, 1H), 4.76 (s, 1H), 6.98 - 7.09 (m, 2H), 7.41 - 7.57 (m, 1H), 8.71 (s, 1H), 11.50(s, 1H) Then prepare: Z 6-Trifluoromethoxy-2 ,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole in the following manner. F 105.0 cde 8 ) 2-(trifluoromethoxy)aniline mmol) is cooled and concentrated 0 hydrochloric acid (Je V+) is added. After cooling to zero a solution of sodium nitrite is added (.Y0) g; 18.0 ml (Use in water (de 01) dropwise. The reaction mixture is stirred when

Af — - same temperature for 0 min when adding can ALO ¥) tin chloride £000 mmol) in V+) hydrochloric (aes ml) dropwise” again keeping the temperature at about zero” M. The reaction mixture was stored in a refrigerator overnight and then re-cooled to zero tm. The resulting substance is filtered; and washed with saturated NaCl (V+) (ml) and then :06”:1:1 hexane before drying to yield a © solid (Y.¥1 solid) 714 g MS (+ve ESI): 193 ( M+H)" 'HNMR(400.132MHz, DMSO) 8 7.04 (t, 1H), 7.25 (d, 1H), 7.30 - 7.39 (m, 2H), 8.34 (s, 1H), 10.26 ( s, 2H) 6-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole rN of te AV F 1

70.71 cana ££Y) is dissolved in 2-(methylthio)phenyl hydrazine mmol) 5 4-piperidone TY) mg; 7.70 mmol) molecule in (Ja©) ethanol and heated initially to reflux for 1 hour. A heavy precipitate forms from the almost pure solution. after that; The reaction mixture is treated with concentrated hydrochloric acid (Jo) and diluted with more ethanol (©mL) to aid stirring and heating continues for an additional € hours. After cooling to room temperature throughout

Overnight the solid was filtered and washed with 1500000001 (7 mL); raw material was used.

Yo example

_ A mg (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-ethoxy- 1,3,4,5-tetrahydro-2H-pyrido[4,3-bindol-2- yl)carbonyl]cyclohexanecarboxamide

FAN

Sah 0 On Noi 1 0 0 ; \ - AN A 8 a ad 1 N > b i > y “ r y y l J N er” 6-ethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b [indole but starting with YE following the example mg +6 ...mmol); The compound mentioned in the title is produced as a white solid (0 YY) 7 (YY) white solid.

MS ) ESI) : 435 (M+H)" "HNMR (400.132MHz, DMSO) 8 0.73 - 1.03 (m, 2H), 1.11 - 1.44 (m, 9H), 1.60-1.85 (m, 4H), 2.41-2.50 (m, 1H), 2.54 - 3.06 (m, 3H), 3.63 -3.94 (m, 2H),4.17(q, 2H), 4.55 (q, 1H),4.70(s, 1H), 6.62 ( t, 1H), 6.83 - 6.92 (m, 1H), 7.02 (q, 1H), 8.69 (s, 1H),10.87 (s, 1H). 6-ethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was synthesized in the following way: (2-ethoxyphenyl)hydrazine yo

4 m pave to live Q} 2-phenetidine (1.07 ml 6 mmol) is cooled and concentrated hydrochloric acid (0 ml) is added. After cooling to zero “m; a solution of 0001 aa 11 ¢ (sodium nitrite se) in 70 ele (ml) is added dropwise the mixture was stirred at the same temperature for 0 min © when adding TT. 4) tin chloride g; 1500 mmol) in hydrochloric acid (+£ ml) by drip" again, keeping the temperature at about 0 °C. The resulting substance was filtered; washing was done with NaCl Then 1:2 ether: hexane before suspension in ice/water and ether and made alkaline using 01 M of 118011. The ether layer separates from the aqueous suspendeddil=all solid material after Combination with additional extract; 0 ether was dried and evaporated to produce a .01 yellow crystalline solid (4.91 g 778( 177 thr : MS (+ve ESI) |HNMR(400.132MHz, DMSO) § 1.33 (t, 3H), 3.93 ( 1H), 3.98 (q, 2H), 5.85 (s, 1H), (t, 1H), 6.76 - 6.83 (m, 1H), 7.00 (d, 1H) 6.58 6-Ethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole N sani f > ~~ kham J N li yo Acco can 7 ) (2-ethoxyphenyl)-hydrazine mmol) is heated and:

4-piperidone hydrochloride (4 g; 0.560 mmol) in (da 01) ethanol to the reflux for 1 hour. 4 M of (Je 1) HCI in dioxane (turns color) is added dark brown immediately) and heating continued for € hours. The reaction mixture was cooled to room temperature. The alg solvent was evaporated. The residue was pulverized with ether (compared to 10mL) to yield a dark brown eo solid. solid The solid is slurred with a small amount of water; filtering and drying (MgSO4) is repeated to yield a yellowish solid (1.14 g; 3 M MS (+ve ESI): 177 (M+H) ' HNMR (400.132 MHz, DMSO) 8 1.42 (t, 3H), 3.00 (t, 1H), 3.44 (q, 2H), 4.18 (q, 2H), (s, 110), 6.67 ( d, 1H), 6.91 (t, 1H), 7.03 (d, 1H), 9.38 (5, 1H), 11.12 (s, 1H). 4.26 Example 7 (1R,2R)-N-(1-cyanocyclopropyl) )-2-[(5 -methoxycarbonylmethyl-1,3,4,5-tetrahydro-2H- pyrido[4,3-b]indol-2-yl)carbonyl] cyclohexanecarboxamide eo Ye a { New”, Ls &— eA 0 oo sa J I NC . 1 bend “ TN h 1 following Example 4 but les with a compound:

5-methoxycarbonylmethyl-2,3,4,5 -tetrahydro-1H-pyrido[4,3-b]indole hydrochloride.

Y44 ) oad) yield the desired compound as a solid of color a (Use 0.6 mM 7910 ) yield). / 2 Cana

MS (+ve ESI) : 463 (M+H)" "HNMR (400 MHz, DMSO) 8 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 1H), 2.65-3.1 (m, 3H), 3.7(m, 3H), 3.9 (m, 2H), 4.5-4.85 (mm, 2H), 5.05 (m, 2H), 7.1 (m, 2H), 7.35 -7.6 (m, 2H), 8.7 (s, 1H). : Synthesis of a 5-methoxycarbonylmethyl-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole hydrochloride

Aud by the method 0 tert-butyl 5-methoxycarbonylmethyl-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indole-2- carboxylate 4 0 no

NT d \ / m = 0 )

TN

1 0 n b x

Wy0

Y14¢.

A 4 —- © - tO ) dissolved N-boc-2,3,4,5-tetrahydro-1 H-pyrido[4,3-bJindole mg; 0.65 mmol) in DMF (V) ml) and stirred at room temperature. Slay the container with sodium hydride 5 argon 0 ) mg; 1.10 mmol). after 0? minute; YO ¥) methyl bromoacetate is added aggregate; mmol) in (Ja Y) DMF and the mixture was stirred overnight. The solvent is removed in 0 vacuo and the residue is divided between brine (Y + brine ml) 5 x Y (50 ml ethylacetate). The combined organics ¢ (sodium sulphate) combined organics were dried, concentrated in vacuo, and adsorbed on silica for purification by flash chromatography (zero —“ 4 / ethyl acetate: this produces (isohexane tert) -butyl S-methoxycarbonylmethyl-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indole-2- carboxylate (AA aaa YAY) as light yellow foam

MS (+ve ESI): 245.2 (M+H)" 'H NMR (400 MHz, DMSO) 1.45 (s, 9H), 2.7 (m, 2H), 3.7 ( 3H), 3.75 (t, 2H), 4.55 (s, 2H), 5.05 (s, 2H), 7.1 (m, 2H), 7.4 (m, 2H).5-methoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-pyrido[ 4,3-bJindole hydrochloride rN ne Eq a carve > SE N pulp” HCI 0

Y14¢

: tert-Butyl 5-methoxycarbonylmethyl-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indole-2- carboxylate is dissolved. 1,4-dioxan in HCI ml). ¢ p in methanol (mmol V0) is added in 0.15 mg; yV v) the solution is concentrated in 0 medium and the mixture is stirred at room temperature overnight (de 0.0) © Toluene pressure-dried once using a vacuum azeotroped; and subjected to separation: to produce a tes 5-methoxycarbonylmethyl-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b] ]indole hydrochloride (HCI assuming salt 72000 cana YY) as a yellow solid

MS (+ve ESI): 245.2 (M+H)" 01 'H NMR (400 MHz, DMSO) 8 3.0 (t, 2H), 3.5 (m, 2H), 3.7 (s, 3H), 4.3 (s, 2H), 5.15 (s, 2H), 7.05 (t, 1H), 7.15 (t, 1H), 7.4 (d, 1H), 7.5 (d, 1H), 9.5 (m, 2H).

Ty example (1R,2R)-N-(1-cyanocyclopropyl)-2-[(5 -hydroxycarbonylmethyl-1,3,4,5-tetrahydro-2H- pyrtle[4,3-b]indol-2 -yl)carbonyl]cyclohexanecarboxamide 3

Jo

fie. AT

Fal 1 A “at 7 mm in a pipe” 1 JL lap yp

(1R,2R)-N-(1-cyanocyclopropyl)-2-[(5 -methoxycarbonylmethyl-1,3,4,5-tetrahydro-2H- pyrido[4,3-blindol-2-yl)carbonyl]cyclohexanecarboxamide. pyridine (mmol) in 7.85 cara 0 ( lithium iodide s vol.; 0.77 mmol) ton )

Yor mL) in a covered microwave-safe bowl. It is heated in a microwave oven at 0 vacuo in vacuo. The pyridine is removed. ) N:iabsorbance for one hour (Absorbency 759 6 Absorbed in toluene The remaining substance is subjected to separation 40 once using and divided using acetic and acidified using acid (Je Yo (brine) brine “ (magnesium sulphate) Drying of combined organic materials a3 ml. Av x Y) ethylacetate and toluene adsorbed once with azeotroped and concentrated in vacuo and subjected to separation 0 1 (zero-flash chromatography) Purification by flash chromatography on silica yields: DCM/ methanol (1R,2R)-N-(1-cyanocyclopropyl)-2-[(5 -hydroxycarbonylmethyl-1,3,4,5-). tetrahydro-2H-pyrido[4,3-blindol-2-yl)carbonyl] cyclohexanecarboxamide (709 cpa Af.) as a pale yellow solid No

MS (+ve ESI): 449 (M+H)" "HNMR (400 MHz, DMSO) 3 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 (m, 1H), 2.65-3.1 (m, 3H), 3.7-4.0(m, 2H), 4.5-4.85 (m, 4H), 7.1 (m, 2H), 7.25 (m, 1H), 7.4-7.55 (m, 1H), 8.8 (s, 1H).

