HK1196610A - New enzyme inhibitor compounds - Google Patents

Description

Novel enzyme inhibitor compounds

Technical Field

The present invention relates to compounds that are inhibitors of SSAO activity. The invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment or prevention of medical conditions in which inhibition of SSAO activity is beneficial (e.g. inflammatory diseases, immune diseases) and in the inhibition of tumor growth.

Background

Semicarbazide-sensitive Amine Oxidase (SSAO) activity is an enzymatic activity expressed by Vascular adhesion Protein-1 (VAscalor adhesive Protein-1, VAP-1) or Copper-Containing Amine Oxidase 3(Amine oxide, Copper Containing3, AOC3), which belongs to the enzyme family of Copper-Containing Amine oxidases (EC.1.4.3.6). Thus, inhibitors of SSAO enzymes may also modulate the biological function of VAP-1 protein. Members of this family of enzymes are sensitive to inhibition by semicarbazides, and copper ions and dopaquinone (TPQ) cofactors derived from proteins are used for oxidative deamination from primary amines to aldehydes, hydrogen peroxide and ammonia according to the following reactions:

R-CH₂-NH₂+O₂→R-CHO+H₂O₂+NH₃。

known substrates of human SSAO include endogenous methylamine and aminoacetone, as well as some exogenous amines, such as benzylamine [ Lyles, int.j.biochem.cell biol.1996,28, 259-274; klinman, Biochim.Biophys.acta2003,1647(1-2), 131-; m < tyus et al, curr. Med. chem.2004,11(10), 1285-1298; o' Sullivan et al, neurooxo 2004,25(1-2),303-315 ]. Similar to other copper-containing amine oxidases, DNA sequencing and structural determination indicate that tissue-bound human SSAO is a homodimeric glycoprotein consisting of two 90 to 100kDa subunits anchored to the plasma membrane by a single N-terminal transmembrane domain [ Morris et al, j.biol.chem.1997,272, 9388-9392; smith et al, J.Exp.Med.1998,188, 17-27; airenne et al, Protein Science2005,14, 1964-; jakobsson et al, Actacrystallogr.D biol. Crystallogr.2005,61(Pt11), 1550-.

SSAO activity has been found in a variety of tissues including vascular and non-vascular smooth muscle tissue, endothelium and adipose tissue [ lewis ohn, braz.j.med.biol.res.1984,17, 223-; nakos (Nakos)&Gossrau, Folia histochem.Cytodiol.1994, 32, 3-10; yu et al, biochem. Pharmacol.1994,47, 1055-1059; castillo et al, neurochem. int.1998,33, 415-; lyles&Pino, J.neural.Transm.Suppl.1998,52, 239-; jaakkola et al, am.J.Pathol.1999,155, 1953-1965; morin et al, J.Pharmacol.Exp.Ther.2001,297, 563-572; saimi&Jalkanen,Trends Immunol.2001,22,211-216]. In addition, SSAO proteins are also found in plasma and this soluble form appears to have similar properties to the tissue-bound form [ Yu et al, biochem. Pharmacol.1994,47, 1055-;et al, J.Immunol.1998,161,1549-1557]. Recently, it has been shown that SSAO in the circulation of humans and rodents is derived from the tissue-bound form [ alpha ], [Et al, am.J.Pathol.2003,163(5), 1921-1928; abella et al, Diabetololia 2004,47(3), 429-438; stolen et al, circ. Res.2004,95(1),50-57]While in other mammals, plasma/serum SSAO is also encoded by an independent gene called AOC4 [ Schwelberger, J.neural.Transm.2007,114(6), 757-762-]。