Y14¢

YA Example (1R,2R)-N-(1-cyanocyclopropyl)-2-[(5-cyclopropylmethyl-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indol-2) -yl)carbonyl]cyclohexanecarboxamide a ¢ a eng? Tr mi lagim 7 p as ska 0 \ f " [ { NS

NE and -. ot the 8 r

OE

A : Following the example response but starting with the compound, ° 5-cyclopropylmethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride. millimoles); The compound mentioned in the title is produced as a brittle solid 0.795 (aaa TY °) yield. 7 40 cana Y44) brittle white solid

MS (+ve ESI) : 445 (M+H)" "HNMR (400 MHz, DMSO) 0.35 (m, 2H), 0.45 (m, 2H), 0.75-1.0 (m, 2H), -1.15 1.4 (m, 7H), 1.75 (m, 4H), 2.4 (m, 1H), 2.75-3.1 (m, 3H), 3.7-4.0 (m, 4H), 4.55-4.75 (m, 2H), 7.05 ( m, 2H), 7.5 (m, 2H), 8.7 (s, 1H). 5-Cyclopropylmethyl-2,3,4,5-tetrahydro- 1 H-pyrido[4,3-b]indole hydrochloride was synthesized.

Y14¢

in the following way. tert-Butyl 5-cyclopropylmethyl-1,3,4,5 -tetrahydro-2H-pyrido[4,3-blindole-2- carboxylate.b and N 0 1 | ser b oN 7 x N= 0. y 0 dissolved tO ) N-boc-2,3,4,5-tetrahydro-1 H-pyrido[4,3-blindole aggregate 0.659 mmol) in (Ja V) DMF and stirred at room temperature. The container is filled with argon (1V)sodium hydride mg; 0.19 mmol). after 71 minutes; Ja +11) cyclopropylmethyl bormideddla 6 mmol) is dissolved in Y (DMF ml) and the mixture is stirred overnight. Solvent 40 is removed in vacuo and the residue is divided between brine 01 (brine 5 mL) ethylacetate 0 x Y (0 mL). The combined organics (sodium sulphate) combined organics were dried and concentrated in vacuo, and J was adsorbed on silica for purification by means of chromatography and flash chromatography (zero (ethyl acetate / isohexane / 5 0- This produces: tert-Butyl 5-cyclopropylmethyl-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indole-2- carboxylate.No as dig. ) light yellow (£01 mg (JAE ‎MS (+ve ESI)) : 327 (M+H)"

'HNMR(400 MHz, DMSO) 6 0.0 (m, 2H), 0.1 (m, 2H), 0.8 (m, 1H), 1.1 (s, 9H), 2.5 (t, 2H), 3.4 (t, 2H) , 3.65 (d, 2H), 4.2 (s, 2H), 6.65 (t, 1H), 6.75 (t, 1H), 7.1 (m, 2H). 5-cyclopropylmethyl-2,3,4,5-tetrahydro-1 H-pyrido[4,3-blindole hydrochloride

TT a RN | J None Sw “N Ba HC

NJ

: 0 tert-Butyl 5-cyclopropylmethyl-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b]indole-2- carboxylate is dissolved. 1,4-dioxan in HCl ml). 6 p (1©) methanol mmol) in V.¥0 mg; (£81 ml) is added and the mixture is stirred at room temperature overnight. The solution was concentrated in vacuo (1-9): zy toluene and separated 226000060 once using 0 5-cyclopropylmethyl-2,3,4,5-tetrahydro-1 H-pyrido[4,3-b}indole hydrochloride. . (HCI assuming salt / 1011 + mg Yv¢ ) Colored solid | yellow tale is pictured

MS (+ve ESI): 227 (M+H)" 'HNMR(400 MHz, DMSO) § 0.15 (m, 2H), 0.25 (m, 2H), 0.9 (m, 1H), 2.85 (t, 2H) , 3.25 (m, 21), 3.8 (d, 2H), 4.1 (s, 2H), 6.8 (t, 1H), 6.9 (t, 1H), 7.25 (m, 2H), 9.2 (m, 2H).

_ q o — ya Example (1R,2R)-N-(1-cyanocyclopropyl)-2-[(5 -methoxyethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3- bindol- 2-yl)carbonyl]cyclohexanecarboxamide 7

Q y (

N ee” 7 Ma A Na et A 0s. NT

CYT > Na : Following Example 4 but starting with 0 0 ( 5-methoxyethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-blindole hydrochloride mmol) is Production of the compound mentioned in the title as 0171 (ZY 10 mg £A) brittle straw colored solid

MS (+ve ESI): 449 (M+H)" 'HNMR(400 MHz, DMSO) § 0.75-1.0 (m, 2H), 1.15-1.4 (m, 6H), 1.75 (m, 4H), 2.4 ( m, 01 1H), 2.75-3.1 (m, 3H), 3.2 (m, 3H), 3.55-4.0 (m, 4H), 4.25 (m, 2H), 4.55-4.8 (m, 2H), 7.05 (m , 2H), 7.5 (m, 2H), 8.7 (s, 1H).: A was synthesized.

_—- 3 9 _ 5-methoxyethyl-2,3,4,5-tetrahydro- 1H-pyrido[4,3-b]indole hydrochloride in the following way: tert-Butyl 5-cyclopropylmethyl-1,3,4 ,5 -tetrahydro-2H-pyrido[4,3-b} indole-2-carboxylate 0 moss 1 sala N J > / lahi nabj 01 - sr - ben N-boc- is dissolved 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.159 mmol) (0.159 mmol) in DME (V) 0 mL) and stirred at room temperature . The vessel is filled with argon and sodium hydride is added (No. 1 mg; 006109 mmol). After 0 minutes, add: YY (1-bromo-2-methoxyethane 0.5 mmol) in (JeY)DMF and the mixture is stirred overnight. The solvent is removed in medium gia and the remaining material is divided between brine (Je Yo ) brine x Y) ethylacetate 5 £4 ml). The combined organics sodium ( combined organics o(sulphate 0) were dried and concentrated in vacuo and adsorbed On silica to purify by flash chromatography (zero- (ethyl acetate / isohexane 7 4 0) this yields: tert-Butyl 5-(2-methoxy)ethyl-1,3,4,5 -tetrahydro -2H-pyrido[4,3-b]indole-2-carboxylate. as light yellow gum (LAY coma £57) gum MS (+ve ESI): 331 (M+H)"

— 3 7 — 'H NMR (400 MHz, DMSO) 5 1.45 (s, 9H), 2.8 (t, 2H), 3.2 (s, 3H), 3.55 (t, 2H), 3.75 (t, 2H), 4.25 (t, 2H), 4.55 (s, 2H), 7.0 (t, 1H), 7.1 (t, 1H), 7.4 (m, 2H). 5-methoxyethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole hydrochloride. i N

Cr t” nl a 0. HCl : 8 tert-Butyl 5-(2-methoxy)ethyl-1,3,4,5 -tetrahydro-2H-pyrido[4,3-b] is dissolved indole-2-carboxylate. and (Ja 1.0) 1,4-dioxan in HCl (ml). A p of (V0) methanol is added in (cane; 01) and the mixture is stirred at room temperature overnight. The solution is concentrated in an incubator medium and reduced and dried under low pressure. This results in: toluene once one using an azeotroped to separate as 5-(2-methoxy)ethyl-2,3,4,5-tetrahydro- 1H-pyrido[4,3-blindole hydrochloride 0 (HCI assuming LY ve salt) mg; YOu gray foam

MS (+ve ESI): 331 (M+H)" 'HNMR(400 MHz, DMSO) 3.2 (t, 2H), 3.4 (s, 3H), 3.6 (m, 4H), 4.3 (m, 4H), 7.15 (m, 2H), 7.5 (d, 2H), 9.6 (m, 2H).

Vo

Yas veo Example (1R,2R)-N-(1-cyanocyclopropyl)-2-{[6-(tri fluoromethyl)-1,3,4,5-tetrahydro-2H-pyrido [4,3-bJindol] -2- yljcarbonyl} cyclohexanecarboxamide.

For Bomb [] All Khud No 9 oy

ttyl

2 2 >< N 0 ا H > I like: ‎; But starting with compound E following example 0 m 0.001 mg £AY) 6-(trifluoromethyl)-2,3,4,5-tetrahydro-1 H-pyrido[4,3-bJindole ]. 0 Y¢ mol) The compound mentioned in the title is produced as a white solid (9 mg

HNMR (400.13 MHz, CDCl) 0.87 - 1.89 (12H, m), 2.58 - 2.64 (1H, m), 2.83 - 3.10 (3H, m), 3.64 - 3.71 (0.5H, m), 3.87 - 3.99 (1H, m), 4.35 - 4.41 (0.5H, m), 4.74 - 4.77 (1.5H, m), 4.88 (0.5H, d), 6.49 and 6.57 (2x 0.5H, 2x5), 7.1 4-721 ( 1H, m), 7.42 (1H, t), 7.62 (1H, t), 8.29 (1H, d) ty 3.18% A a 6-(Trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[ 4,3-b] indole.

Y14¢

In the following way: 6-(Trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.0 TN] To ) — NH to 0171( 4opiperidone .

HCI g; 0001 mM (Use f : 5.1 Y) 2-trifluoromethylphenylhydrazine HCl 0 g; 0001 mmol) in acetic acid (+0 mL); 100 1 M of 0001 “Ja Y.£7 (mmol borontrifluoride etherate) was added and the reaction mixture was stirred at 80 °C A sad hours and then allowed to cool. The mixture was concentrated in vacuo to which ethanol (about 10 ml) was added and then cooled to 0 * m; Solid 80 is filtered and the mother solution is concentrated in vacuo and water (adjusted to 16 pH 0 using ?molar of NaOH) is added to the residue. The solid is filtered, washed with water and dried under -high vacuum adie MS (+ve ESI) : 240 (M+H)" (2H, 1),3.47 (2H, 1),4.33 (2H, 5),7.19 (1H, 1) ,7.45 3.07 HNMR (400.132MHz, DMSO) (1H, d),7.79 (1H, d),11.52 (1H, s) \o

- Nea — vy Example ‎(1R,2R)-N-(1-cyanocyclopropy!)-2-{ [6-(methylsulfonyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3] -b]indol-2-yl]carbonyl} cyclohexanecarboxamide eee - and b © ak no

TT 0 a a 10

No. N 7 2

Ox.” =( I | 7 < 5 NE 5 l /, 0 ' : but starting with oY E following the example ° mVY mg 1 co) 6-methanesulfonyl-2,3,4, 5-tetrahydro-1H-pyrido[4,3-b]indole

YY. (8) mol) The compound mentioned in the title is produced as a yellow solid (LAY mg; MS (+ve ESI): 469 (M+H)" HNMR (400.132 MHz, DMSO) 3 0.70 - 1.08 (m, 2H), 1.09 - 1.49 (m, 6H), 1.52 - 1.87 (m, 4H), 2.32 - 2.47 (m, 1H), 2.54 - 3.21 (m, 3H), 3.33 (s, 3H) ), 3.69 - 3.97 (m, 2H), 4.64 (q, 1H),4.80(s, 1H), 7.16 - 7.25 (m, 1H), 7.56 (t, 1H), 7.87 (q, 1H), 8.71 ( d, 1H), 11.24(d, 1H): Then, the synthesis of 6-methanesulfonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

— \ 1 0 — In the following way: 6-methylsulfanyl-1 3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester Ser 0 6 L J A

Nee ~say oY / \ { | L 1 lyme 5 / 0 6-methylsulfanyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1010 g 5..6 mmol) was treated in dry 111 °C. (de 00(using Y.£1) di-t-butyl-dicarbonate g 1101 mmol) and then a few crystals of .4-dimethylaminopyridine The mixture was stirred at 10 °C for 2 hours. Crushing with a little cether yields a pure product as a white solid (VY mg). raw material was used.

MS (+ve ESI): 319 (M-tBu)" 01

HNMR (400.132 MHz, DMSO) 5 1.50 (s, 9H), 2.85 (t, 2H), 3.34 (s, 3H), 3.76 (t, 2H), 4.57 (s, 2H), 7.03 (t, 1H), 7.12 (d, 1H), 7.34 (d, 1H), 10.93 (s, 1H) 6-methanesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3 -bJindole-2-carboxylic acid tert-butyl ester — 0 7 { to # no

Osg = | \ ; 20 N

Vo: to be cooled

111.1 - - 6-methylsulfanyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester )8.4 mg; 171 mM (Use in (Je) +) DCM to more than ica » and add MCPBA 1-717 coma V £4 mmol) in DCM (©ml) Drip within ve minutes. Leave the reaction to warm to room temperature. The reaction mixture was washed with a saturated NaHCO3 solution (¥) Je Ye x (7700 cama Ved), drying (04850), and evaporation to produce a yellow gum 0

MS (+ve ESI): 249 a('H NMR (400.132 MHz, DMSO) 81.45 (s, 9H), 2.86 (t, 2H), 3.26 (s, 3H), 3.72 (t, 2H), 4.58 (s, 2H), 7.20 (t, 1H), 7.56 (d, 1H), 7.80 (d, 1H), 11.17 (s, 1H) 6-methanesulfonyl-2,3,4,5-tetrahydro-1H- pyrido[4,3-b]indole 7 1 a a a N

Ox1

Seg N™ / 1 0 : 6-methanesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-blindole-2-carboxylic acid tert-butyl ester is dissolved. (1) dioxane in HCl and 4 molar of (Ja 1 (DCM mmol) in 171 cana 04) are added immediately and the mixture is stirred for 0.¥ hour when no gas commenced gas generation begins (Je 10) is a black solid from the reaction.

Yat a —

MS (+ve ESI) : 251 (M+H)" min + Y retention time LCMS ? 17 Jud (1R,2R)-2-{[6-(benzyloxy)-1, 3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]carbonyl }-N- (1-cyanocyclopropyl)cyclohexanecarboxamide

Vo - B A — 0 Pn N a

J ] SN 1 eT Pe Stone Mn N of 10 1 a N™TS SN

ST \ 0 2» 0 : but starting with YE compound following the example mmol) Vere mg; 4 0) 6-benzyloxy-2,3,4,5-tetrahydro-1H-pyrido[4, 3-b] indole. HCI mg; AYY) The compound mentioned in the title is produced as a yellow solid (oo

MS (+ve ESI): 497 (M+H)" 01 'H NMR (400.132 MHz, DMSO) 0.72 - 1.04 (m, 2H), 1.15 - 1.44 (m, 6H), 1.60 - 1.86 (m , 4H), 2.42 - 2.49 (m, 1H), 2.64 - 3.09 (m, 3H), 3.63 - 3.96 (m, 2H), 4.56 (q, 1H), 4.71 (s, 1H), 5.25 (s, 2H) ), 6.73 (t, 1H), 6.88 (quintet, 1H), 7.05 (q, 1H), 7.34 (t, 1H), 7.41 (t, 2H), 7.56 (d, 2H), 8.64 (s, 1H) , 10.94 (s, 1H)

1 0 _ Then prepare: 6-Benzyloxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

HCI in the following way. (2-Benzyloxyphenyl)-hydrazine. Concentrated hydrochloric acid (Vo) ml) to less than 0 M and a solution of (Y.+V)sodium nitrite g + 011 mmol) in (Je Yo ) ela is added dropwise. Then the reaction mixture was stirred at the same temperature for +V min; when adding tin chloride (11.4 g; 79.00 mL (Use in hydrochloric acid 01(0 mL) another Be drip with the temperature maintained at about 0 C. The reaction mixture is stored overnight in the refrigerator. The aqueous liquid has been filtered of the resulting black oily gum and pulverized with saturated NaCl (Ja 0+ (Msn) then 1:2 ether: hexane (+0 mL) before equilibration with 10 M of (Als) NaOH with external cooling and extraction to 001 #7 (ether mL). The collected ether layers were washed with water (Jo 001) and dried (MgSO,) and evaporated 1 to produce a brown oil that crystallized when left (07.£ (EA £ con). The material was used without Do more purification

—-— \ «0 —- '"H NMR (400.132 MHz, DMSO) 5 3.95 (s, 2H), 5.09 (s, 2H), 5.96 (s, 1H), 6.58 (t, 1H), 6.79 - 6.90 (m, 2H), 7.04 (d, 1H), 7.29 - 7.36 (m, 1H), 7.40 (t, 2H), 7.49 (d, 2H). 1H-pyrido[4,3-b]indole.HCL

I

The text of Ria M I

J 0 Meh Al a A 7 : mmol) and VO.A g; Y.T4) (2-benzyloxyphenyl)-hydrazine © heated to reflux (Ja Yr) ethanol in (Use 05.8 mM Y.0) 4-piperidone hydrochloride (ml) and heating continues. 1 M;001 dioxane in HCI for £0 min. Addition of 4 M of ill The reaction mixture was cooled under heavy precipitate min; a heavy precipitate formed Fo after (approximately slightly cooled ether) then isopropyl alcohol and the solid was filtered; washed with white solid sala 7 5 + 0.11 g before drying to yield Ja o 1 'HNMR (400.132 MHz, DMSO) 3.01 (t, 2H), 3.40 - 3.49 (m, 2H), 4.27 ) 2H), 5.27 (s, 2H), 6.78 (d, 1H), 6.92 (t, 1H), 7.31 - 7.38 (m, 1H), 7.42 (¢, 3H), 7.56 (d, 2H ), 9.34 (s, 2H), 11.22(s, 1H) (2-Benzyloxyphenyl)-hydrazine.8 Lacya 4 ) y

NJ vo t

- Vo =

2-benzyloxyaniline (can mmol) partially dissolved in concentrated hydrochloric acid (Js 11) was cooled to less than ia m and a solution of sodium nitrite (0.7) was added g; 7001 mmol) in 01 (mL) water drip. The reaction mixture was stirred at the same temperature for 710 minutes; when tin chloride (V1.9 c. 15.06 mmol) was added in acid

(Je Yo ) hydrochloric 0 drip again keeping the temperature at about 0°C. The reaction mixture is stored overnight in the refrigerator. The aqueous liquid of the resulting black oleoresin is filtered off and pulverized with saturated NaCl (approx. 0 9 mL) then 1:2 1 ( ether: hexane © mL) before equilibration with 10 M of (Sl) NaOH with external cooling and extraction to (x V) ether (Ja Yoo). Then the collected ether layers were washed with Yoo (ela) ml) and then dried (50p11).

0 and fumigation to produce a brown oil that crystallizes when left (£.0Y) total (LAE) the material was used without further

from purification. 'H NMR (400.132 MHz, DMSO) 53.95 (s, 2H), 5.09 ( 2H), 5.96 (s, 1H), 6.58 (t, 1H),

6.79 - 6.90 (m, 2H), 7.04 (d, 1H), 7.29 - 7.36 (m, 1H), 7.40 (t, 2H), 7.49 (d, 2H).

FY Example (IR2R)-N-(1-cyanocyclopropyl)-2-[(6-hydroxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b] indol-2 -yl)carbonyl]cyclohexanecarboxamide.

Vo 7 a OH To, ( > AA 0 1 - ] Nab.”