The precise physiological role of this abundant enzyme has not been fully established, but it appears that SSAO and its reaction products may have several functions in cell signaling and regulation. For example, recent findings indicate that SSAO is responsible for GLUT-4 mediated glucose uptake [ Enrique-Tarancon et al, J.biol.chem.1998,273, 8025-8032; morin et al, J.Pharmacol.Exp.Ther.2001,297,563-572]And adipocyte differentiation [ Fontana et al, biochem. J.2001,356, 769-777; mercier et al, biochem. J.200l,358,335-]Play a role in the process. In addition, SSAO has been shown to be involved in inflammatory processes, where SSAO acts as an adhesion protein for leukocytes [ Salmi&Jalkanen，Trends Immunol.2001,22,211-216；Salmi&Jalkanen, in "addition Molecules: ley in Functions and Inhibition ", 2007, pp 237-]And may also play a role in connective tissue matrix production and maintenance [ Langford et al, Cardiovasc. Toxicol.2002,2(2), 141-;et al, am.J.Pathol.2003,163(5),1921-1928]. Furthermore, a link between SSAO and angiogenesis has recently been discovered [ Noda et al, FASEB J.2008,22 (8); 2928-]And based on this association SSAO inhibitors are expected to have anti-angiogenic effects.

Several studies in humans have demonstrated increased SSAO activity in plasma in conditions such as congestive heart failure, diabetes, alzheimer's disease and inflammation [ lewis sohn, braz.j.med.biol.res.1984,17, 223-; boomsma et al, Cardiovasc. Res.1997,33, 387-391; ekblom, pharmacol. res.1998,37, 87-92;et al, J.Immunol.1998,161, 1549-1557; boomsma et al, Diabetologia1999,42, 233-; meszaros et al, Eur.J.drug Metab.Pharmacokinet.1999,24, 299-302; yu et al, Biochim.Biophys.acta2003,1647(1-2),193- > 199; m < tyus et al, curr. Med. chem.2004,11(10), 1285-1298; o' Sullivan et al, neuromicrobiology 2004,25(1-2), 303-315; del Mar Hernandez et al, neurosci. Lett.2005,384(1-2),183-]. The mechanism behind these enzymatic activity changes is not clear. It has been proposed that active aldehydes and hydrogen peroxide produced by endogenous amine oxidases promote the progression of cardiovascular disease, diabetic complications and alzheimer's disease [ Callingham et al, prog.brain res.1995,106, 305-321; ekblom, pharmacol. res.1998,37, 87-92; yu et al, Biochim.Biophys.acta2003,1647(1-2),193- > 199; jiang et al, Neuropathol applied neurobiol.2008,34(2),194-]. Furthermore, SSAO enzymatic activity is involved in leukocyte extravasation at sites of inflammation, where SSAO has been shown to be highly expressed in vascular endothelium [ Salmi et al, Immunity2001,14(3), 265-276; salmi&Jalkanen, in "addition Molecules: ley in function and Inhibition ", 2007, pp 237-]. Thus, inhibition of SSAO has been shown to be of therapeutic value in the prevention of diabetic complications and inflammatory diseases [ Ekblom, pharmacol. res.1998,37, 87-92; salmi et al, Immunity2001,14(3), 265-276; Salter-Cid et al, J.Pharmacol. exp.Ther.2005,315(2),553-562]。

SSAO knock-out animals are phenotypically apparently normal, but show a significant reduction in the inflammatory response elicited in response to a variety of inflammatory stimuli [ Stolen et al, Immunity2005,11 (1); 105- & 115 ]]. In addition, inflammation of the paw induced by carrageenan (carrageenan), in a variety of animal models of human disease,Oxazolone-induced colitis, lipopolysaccharide-induced lung inflammation, collagen-induced arthritis, endotoxin-induced uveitis) by antagonizing SSAO function using antibodies and/or small molecules have been shown to reduce leukocyte infiltration, reduce the severity of disease phenotype, and reduce inflammatory cytokine and chemokine levelsHas protective effect [ Kirton et al, Eur. J. Immunol.2005,35 (11); 3119-3130; Salter-Cid et al, J.Pharmacol.Exp.Ther.2005,315(2), 553-562; McDonald et al, Annual Reports in medicinal Ch emistry2007,42, 229-; salmi&Jalkanen, in "Adhesion Molecules: K.Ley (eds.) in Functions and Inhibition ", 2007, pp 237-; noda et al, FASEB J.200822(4), 1094-1103; noda et al, FASEB J.2008,22(8),2928-]. It appears that this anti-inflammatory protection is provided in a variety of models of inflammation with independent pathogenic mechanisms, rather than being limited to one particular disease or disease model. This suggests that SSAO may be a key node in the regulation of inflammatory responses, and therefore SSAO inhibitors may be potent anti-inflammatory agents for a variety of human diseases. VAP-1 is also involved in the progression and maintenance of fibrotic diseases, including those of the liver and lung. Weston and Adams (J Neural Transm.2011,118(7),1055-64) summarize experimental data relating to VAP-1 in liver fibrosis, and Weston et al (EASL Poster2010) reported that blocking VAP-1 accelerated the regression of carbon tetrachloride-induced fibrosis. Furthermore, VAP-1 is involved in pulmonary inflammation (e.g., Singh et al, 2003, Virchows Arch 442: 491-.