- VV - hydrogenated : The (1R,2R)-2-(6-Benzyloxy-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carbonyl)- cyclohexanecarboxylic acid (1-cyano-cyclopropyl)-amide in ethyl acetate (Ja 0) over 70 palladium over 01 (carbon mg). After an apparent absorption of an amount of © mL (Ye min.); The reaction stops and die is taken to test 1.0145. The catalyst is filtered and a different batch of catalyst (Je©) ethanol y is added and the hydrogenation continues although there was no apparent further absorption after ¥ hours; The reaction stops and LOMS indicates that reduction has continued to the desired product. Purified by preparative HPLC (0.+7 ¢HCOOH grade JCH;CN (7 47 mg TEV) to produce a white powder (H0

MS (+ve ESI): 407 (M+H)+01 'H NMR (400.132 MHz, DMSO) 0.73 - 1.07 (m, 2H), 1.10 - 1.48 (m, 6H), 1.61 - 1.86 (m , 4H), 2.54-2.58 (m, 1H), 2.64 - 3.07 (m, 3H), 3.60 - 3.97 (m, 2H), 4.54 (q, 1H), 4.68 (s, 1H), 6.48 (t, 1H) ), 6.76 (quintet, 1H), 6.88 (q, IH), 8.64 (s, 1H), 9.35 (d, 1H), 10.63 (s, 1H). 7 Fl Example Yo (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-propoxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b] indol- 2-yl)carbonyl]cyclohexanecarboxamide

- VA = er me 0 Og N=

son

OT i : 1R,2R)-2-(6-Hydroxy-1,3,4,5-tetrahydro-pyrido{4,3-b]indole-2-carbonyl)- cyclohexanecarboxylic acid (1-cyano) heated -cyclopropyl)-amide (0.380 mmol) 5)&a YA.+) 1-bromopropane s mmol); YO cana 0171( m sad ml) to reflux ©( acetone mmol) in +. YO mg; YO. +) potassium carbonate mmol) 8.68 al micro OAL) 1-0:00000:00806 Add more .taas ¥ mmol) and heat overnight. 1901 mg; Vo.) potassium carbonate of desired product and 7560 7210 LCMS reaction mixture darkens considerably and becomes clear in redissolving dehydration before redissolving Sa Reaction mixture is filtered and liquids evaporate SM 0 (1:0/01:07[¢ HCOOH /+.0) grade preparative HPLC and tempered with acetonitrile (718 cana YV.¥) brown glass to produce brown glass

MS (+ve ESI): 449 (M+H)+ 1HNMR(400.132MHz, DMSO) 6 0.64 - 1.00 (m, SH), 1.01 - 1.34 (m, 6H), 1.47- 1.76 (m, 6H), 2.42 - 2.96 (m, 4H), 3.49 - 3.84 (m, 2H), 3.94 (t, 2H), 4.43 (q, 1H), 4.58 (s, 1H), 6.49 (t, 1H), 6.70 - 6.98 (m , 2H), 8.51 (s, 1H), 10.67 (s, 1H). vo example (1R,2R)-N-(1-cyanocyclopropyl)-2-{[6-(cyanomethoxy)-1,3,4,5-tetrahydro-2H-pyrido [4,3-b] indol-2-yl]carbonyl}cyclohexanecarboxamide

- 01.9 - 1 g im CG On N= 7 HW “EN

Yo TN aN | b

S70NS2

N

Following example 4: (1R,2R)-2-(6-hydroxy-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carbonyl)- cyclohexanecarboxylic acid (1) was heated -cyano-cyclopropyl)-amide µl; 0.75 mmol) (0.75 mmol) acetonitrile bromo (mmol) +. 011 YO cama (m for a Av heated to (Ja©) DMF mmol) in 0110© mg; Yellow solid (HO /011:077 ¢HCOOH 7 0.8 grade (preparative HPLC .) 67 01.4) yellow solid

MS (+ve ESI): 446(M+H)+01 1H NMR (400.132 MHz, DMSO) 6 0.71 - 1.04 (m, 2H), 1.09 - 1.47 (m, 6H), 1.59 - 1.85 (m, 4H) , 2.54-2.57 (m, 1H), 2.59 - 3.28 (m, 3H), 3.62 - 3.98 (m, 2H), 4.57 and) 1H), 4.72 (s, 1H), 5.29 (s, 2H), 6.80 (t, 1H), 6.95 (quintet, 1H), 7.18 (q, 1H), 8.70 (s, 1H), 11.14 (s, 1H). 13 Example Vo

_ 1 \ Su (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-(dimethylamino)ethoxy)-2,3,4,5-tetrahydro- 1H-pyrido[ 4,3-b]indole-2-carbonyl)cyclohexanecarboxamide

MB : ig NO == 0 for mer ' J AY cana Y YO) (3aR,7aR)-hexahydroisobenzofuran-1,3-dione + mmol) is added to: N,Nedimethyl- 2-(2,3,4,5-tetrahydro- 1H-pyrido[4,3-b]indol-6-yloxy)ethanamine. 70 mg; LAN mmol) in DMF (10 ml) at room temperature in air 0 The resulting solution was stirred at room temperature Badd 2 hours. after that; Add : N,N-Diisopropylethylamine (0¥0.+ ml » 7.74 mmol); €1Y) HATU mg 0111 mmol) and 1101 ana VEE (l-amino-1-cyclopropanecarbonitrile mmol) to 0 - the mixture. The resulting solution was stirred at room temperature for 10 hours. The crude product was purified by preparative HPLC (7001 «NH;(HyO[CH;CN] listed as eluent to produce Ad) brown gum mg; YY %( . MS (+ve ESI): 478(M+H)+ (4H,m), 1.64 - 2.00 (8H, m), 2.56 - 2.60 1.52 - 0.71 E' HNMR (400.13 MHz, CDCI3) (1Hym), 2.64 (3H, 5), 2.65 (3H, 5), 2.91 - 3.03 (3H, m), 3.11 (2H, t), 3.88 - 3.90 (1H, m), and 4.40 (1H , m), 4.29 (2H, t), 4.73 -4.78 (1H, m), 4.78 -4.81 (1H, m), 6.53 - 6.61 4.13 (2H, m), 6.93 - 7.01 (1H, m), 7.09 - 7.12 (1H, m), 8.59 (1H, s)

1111 - -: N,N-dimethyl-2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yloxy)ethanamine was prepared by the following method . tert-Butyl 6-(2-(dimethylamino)ethoxy)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)- carboxylate i 0 Ny NL kL 0 ¢ kl i 1 1 oo he J N~ Pg and tert-Butyl-6-iodo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(SH) is suspended )-carboxylate (+0,0176 cane mmol); VY v) copper(I) iodide s mg; mM YA (Use and tri-potassium 0YY) orthophosphate mg 7.01 mmol) in “Ja +) 2-dimethylaminoethanol 0 11.46 mmol) and placed in a microwave tube tight. The reaction mixture is heated to 0 100 °C for 1 hour in a microwave reactor and cooled to room temperature. The reaction mixture is diluted with 001 (DCM mL); and washed with “p of 7 x (NaOH 00 mL). The organic matter was dried by ,218250; Filtered and evaporated are evaporated to produce a crude product. The crude product is purified by preparative 1171.0 (000) 7 and gradient 3111 (H20 [CH3CN z wy \o : tert-butyl 6-(2-(dimethylamino)ethoxy)-3,4-dihydro-1H -pyrido[4,3-b]indole-2(5H)- carboxylate Y14¢

- 1117 - in the form of yellow gum.‎ (% Tv (ada Ye. £)

MS (+ve ESI): 360 (M+H)+

Yi4¢

11101 - - ‎N,N-dimethyl-2-(2,3,4,5-tetrahydro- 1H-pyrido[4,3-b]indol-6-yloxy)ethanamine TR 7 people A] > He 0-cm 1 2 is added: tert-Butyl 6-(2-(dimethylamino)ethoxy)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H) - carboxylate Yet ) mg; d mmol) to Ja 00 ) Methanolic HCI ¢ reactant 01 ) at zero a in air. The resulting solution is stirred at room temperature for 19 hours. The solvent 0 is removed under Low pressure to produce : N,N-dimethy!-2-(2,3,4,5-tetrahydro- 1 H-pyrido[4,3-b]indol-6-yloxy)ethanamine. AY aaa YO) 0 %) as a yellow solid Example YY (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-morpholinoethoxy)-2,3,4, 5-tetrahydro-1H- pyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide NE 0 - i : “FN the 7 HTT NT ai] º l 0 SX “0 for Che Y14t¢

- 114 - 0. cana 001( 4-(2-Chloroethyl)morpholine hydrochloride Continuing with Example 4 7; : mmol) is added to (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-hydroxy-2 ,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole-2-carbonyl)cyclohexanecarboxamide

DMF in (Use 091 mm cane 17 4( potassium carbonate gy mmol) 1.77 cana (171 0) in air. The resulting solution was stirred at room temperature for £0 hr; 2°F0 ml) at ©). 0 (0.4 mg £00) cream solid to produce after purification a creamy solid

MS (+ve ESI): 520(M+H)+ "HNMR (400.13 MHz, CDCI3) & 1.05 -1.75 (8H, m), 1.83-1.90 (4H, m), 2.61 (4H, t), 2.7% -2.84 (2H, m), 2.82 (2H, t), 2.97-2.98 (2H, m), 3.40 and 4.38 (1H, 2 x m), 3.61-3.92 (1H, m), 3.75 - 3.78 (4H, m) ), 4.24 - 4.27 (2H, m), 4.73-4.78 (2H, m), 6.42 and 6.53 (1H, 2xs), 6.66 (1H, t), 6.96 - 7.03 (1H, m), 7.08 - 7.12 (1H , m), 9.13 (1H, m)

YA Example (IR,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-(pyrrolidin-1-yl)ethoxy)-2,3,4,5-tetrahydro- 1H- pyrido[4,3-b}indole-2-carbonyl)cyclohexanecarboxamide <> a NK 5 s 7-7 Vo a a re N ¢ (a for pyrr - r MN wa 0 NTN N

L.,

m \ \ pu Continuing from Example 4 ?; AY is added. +) 1-(2-chloroethyl)pyrrolidine hydrochloride mg EA + mmol) to : (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-hydroxy-2,3,4,5 -tetrahydro-1H-pyrido[4,3-b] indole-2-carbonyl)cyclohexanecarboxamide

DMF mmol) in 0.97 cana 17 4( potassium carbonate 5 (se mM 1.7 cana YTV) 0 ml) at 75 m in air. The resulting solution was stirred at room temperature for 0 hr; 0). 0 Y.V (mg Nev) cream solid To produce, after purification, a cream-colored solid

MS (+ve ESI): 504 (M+H)+ "HNMR (400.13 MHz, CDCI3) § 1.27- 1.88 (13H, m), 1.90- 1.92 (2H, m), 2.01 -2.05 (1Hym), 2.38 ( 1H, t) 2.59 (1H, t), 2.71 - 2.82 (4H, m), 2.86 - 3.04 (4H, m), 3.85 and 4.41 (1H, 2 x m), 3.87-3.89 (1H, m), 4.26 ( 2H, t), 4.73 - 4.77 (2H, m), 6.51 and 6.59 (1H, 2 x s), 6.64 (1H, t), 6.94 - 7.01 (1H, m), 7.08 - 7.11 (1H, m), 10.03 (1H, m).95 Jud (IR,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-(piperidin-1-yl)ethoxy)-2,3,4,5-tetrahydro- 1 H-pyridde[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide

A a H 2 . Laci Ah 2 83 ~~ i

YS P 1 <A > ( 0

-1101- : Continuing from Example 4 7 but starting with compound 6-(2-(piperidin-1-yl)ethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole . mmol) the compound mentioned in the title is produced as a white solid (7.74 aa doe) yielding 771 mg; Yo) white solid

MS (+ve ESI): 518 (M+H)+° "HNMR (400.13 MHz, CDCI3) 0.86-1.21 (2H, m), 1.27-1.51 (6H, m), 1.64-1.68 (5H, m), 1.72 - 1.89 (4H, m), 2.63-2.67 (8H, m), 2.70 - 3.05 (3H, d), 3.55 and 4.45 (2 x 1H, m), 3.86 - 3.92 (1H, m), 4.24 (2H, t), 4.70-4.91 (2H, m), 6.66 - 6.75 (2H, m), 6.95 - 7.03 (1H, m), 7.12 (1H, t), 9.90 - 9.96 (1H, m). Then prepare 6-(2-(Piperidin-1-yl)ethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. in the following manner. tert-Butyl 6-(2-(piperidin-1-yl)ethoxy)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)- carboxylate. — 0 7 “+ d CY A 0

Q Se LJ \ { { > \o

Y14¢

117 - - 0.97 ( tri-potassium orthophosphate g; 9.004 mmol) suspended; and : 0 ) tert-butyl 6-iodo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate g £07 mmol) 5 can + £Y 4 ) copper(l) iodide 7.76 mmol) in: “Je V0) 2-(piperidin-1-yl)ethanol in large excess) and placed in a sealed microwave tube after bubbles in the solution for © minutes. The reaction mixture was heated to Vor for 0.5 h in a microwave reactor and cooled to room temperature. This reaction is repeated three times and the combined crude reaction mixture is treated as follows. The mixture is diluted with (Je © 1) DCM, washed with (Ja 7 0 x 7) NaOH, dried 0 with sodium sulphate, and solvent removed under reduced pressure. The crude product is purified by Preparative HPLC (7001 «CH;CN (HCOOH 11:0). Fractions containing the compound mentioned in the title were evaporated to dryness to produce: tert-butyl 6-(2-(piperidin-1-yl)ethoxy) -3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)- carboxylate (1 XY) Vo (1 g and 1 product) as yellow gum LCMS Detention time MS (+ve ESI): 400 (M+H)+4583 0.51 Yd

YA - - 6-(2-(Piperidin-1-yl)ethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 75 pa on \ b = Al Ser 9 L { MH \ /_\ Add : tert-Butyl 6-(2-(piperidin-1-yl)ethoxy)-3,4-dihydro-1H-pyrido[ 4,3-b]indole-2(SH)- carboxylate 1 YY) g; 7.71 mmol) to HCI in MeOH (reactant (Je Yo 01) at 0007 C in air. The resulting solution was stirred at room temperature s.d. days. The solvent is removed removed under low pressure to produce (10.0 g; 001 7) in the form of yellow gum 1 and then use the raw material. LCMS 0 retention time 0.11 min MS (+ve ESI) : 300 (M+H)+ eg 0 (1R,2R)-N-(1-cyanocyclopropyl)-2-[(5-methanesulphonyl-1,3,4,5-tetrahydro) -2H-pyrido [4,3-blindol-2-yl)carbonyl]cyclohexanecarboxamide 23 b ol N - = a A N. 0 0 7 d “A pa” 1 lp 0 — ~ARE

- 11 - tas But of course Ye Following the example 5-methanesulphonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-blindole hydrochloride. solid sale (mmol) The compound mentioned in the title is produced in the form of LOY + mg YY (7176 dana TY). Its color is light brown.

MS (+ve ESI): 469 (M+H)+° 'H NMR (400 MHz, DMSO) § 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 2.4 ( m, 1H), 2.9-3.3 (m, 3H), 3.35(s, 3H), 3.9 (m, 2H), 4.5-4.8 (m, 2H), 7.3 (m, 2H), 7.65 (m, 1H) , 7.9 (d, 1H), 8.7 (s, LH). Then prepare 5-Methanesulphonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b}indole hydrochloride. In the following way.

N-Boc-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

N b — | , \ / arc: { TH 11.4 g Y.1¢) 2,3,4,5-Tetrahydro-1H-pyrido[4,3-blindole hydrochloride] is suspended and stirred at At room temperature (Je VY) dichloromethane in (Use mM Vo di-tert-butyl dicarbonate (79./fill 807.7 mmol) then triethylamine .argon is added

171. - - T.AY) g; 17.4 mmol) in (Ja V0) DCM and the resulting solution was stirred overnight with the 800:2 source removed. The DCM is removed in vacuo and the residue is divided between brine (+0 mL) 5 001 x Y (ethylacetate mL). The combined organics (sodium sulphate) were dried and concentrated in an incubator medium to produce: 0H N-boc-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole in Photograph of a pale yellow solid £.YY) solid g (AA MS (+ve ESI): 271 (M+H)+ (s, 9H), 2.8 (t, 2H), 3.7 ( t, 2H), 4.55 (s, 2H), 6.95 ) 1.45 e' H NMR (400 MHz, DMSO) 1H), 7.05 (¢, 1H), 7.3 (d, 1H), 7.4 (d, 1H), 10.85 (s, 1H). | 5-Methanesulphonyl-2,3,4,5-tetrahydro- 1 H-pyrido[4,3-b]indole and “Ne. I” dissolved 0.94 cana Av) N-Boc-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole mmol) in (Je Yo) DMF and stirred at room temperature. b argon and sodium hydrid (© 77 mg; ©.AY mmol) is added.After ABA the reaction mixture is cooled to zero 0 then 0.AY «Ja + .£7 is added (methanesulphonyl chloride mmol) dropwise over 0 min. The reaction mixture is stirred, allowed to warm to room temperature overnight, and the solvent is removed in incubator medium. LOMS STLC indicated that the BOC group was removed during this process. For this; x Y) dichloromethane 5 ml) 1 0 (aqueous sodium hydroxide) the residue is divided between ? molar of ml) and Ye ) brine the collected organic materials are treated using brine aids (J= 0 and concentration in vacuo. Brittle S-methanesulphonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (718 mg YYO) brittle solid.

MS (+ve ESI): 251 (M+H)+ 'H NMR (400 MHz, DMSO) 6 2.85 (t, 2H), 3.1 (t, 2H), 3.35 (s, 3H), 3.9 (s, 2H) ), 7.25 (m,

H), v.5 (d, 1H), 7.9 (d, 1H). 61 Example (IR,2R)-2-(7,8-Dihydro-5H-furo[2,3-b:4,5-¢'|dipyridine-6-carbonyl)- cyclohexanecarboxylic acid (1- cyano-cyclopropyl)-amide.

Teer,

CT

Hoss and Se Asai. B B “ I BN a ; | N “FN a 1,5,6,7,8,9a-hexahydro-furo[2,3-b:4,5-c'ldipyridine following example 4 7; But starting with a vo solid compound (mmol) the compound mentioned in the title is produced in the form of a solid (0.01 + mg 7.4) (FAY aaa te) light brown in color

- 1177 -

MS (+ve ESI): 393 (M+H)+

TH NMR (500.13 MHz, DMSO-d6) 0.93 (2H, d), 1.26 - 1.43 (6H, m), 1.73 - 1.86 (4H, m), 2.52 - 2.56 (2H, m), 2.90 (1H , obs), 3.00 - 3.07 (1H, m), 3.89 - 3.98 (2H, m), 4.66 - 4.71 (2H, m), 7.29 - 7.32 (1H, m), 8.03 (1H, d), 8.22 - 8.23 (1H, m), 8.29 (1H, s). : Then prepare 0 in the following way. 1,5,6,7,8,9a-Hexahydro-furo[2,3-b:4,5-¢'|dipyridine tert-Butyl 4-0x0-3- (2-oxo-1,2-dihydropyridin-3-yl)piperidine-1-carboxylate. mO m 1 m Ko N 0 cl NiT ~ 5 : mmol) to #0011 g; 0111) potassium tert-butoxide tert-butyl 4-(hydroxyimino) is added ) piperidine-1-carboxylate 0 (11.7_v; 9.85 mmol) in Vo (DMF ml) at 0 °C in an atmosphere of 22801. The resulting suspension was stirred for 1 min. (A) 2-fluoropyridine .+ filling 9.480 mmol) is digested into the reaction mixture and the resulting solution is stirred at C for YY hours. The reaction mixture was decanted in 100 (100) ice water and extracted using 901 x Y (EtOAc Vo mL). Organic layers were collected and washed using 0 (Se ov x 1) brine. The organic matter was dried by Na, SO, filtration and evaporation.