SSAO (VAP-1) is upregulated in gastric cancer and is identified in the tumor vasculature of human Melanoma, hepatoma and head and neck tumors (Yoong KF, McNab G, Hubscher SG, Adams DH (1998), J Immunol160, 3978-88.; Irjala H, Salmi M, Alanen K, Gre' nmann R, Jalkane S (2001), Immunol.166, 6937-6943; Forster-Horvath C, Dome B, Paku S, et al (2004), Melanoma Res.14, 135-40.). One report (Marttila-Ichiahara F, Castermans K, Auvine K, Oude Egbrink MG, Jalkanen S, Griffien AW, Salmi M. (2010), J Immunol.184,3164-3173.) has shown that melanoma grows more slowly in mice with enzyme-inactivated VAP-1 and its tumor vessels decrease in number and diameter. The reduced growth of these tumors is also manifested by a reduction in myeloid suppressor cell infiltration (60% to 70% reduction). Encouraging, VAP-1 deficiency had no effect on the formation of blood vessels or lymph in normal tissues.

Different structural classes of small molecules have been previously disclosed as SSAO inhibitors, for example in WO02/38153 (tetrahydroimidazo [4, 5-c ] pyridine derivatives), in WO03/006003 (2-indanylhydrazine derivatives), in WO2005/014530 (allylhydrazine and hydroxylamine (aminooxy) compounds), and in WO2007/120528 (allylamino compounds). Additional SSAO inhibitors are disclosed in PCT/EP2009/062011 and PCT/EP 2009/062018.

The invention described herein relates to a novel class of SSAO inhibitors whose biological, pharmacological and pharmacokinetic properties make them suitable for use as prophylactic or therapeutic agents in a variety of human inflammatory and immune diseases. This therapeutic capacity is designed to block SSAO enzyme action, reducing the levels of pro-inflammatory enzyme products (aldehydes, hydrogen peroxide and ammonia), while also reducing the adhesion capacity of immune cells and correspondingly reducing their activation and eventual extravasation. Diseases for which such activity is expected to be therapeutically beneficial include all diseases in which immune cells play a significant role in the initiation, maintenance or regression of pathogenesis, such as multiple sclerosis, arthritis and vasculitis.

Detailed Description

It has been unexpectedly found that the compounds of formula (I) below are SSAO inhibitors. Thus, they are useful for treating or preventing diseases (e.g., inflammation, inflammatory diseases, immune or autoimmune disorders) in which inhibition of SSAO activity is beneficial, as well as for inhibiting tumor growth.

According to the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof:

R¹-X-R²

(I)

wherein

R¹Is phenyl or 6-membered heteroaryl, optionally substituted with one or more substituents selected from: halogen, cyano, C_1-4-alkyl, halo-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl, hydroxy-C_1-4-alkyl, cyano-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-4-alkylamino-C_1-4Alkyl, di (C)_1-4-alkyl) amino-C_1-4-alkyl, -NR^4AR^4B、-NR⁶C(O)OR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)NR^4AR^4B、-C(O)NR^4AR^4B、-C(O)R⁵、-C(O)OR⁵and-NR⁶S(O)₂R⁵；

R²is-B-Q- [ R³]_nor-B-R³；

Wherein n =1, 2,3 or 4,

b is a bond, O, NR⁴-C (O) -or C_1-3-an alkylene group;

q is a saturated or partially unsaturated monocyclic 3-to 7-membered heterocycle or C_3-7-a cycloalkyl ring;

when R is²is-B-Q- [ R³]_nWhen R is³Independently selected from: 3-to 7-membered heterocyclyl-, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-, amino-C_1-4-alkoxy-C_1-4-alkyl-, (amino-C)_1-4-alkyl) -amino-C_1-4-alkyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、-C_1-4-alkyl-NR⁶C(O)NR^4AR^4B、-C_1-4alkyl-C (O) NR^4AR^4B(3-to 7-membered heterocyclic group-C)_1-4-alkyl) -C (O) -, -C_1-4alkyl-C (O) OR⁵、-OC(O)R⁵Or

-C(O)NR^9AR^9BWherein R is^9AAnd R^9BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, which is substituted with one or more substituents selected from: c_1-4-alkyl radical、C_1-4alkoxy-C_1-4Alkyl-, C_3-7-cycloalkyl, or

-C(O)NR⁶R^10BWherein R is^10BThe method comprises the following steps:

(i) 3-to 7-membered heterocyclyl-or 3-to 7-membered heterocyclyl-C_1-4-alkyl-or-C_1-4-alkyl-NR⁶C(O)R⁵(ii) a Or

(ii) 5-or 6-membered heteroaryl-C_1-4-alkyl-, wherein the heteroaryl ring is optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, C_1-4-alkyl, halo-C_1-4-alkyl, and wherein said C_1-4-alkyl moieties optionally substituted by one or more C_1-4-alkyl-group substitution, or said C_1-4Alkyl moieties by two C_1-4-alkyl substitution, said two C_1-4-alkyl groups taken together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl spirocycle; and wherein

When R is²is-B-R³When R is³is-NR⁶R^11BAnd R is^11BIs a 3-to 7-membered heterocyclyl-C_1-4-alkyl-;

R^4A、R^4Band R⁵Each independently selected from hydrogen and C_1-4-alkyl-, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, amino-C_1-4-alkyl-, 3-to 7-membered heterocyclyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、C_3-7-cycloalkyl, or

R^4AAnd R^4BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, optionally substituted with one or more substituents selected from: c_1-4-alkyl, -NR^4AR^4B(ii) a And wherein

Unless otherwise specified, a 3-to 7-membered heterocyclyl group, or a 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-Or (3-to 7-membered heterocyclyl-C)_1-4-the heterocyclyl part of the-alkyl) -c (o) -group is optionally substituted with one or more substituents selected from: oxo, C_1-4Alkyl-, -C (O) OR⁵、-C(O)R⁵、-C(O)NR^4AR^4B、-NR^4AR^4B、-C_1-4alkyl-C (O) NR^4AR^4BOr C_1-4alkoxy-C_1-4An alkyl group; and is

diradical-C directly linked to Q when present_1-4-the alkyl-group is optionally substituted with one or more groups independently selected from: halogen, amino, methoxy, hydroxy; and wherein

R⁴And R⁶Each independently selected from hydrogen or C_1-4-an alkyl group; and is

X is selected from the group of formula (1-16) wherein the bond marked with < i > ANGSTROM </i > and R¹-linked, with a bond labelled with < u > ANG </u > and-R²And (3) connection:

wherein Y is selected from hydrogen, hydroxy, amino, -NHR⁶、-OCH₃；

Z is selected from hydrogen, fluorine, hydroxyl and C_1-4-alkoxy, halo-C_1-4Alkyl, CONH₂Cyano, SO₂NH₂Amino, -NHR⁶；

W is selected from H, C_1-4-alkyl, halo-C_1-4-an alkyl group,

provided that when R is²is-B-Q- [ R³]_nAnd R is³R directly bonded to Q when it is a 3-to 7-membered heterocyclyl-group³The heterocyclic atom is not nitrogen.