1177 - - crude product producing flash chromatography column (1168:5; © scaling to 7000 EtOAc in (isohexane: (ax 84 ) tert-butyl 4-oxo-3-) 2-ox0-1,2-dihydropyridin-3-yl)piperidine-1-carboxylate YY 7) as a creamy solid.MS (+ve ESI): 293 (M+H)+° HNMR (400.13 MHz, CDCI3) 6 1.50 (9H, s), 2.64 (2H, s), 3.41 (1H, 5), 3.48 (2H, t), 3.73 (1H, s), 4.26 (2H, s), 6.26 (1H, t), 7.24 - 7.27 (1H, m), 7.30 - 7.32 (1H, m). 1,5,6,7,8,9a-Hexahydro-furo[2,3- b:4,5-c']dipyridine. Use to : You tert-butyl 4-oxo-3-(2-oxo-1,2-dihydropyridin-3-yl)piperidine-1-carboxylate mg 0 mmol).The resulting thick solution is stirred. resulting thick at room temperature overnight The reaction mixture is heated at a Te until completion of the reaction by LCMS The reaction mixture is diluted with 7468 ele 70 acetonitrile and solid potassium carbonate is carefully added 1 _ to equation pH number (fizziness); The slurry is filtered and the filtrate is evaporated; The resulting residue is used without further purification. MS (+ve ESI): 175 (M+H)+

- 1764 - 7 Ex. (1R,2R)-2-(7-Methanesulfonyl-1,3,4,5-tetrahydro-pyrido{4,3-b]indole-2-carbonyl)- cyclohexanecarboxylic acid ( 1-cyano-cyclopropyl)-amide. aM g A . os that Os, HH 7 Ny 1 yer pour yna hl l gy m example (IR,2R)-2-(9-Methanesulfonyl-1,3,4,5-tetrahydro-pyrido[ 4,3-blindole-2-carbonyl)-cyclohexanecarboxylic acid (1-cyano-cyclopropyl)amide.

A Pa 2 M — o Os NE Ma . 3

NLS WN >

Or : mixture of YY following on from the example 9-methanesulfonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 7-methanesulfonyl- 2,3,4,5-tetrahydro -1H-pyrido[4,3-b]indole 1:1. 7001 = A chiral (HPLC solvent, mmol). The two products are separated by AM + mg; YY): (CH3CN = B water; the solvent /NH3

Y14¢

_ 1 Y mg — (IR,2R)-2-(7-Methanesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carbonyl)- cyclohexanecarboxylic acid (1- cyano-cyclopropyl)-amide. (4 71 mg; 19.0) white solid as white solid and: (IR£R)-2-(9-Methanesulfonyl-1,3,4,5-tetrahydro-pyrido[4, 3-b]indole-2-carbonyl)- cyclohexanecarboxylic acid (1-cyano-cyclopropyl)-amide .. 0 VY mg; 9.6 ) & Lay ila sala 5) pa in ey example ( +ve ESI) : 469 (M+H)+ min 0111 retention time 65 &y Example 0 (+ve ESI): 469 1111771 .976 retention time LCMS : 9 mixture prepared -methanesulfonyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b}indole and 7-methanesulfonyl- 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole In the following way. Vo 0 0 El 7 2 I - Did Yul e Ra SN 7 Here TT 1

N A N™ SA Yi4¢

1771 - - then a suspension of (3-Methanesulfonyl-phenyl)-hydrazine) 0 +1 mg; 75.mmol (££Y) 4-piperidone hydrochloride 5 mg; 7.75 mmol) in (Je V0) acetic acid and stirred at room temperature in an atmosphere of 8:800. Add: A+) boron trifluoride diethyl etherate + ml; 1.501 mmol) on one ratio and the yellow suspension 6 is stirred at © 0011 C s.d. 2 hours, resulting in a dark red solution. It is cooled to room temperature and the acetic acid is removed in vacuo. The residue was divided between “p of All sodium hydroxide (+¥ ml) (Je 001 x Y) dichloromethane s The combined organics ¢(NaSOs) combined organics were dried and concentrated in vacuo. The flash chromatograph column produced dichloromethane 0 silica) graded to Zo 0 aqueous ammonia in (dichloromethane / ethanol 0 products as EA mixture) 1:1 mg; 1:0 (LCMS). 011 retention time min (+ve ESI) : 251 (M+H)+ Example 4 6 (1R,2R)-N-(1-cyanocyclopropyl)-2-(2,2-difluoro-7, 8,9,10-tetrahydro-6 H-[ 1,3]dioxolo [4,5-g]pyrido[4,3-b]indole-7-carbonyl)cyclohexanecarboxamide ye ZH "0 0 . HH Sarh 8 7 \ - i Ben Labhab Jey Sj Ng Vo Asila 0 FE Continuing from the example Lad YE except for the use of:

- 17 - (no) aggregate; 2,2-difluoro-7,8,9,10-tetrahydro-6H-[1,3]dioxolo[4,5-g]pyrido[4,3-b]indole : purification (mmol); The product after purification yields + 0A (IR,2R)-N-(1-cyanocyclopropyl)-2-(2,2-difluoro-7,8,9,10-tetrahydro-6H-[1,3]dioxolo[4] ,5-g]pyrido[4,3-b]indole-7-carbonyl)cyclohexanecarboxamide. A beige solid. sala as (71% mg; OA.”) 0

MS (+ve ESI): 175 (M+H)+ 1HNMR(400.132MHz, DMSO) 5 0.70 - 1.07 (m, 2H), 1.10 - 1.56 (m, 6H), 1.55 - 1.87 (m, 4H), 2.61 - 3.15 (m, 4H), 3.66 - 3.96 (m, 2H), 4.58 (q, J = 23.0 Hz, 1H), 4.74 (s, 1H), 6.98 - 7.39 (m, 2H), 8.65 (s, 1H ), 11.52 (s, 1H): then prepare 1 2,2-Difluoro-7,8,9,10-tetrahydro-6H-[1,3]dioxolo[4,5-g]pyrido[4,3] -b] indole. In the following way: (2,2-Difluoro-1,3-benzodioxol-4-yl)hydrazine

Co.

QF

\ i ml FA F mmol) and V1.0 g” (1.49) 2,2-Difluoro-benzo[ 1,3]dioxol-4-ylamine 0 is added after cooling to zero * m or less; A solution of (Je 01) concentrated hydrochloric acid Yi4¢ is added

- M701 - AVY) sodium nitrite mg; 1711 mmol) in 01 (ele) dropwise The reaction mixture was stirred at the same temperature for 1 min when adding tin chloride (1.00 g 4.0 7 mmol) in 01 acid hydrochloric ml) drip again keeping the temperature at about zero degrees. (Note the initial SC additions were highly exothermic 0 and the initial thick precipitate required extensive agitation to keep things moving.) The reaction mixture was stored in the refrigerator overnight at 0 Tm. The resulting solid was filtered; and washed with [16!1 saturated (5 mL) then 1:2 (Je© +) ether: hexane before drying to produce a sale white solid The solid is treated with 786 sodium hydroxide 001 (ml) aqueous and extracted with ether (? 0 x © ml). The combined extract 0 was dried and filtered to produce a yellow oil that crystallizes into long needles when left (0178 g (FN MS (+ve ESI): 205 (M+H)+' H NMR ( 400.132 MHz, DMSO) 4.15 (s, 2H), 6.57 (d, 1H), 6.89 (d, 1H), 6.99 ) 1H), (s, 1H) 7.07 2,2-Difluoro-7,8 ,9,10-tetrahydro-6H-[ 1,3]dioxolo[4,5-g]pyrido[4,3-b]indole N - )m 0 Vo F was heated VOY) (2,2-difluoro-benzo[ 1,3]dioxol-4-yl)-hydrazine mg; 4.00 mmol (©£Y) piperidone—¢ hydrochloride mg 4.50 mmol) in (Je V+) ethanol reflux for £0 min. is added; molar of HCI in (JaY) dioxane and the heating continues for

179 - - Two hours. A sample is removed and shortly after gas 1101 is bubbling; It is heated in a microwave oven to 1100°C for 10 minutes. The remaining material is treated in batches and the combined black reactions filtered, washed with a little water, and precipitated with 1:2 EbO:Hexane (approximately 10 mL) before drying 0 to yields a gray solid (£Y) 1 mg; 717 output) MS (+ve ESI): 253 (M+H)+ (s, 1H), 3.26 - 3.54 (m, 5H), 4.30 (s, 1H), 7.07 - 3.04 E'H NMR (400.132 MHz, DMSO) (m, 2H).7.40 Example go (1IR,2R)-N-(1-cyanocyclopropyl)-2-(8-fluoro-6-methoxy-2,3) ,4,5-tetrahydro-1H-pyrido [4,3-blindole-2-carbonyl)cyclohexanecarboxamide J ZN 7 Um 0 Ah: So Go Cam N: : 8 and love from the M oe : A br 1 MN “i 5 a 1 24 m a b W he 2 on \ Continuing from the example Lad YE except using: 00) 8-fluoro-6-methoxy- 2,3,4,5-tetrahydro- 1 H-pyrido[4,3-b]indole (or m vo mole); The compound mentioned in the title is produced as 358 white foam (¥1.7 mg 779).

- 3.0

MS (+ve ESI): 439.4 (M+H)+ 'HNMR (400.13MHz, CDCI3) 0.83 -0.89 (0.5H, m), 0.98- 1.50 (6H,m), 1.62 1.90 (5H, m) ), 2.56 - 2.62 (1H, m), 2.75 - 2.98 (3H, m), 3.62 - 3.90 (2H, m), 3.92 (3H, d), 4.29 -4.35 (0.5H, m), 4.60 - 4.85 ( 2H, m), 6.37 - 6.47 (2H, m), 6.69 - 6.75 (1H, m), 7.99 (1H,

Ss). © Then prepare: 8-Fluoro-6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole in the following way

Diphenylmethanone (4-fluoro-2-methoxyphenyl)hydrazone 7 Jy Lia YL / 2 grain 3 m tis 7 hf 0 A mixture of 4.01 “Ja +. 0Y) 2-chloro-5-fluoroanisole (mmol) 5 benzophenone (+.4A) hydrazone g++©.mmol); sodium-tert-butoxide s (071 mg 8.80 mmol); in (da A. +) toluene b YY.) Pdy(dba); mg; 00 mmol) and : 2-(di-t-butylphosphino)bipheny! ) 06 mg; IY mmol) and heated to 00“#”C in a Vo atmosphere of argon The reaction mixture was stirred overnight and examined using TLC 3 LCMS The mixture was allowed to Yi4¢

1071 - - by cooling to room temperature and the reaction mixture was dried with (Ja Yo) EtOAC and filtered. The raw material was used in the next step. 8-Fluoro-6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.a TY 2 SN: ! and Je Ne 2 A © YY acid (4) p-toluenesulfonic acid is added mg; 0175 mmol) to : A) piperidin-4-one hydrochloride 0 mg 0.117 mmol) and : I-(diphenylmethylene)-2-(4-fluoro-2-methoxyphenyl)hydrazine ) mg V0 + mmol) in (Ja 01©) ethanol at ©"C over a period of 1 min in air. The resulting suspension was stirred at 80°C for V1 h. The reaction mixture was dried using EtOAC 5 ¢(d= 01( EtOH (Je Yoo ) 1) then successively washed with NaHCO; saturated ) NaHCO; ' (Se Yo saturated YO) mL); and saturated brine VO) saturated brine mL). The organic layer is dried by Ag «Na,SO, filtration and evaporation to produce a crude product. The crude product is purified by debt exchange chromatography using a Sy SCX column Separation of the desired product from the column with 1 M of MeOH NH; the pure fractions are evaporated to dryness to yield a Vo crude product. The crude product is purified by preparative HPLC (Protection 7001 Metl 11:011/ ) H,0 as separating material.The fractions containing the compound mentioned in the title were evaporated to dryness to produce:

1177 - - cana YOu ) 8-fluoro-6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole £1 0 as a yellow solid . MS (+ve ESI): 221.3 (M+H)+ (1H, bs), 2.75 (2H, 0, 3.21 (2H, 1), 3.92 (3H, 5), 1.63 HNMR ( 400.13 MHz, CDCI3) 3.99(2H, 1), 6.39 - 6.42 (1H, m), 6.67 - 6.70 (1H, m), 7.99 (1H, s) Experiment to identify inhibitors of K cathepsins The technique was used QFRET: Quenched Fluorescent Resonance Energy Transfer to measure measurement inhibition by test compounds for the cleavage of the synthetic peptide Z-Phe-Arg-AMC 0 to which cathepsins contribute C. Twelve concentrations (7.5 * 01 - 8-1-01 µM) were investigated on two separate conditions and average values of 1650 M were reported.. +0 nM [final] of rhuman cathepsin K is added in solution phosphate buffer to a black microtitre plate 01861 with YAEL eye containing compounds subject to test Vo. The enzyme and compound were pre-incubated at room temperature for Ye min before adding 50 mM [Sled] of Z-Phe-Arg-AMC synthetic substrate in buffer 8. Plates are covered and incubated for 1 hour at room temperature;

TY -

and protect it from light. After cincubation the reaction was stopped using 77.5 [Sle] of

Acetic acid Relative fluorescence was measured using an Ultra plate reader

The die reader has a wavelength of Fe nano-jie alert and an emissivity of £Y0 nm.

Data corrected for background fluorescence (lowest control samples without 0 enzyme). This data was used to plot plot inhibition curves and calculate values

0 by non-linear regression using a variable slope; fork

Origin 7.5 Model zero in parse set = offset

Data reproducibility was evaluated using a statistical analysis suite using a comparison sample test

Quality as it indicates the internal diversity of what is being tested.” Iterative testing (n = ©) if SD 1650m 0 more than Fie and example compounds Cat 16 FRET competitor binding as measured by the described experiment

code] All of them with 1050m greater than 1.0 Single values will be illustrated below.

- 14 - Aaas S Z Yv Eh Y14¢

Claims (1)

— FY- protection elements (I) A compound of formula 1 - 1 = z N 1 z Lo RIN"> 1 m elk 0) a where: Ag is an aliphatic ring with from © to 1 atoms optionally containing a double bond and optionally including an oxygen atom as ring member 4 and having a substituent Optional Lay up to three individually selected substituent groups of halogen 1 Roeb ¢Cs4carbocyclyl 5 alkyl RA is a hydrogen that “Crsalkyl 4 is a ligand form with a nitrogen atom bonded It has a heterocyclic ring 0 is partially unsaturated or monocyclic The ring has from © to 1 1 1 hy and this ring shares one atom with the unsaturated or unsaturated ring ia or saturated 0 second monocyclic ring to form a ring system A thicyclic ring system yy The dicyclic ring system shares at least one atom with a third saturated ring; or unsaturated 4 Win or unsaturated to form a tricyclic ring system yo includes up to 14 014 ring atoms where the tricyclic ring system optionally includes up to to five 17 heteroatoms each selected separately from an atom of ©0; or 5 or oN with substitution 1 - - 08 optional including Jay into three inference groups 4 each of which were selected separately from “phenyl” or “benzyl” or “naphthyl” or “cis alkyl” or “C, .salkenyl 0 i.e. cyano ie COOR® J chalogen R XO R NO, or J OR' < CONR'R® 11 R (NR'R® R,alkanesulfonyl-Ren A monocyclic YY ring containing up to 7 atoms of the ring; 5 heteroaryl bicyclic ring containing up to a YY atom of VY” carbon YE, and in the tricyclic ring system, optionally replace the neighboring carbon atoms with the “—O-C(R®),-0- group, where 18 expresses 53 hydrogen or chalogen 7 to form the ¢V group? Up to three substitution groups each selected on the aa 0 of the 5 “NR*R® rotary rotary instrument SO,NR’R’ 5 “OR? 5” cyano s and the NR tromole 'COR 1) and the same Crs alkyl group optionally substituted by up to three TY substituent groups selected separately from «OR? 5 {(NR'R' 5 ¢<SO,R® 5 “cyano s” halogen YY and scramble 5 “CONRR' 3 NR*COR' 5 (NSO,R®) (1) YE as is with a monocyclic or bicyclic aryl group optionally substituting Yo for Lay up to three individually selected substituent groups from «(NR'COR'; «(NSOR's SO, NR'R'; (NR'R'; halogen Y¥1 OR' 5 coyanos 1 and the phenyl itself optionally substituted with up to three YA groups <halogen or SO ,R? or have the same ,© alkyl group an optional substitution of 4 with up to three separately selected substitution groups of SOR' 5 scyano 5 chalogen (NR*COR' 5 (NSO,R> 5 «SO NR'R® 5 0 RTTA'AL 5 {CONR'R'® 5 Cs 7carbocyclyl 5 «OR? M - 1 hydrogen (sR?) was chosen and a wreath of 5 heteroaryl 5 “phenyl 5 “Cs.scarbocyclyl monocyclic ¢Y” or a saturated heterocyclic monocyclic heterocyclic saturated £7 having from ; to 1” atoms comprising up to three heteroatoms selected ge separately from SO 8 or “IN and where each Cys alkyl can be substituted and phenyl heteroaryl 3 £0 monocyclic optionally with up to three individually selected groups 1 of NSO,R' 5 < SO,NR'R® 5 <NR'R' 5 "CONR'R' 5 "cyano 5 chalogen VY and 0:83 ?; R'4R* separately expresses alkyl 5 hydrogen C 5 heteroaryl 5 "COR?; monocyclic Comprising up to V ring atoms or heteroaryl bicyclic £4 Comprising up to 11 ring atoms or forming with the two nitrogen atoms on which a non-ring is attached A heterocyclic monocyclic saturated ring 51 has from © to 7 atoms optionally comprising up to three additional non-monocyclic “©” atoms each selected separately from the © atoms; or 5 or N and have an optional substitution of OF with an alkyl group © , which has an optional substitution with NROR 18 and 18 separately express either chydrogen 4 or a Cie alkyl or with nitrogen attached to it heterocyclic ring 00 monocyclic saturated The ring in it © to ald 1 optionally includes 01 up to three additional hetero-atoms each selected separately from the 0 atoms; ov, 8, or iN 0A _ and salts thereof are pharmaceutically acceptable. 1-7 Compound of claim A Cua) is an aliphatic ring having from 0" to v atoms substituted by up to three separately selected Y substituent groups of Ci4carbocyclyl halogen 1 *- Compound according to any of the protection elements from 1 to oF where it forms L-18 and RP with an atom nitrogen "bonded to which a heterocyclic ring is saturated or partially saturated" is monocyclic with © to + atoms; This ring shares two atoms with; A saturated or unsaturated binary ring to form a bicyclic ring system 0 where the bicyclic ring system shares one or two atoms with 1 a third saturated or unsaturated ring to form a tricyclic ring system system 1" contains a total of up to 15 atoms; the tricyclic system A can optionally contain up to three heteroatoms each selected on saa 4. of atoms ©; , 5 or 18 and optionally interchangeable with up to three sets Yo replace as then defined in Clause 1 1 ;- mounted according to Clause oF where the second ring is a non-ring ¥ an unsaturated ring has 0—1 atoms; Comprising one heteroatom ¥ chosen from 17 and ©0; And the third ring is a ring with 1 atoms that includes ; Optionally on a single heteroatom chosen Ne 1*- a process for preparing a compound of formula (I) as then defined in claim 1 where Y includes: “(a) treatment of a compound It has the formula (11): © 87 F M 7 .5 FY l ¢ > = > {II using a compound of formula (1m): o Rub any R 1 (IIT Cun y is R and l8; and 82 as defined in any of the claims 1 through ©; or + (b) treat a compound of formula (17): rub P except for sat q and A DE A {Iv} 0 using a compound of formula (7): RT nar Ra 11 7 VY where it is 8 and 8; passion as Defined in any of the claims 1 to © 0” and optionally after the formation of (a) or (b) a pharmaceutically acceptable salt. 1 “- a compound of formula (I) as defined in accordance with for any of the claims 1 to 0 for therapeutic use. Copically, K cathepsins = A 1 A compound of formula (1) as defined according to any of the claims 1 to 0 1 115 117 - - Y For use in the treatment of costeoporosis, rheumatoid arthritis ¥, costeoarthritis, metastatic bone disease ¢, osteolytic bone disease or 0 | For neuropathic pain related to bones. 1 4- A pharmaceutical composition comprising a compound of formula (I) according to any of the claims from 1" to * or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier diluent or sale. 1-01 Use a compound of formula (I) according to any of the claims 1 to © or a salt thereof "pharmaceutically acceptable"; In the manufacture of a drug for use in the inhibition of cathepsins 16 in an animal .warm blooded animal lll ¥ -11 1 Compound of claim 0 where or a pharmaceutically acceptable salt thereof may be chosen from any of: (IR,2R)-N-(1-cyanocyclopropyl)-2-[ (8-fluoro-1,3,4,5-tetrahydro-2 H-pyrido[4,3- v blindol-2-yl)carbonyl]cyclohexanecarboxamide; ¢ (1R,2R)-2-[(8-chloro-1,3,4,5-tetrahydro-2 H-pyrido[4,3-b]indol-2-yl)carbonyl]-N-© (1-cyanocyclopropyl)cyclohexanecarboxamide; 1 L (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-fluoro-1,3,4,5-tetrahydro-2 H-pyrido[4,3-blindol-2) -yl)carbonyl]cyclohexanecarboxamide; A (1R,2R)-N-(1-cyanocyclopropyl)-2-(1,3,4,5-tetrahydro-2H-pyrido[4,3-4]indol-2- A ylcarbonyl) cyclohexanecarboxamide; Ye (1R,2R)-2-[(8-bromo-1,3,4,5-tetrahydro-2 H-pyrido[4,3-b]indol-2-yl)carbonyl]-N- 1 Y14¢ - ra - (1-cyanocyclopropyl)cyclohexanecarboxamide; VY (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-0 blindol-2-yl)carbonyl [cyclohexanecarboxamide; Vi(1R,2R)-N-(1-cyanocyclopropyl)-2-{[8-(trifluoromethyl)-1,3,4,5-tetrahydro-2 H- Ve pyrido[4,3-b]indol-2 -yl]carbonyl} cyclohexanecarboxamide; 5 (1R,2R)-N-(1-cyanocyclopropyl)-2-[(8-methoxy-1,3,4,5-tetrahydro-2H-pyrido[4,3- Wwblindol-2-yl)carbonyl [cyclohexanecarboxamide; YA (1R,2R)-N-(1-cyanocyclopropyl)-2-[(8-isopropyl-1,3,4,5-tetrahydro-2H-pyrido 4[4,3-b]indol-2-yl )carbonyl]cyclohexanecarboxamide; v. (1R,2R)-N-(1-cyanocyclopropyl)-2-[(9-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3- 9 blindol-2-yl)carbonyl] cyclohexanecarboxamide; vy (1R,2R)-N-(1-cyanocyclopropyl)-2-[(7-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-YY blindol-2-yl)carbonyl [cyclohexanecarboxamide; vt (1R,2R)-N-(1-cyanocyclopropyl)-2-[(8-fluoro-5-methyl-1,3,4,5-tetrahydro-2 H- vo pyrido[4,3-b]indol -2-yl)carbonyl]cyclohexanecarboxamide; 571 (1R,2R)-2-[(6-bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]-N- TY (1) -cyanocyclopropyl)cyclohexanecarboxamide; YA (1R,2R)-N-(1-Cyanocyclopropyl)-2-[1,3,4,5-tetrahydro-1H-pyrido[4,3-3]-7- Ya azaindol-2-yl)carbonyl] cyclohexanecarboxamide ve (1R,2R)-N-(1-cyanocyclopropyl)-2-({8-[(dimethylamino)methyl]-1,3,4,5-9 tetrahydro-2H-pyrido[4,3-b] [indol-2-yl} carbonyl)cyclohexanecarboxamide; vy (1R,2R)-N-(1-cyanocyclopropyl)-2-{[8-(methylsulfonyl)-1,3,4,5-tetrahydro-2H- ¥¥ pyrido[4,3-b}indol- 2-yl]carbonyl}cyclohexanecarboxamide; vi (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-methoxy-1,3,4,5-tetrahydro-2H-pyrido{[4,3- yo 166 = 1 blindol-2-yl)carbonyl]cyclohexanecarboxamide; vi (1R,2R)-N-(1-cyanocyclopropyl)-2-(1H-spiro[isoquinoline-4,4'-piperidin]-2(3H)- 9ylcarbonyl)cyclohexanecarboxamide; YA (1R,2R)-2-[(6-chloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]-N- 71 (1 -cyanocyclopropyl)cyclohexanecarboxamide; 3 (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-cyano-1,3,4,5-tetrahydro-2H-pyrido[4,3-3 blindol-2-yl)carbonyl [cyclohexanecarboxamide; ¢Y (1R,2R)-N-(1-cyanocyclopropyl)-2-[(9-methyl-5,7,8,9-tetrahydro-6 H-pyrrolo[2,3-l b:4] ,5-¢"]dipyridin-6-yl)carbonyl]cyclohexanecarboxamide;tt (1R,2R)-N-(1-cyanocyclopropyl)-2-{[6-(methylthio)-1,3,4,5-tetrahydro -2 H- to pyrido[4,3-b}indol-2-yl]carbonyl}cyclohexanecarboxamide;£1 (1R,2R)-N-(1-cyanocyclopropyl)-2-[( benzofuro[3,2-c] ]-1,2,3,4- &v tetrahydropyridyl)carbonyl]cyclohexanecarboxamide; EA (1R,2R)-N-(1-cyanocyclopropyl)-2-{[6-(trifluoromethoxy)-1,3,4,5- tetrahydro-2H-£4pyrido[4,3-b]indol-2-ylJcarbonyl}cyclohexanecarboxamide; or (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-ethoxy-1,3, 4,5-tetrahydro-2 H-pyrido [4,3- 2 blindol-2-yl)carbonyl]cyclohexanecarboxamide;ov (1R,2R)-N-(1-cyanocyclopropyl)-2-[(5-methoxycarbonylmethyl-1) ,3,4,5-tetrahydro- ~ °¥ 2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide; ot (1R,2R)-N-(1-cyanocyclopropyl)-2-[ (5-hydroxycarbonylmethyl-1,3,4,5-tetrahydro-°° 2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide; 91 (1R,2R)-N-(1-cyanocyclopropyl) )-2-[(5-cyclopropylmethyl-1,3,4,5-tetrahydro-2 H- ev pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide; oA(1R,2R)-N-(1-cyanocyclopropyl)-2-[(5-methoxyethyl-1,3,4,5-tetrahydro-2H-od) - 161 - pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide; A (1R,2R)-N-(1-cyanocyclopropyl)-2-{[6-(trifluoromethyl)-1,3,4,5-tetrahydro-2 H- 1 pyrido[4,3-b]indol-2 - yl]carbonyl} cyclohexanecarboxamide; 17 (1R,2R)-N-(1-cyanocyclopropyl)-2-{[6-(methylsulfonyl)-1,3,4,5-tetrahydro-2H- 1" pyrido[4,3-b]indol- 2-yl]carbonyl} cyclohexanecarboxamide;14 (1R,2R)-2-{[6-(benzyloxy)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl ] ne carbonyl}-N-(1-cyanocyclopropyl)cyclohexanecarboxamide;11 (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-hydroxy-1,3,4,5-tetrahydro-2H- pyrido [4,3- wv blindol-2-yl)carbonyl]cyclohexanecarboxamide;TA (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-propoxy-1,3,4,5-tetrahydro- 2 H-pyrido [4,3- 23 bjindol-2-yl)carbonyl]cyclohexanecarboxamide; Ve (1R,2R)-N-(1-cyanocyclopropyl)-2-{[6-(cyanomethoxy)-1,3,4,5-tetrahydro-2H- the pyrido[4,3-b]indol-2 -yl]carbonyl}cyclohexanecarboxamide; L (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-(dimethylamino)ethoxy)-2,3,4,5-L tetrahydro-1H-pyrido[ 4,3-b}indole-2-carbonyl)cyclohexanecarboxamide; ve (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-morpholinoethoxy)-2,3,4,5-tetrahydro- ve 1H-pyrido[4,3-b]indole-2 -carbonyl)cyclohexanecarboxamide; vi (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-(pyrrolidin-1-yl)ethoxy)-2,3,4,5- vy tetrahydro-1H-pyrido[4, 3-b]indole-2-carbonyl)cyclohexanecarboxamide; vA(IR,2R)-N-(1-cyanocyclopropyl)-2-(6-(2-(piperidin-1-yl)ethoxy)-2,3,4,5- va tetrahydro-1H-pyrido[4, 3-b]indole-2-carbonyl)cyclohexanecarboxamide; A (1R,2R)-N-(1-cyanocyclopropyl)-2-[(5-methanesulphonyl-1,3,4,5-tetrahydro-2 H- A) pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide; AY (1R,2R)-2-(7,8-Dihydro-5H-furo[2,3-b:4,5-c']dipyridine-6-carbonyl)-AY E: - 167 - cyclohexanecarboxylic acid (1-cyano-cyclopropyl)-amide; At (IR,2R)-2-(7-Methanesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b] indole-2-carbonyl)- AS cyclohexanecarboxylic acid (1-cyano-cyclopropyl)- amide; Al (1R,2R)-2-(9-Methanesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-5] indole-2-carbonyl)- AY cyclohexanecarboxylic acid (1-cyano-cyclopropyl)- amide; AA (1R,2R)-N-(1-cyanocyclopropyl)-2-(2,2-difluoro-7,8,9,10-tetrahydro-6H-Ad[1,3]dioxolo[4,5-g] ]pyrido[4,3-b]indole-7-carbonyl)cyclohexanecarboxamide; 1 and: 91 (1R,2R)-N-(1-cyanocyclopropyl)-2-(8-fluoro-6-methoxy-2,3,4,5 -tetrahydro-1H-9 pyrido[4,3-b]indole-2- carbonyl)cyclohexanecarboxamide. 97 Y14¢