In a related embodiment, the present invention may employ a compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof:

R¹-X-R²

(I)

wherein

R¹Is phenyl or 6-membered heteroaryl, optionally substituted with one or more substituents selected from: halogen, cyano, C_1-4-alkyl, halo-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl, hydroxy-C_1-4-alkyl, cyano-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-4-alkylamino-C_1-4Alkyl, di (C)_1-4-alkyl) amino-C_1-4-alkyl, -NR^4AR^4a、-NR⁶C(O)OR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)NR^4AR^4B、-C(O)NR^4AR^4B、-C(O)R⁵、-C(O)OR⁵and-NR⁶S(O)₂R⁵；

R²is-B-Q- [ R³]_nor-B-R³；

Wherein n =1, 2,3 or 4,

b is a bond, O, NR⁴-C (O) -or C_1-3-an alkylene group;

q is a saturated or partially unsaturated monocyclic 3-to 7-membered heterocycle or C_3-7-a cycloalkyl ring;

when R is²is-B-Q- [ R³]_nWhen R is³Independently selected from: 3-to 7-membered heterocyclyl-, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-, amino-C_1-4-alkoxy-C_1-4-alkyl-, (amino-C)_1-4-alkyl) -amino-C_1-4-alkyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、-C_1-4-alkyl-NR⁶C(O)NR^4AR^4B、-C_1-4alkyl-C (O) NR^4AR^4B(3-to 7-membered heterocyclic group-C)_1-4-alkyl) -C (O) -, -C_1-4alkyl-C (O) OR⁵、-OC(O)R⁵Or

-C(O)NR^9AR^9BWherein R is^9AAnd R^9BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, which is substituted with one or more substituents selected from: c_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl-, C_3-7-cycloalkyl, or

-C(O)NR⁶R^10BWherein R is^10BIs 3-to 7-membered heterocyclyl-or 3-to 7-membered heterocyclyl-C_1-4-alkyl-or-C_1-4-alkyl-NR⁶C(O)R⁵(ii) a Or

When R is²is-B-R³When R is³is-NR⁶R^11BWherein R is^11BIs a 3-to 7-membered heterocyclyl-C_1-4-alkyl-;

R^4A、R^4Band R⁵Each independently selected from hydrogen and C_1-4-alkyl-, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, amino-C_1-4-alkyl-, 3-to 7-membered heterocyclyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、C_3-7-a cycloalkyl group,

or R^4AAnd R^4BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, optionally substituted with one or more substituents selected from: c_1-4-alkyl, -NR^4AR^4B；

Unless otherwise specified, a 3-to 7-membered heterocyclyl group, or a 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-or (3 to 7 membered heterocyclyl-C)_1-4-the heterocyclyl part of the-alkyl) -c (o) -group is optionally substituted with one or more substituents selected from: c_1-4Alkyl-, -C (O) OR⁵、-C(O)R⁵、-C(O)NR^4AR^4B、-NR^4AR^4B、-C_1-4alkyl-C (O) NR^4AR^4BOr C_1-4alkoxy-C_1-4An alkyl group; and is

When present, diradical-C directly attached to Q_1-4-the alkyl-group is optionally substituted with one or more groups independently selected from: halogen, amino, methoxy, hydroxy;

R⁴and R⁶Each independently selected from hydrogen or C_1-4-an alkyl group; and is

X is selected from the group of formula (1-16) wherein the bond marked with < i > ANGSTROM </i > and R¹-linked, with a bond labelled with < u > ANG </u > and-R²And (3) connection:

wherein Y is selected from hydrogen, hydroxy, amino, -NHR⁶、-OCH₃；

Z is selected from hydrogen, fluorine, hydroxyl and C_1-4-alkoxy, halo-C_1-4Alkyl, CONH₂Cyano, SO₂NH₂Amino, -NHR⁶；

W is selected from H, C_1-4-alkyl, halo-C_1-4-an alkyl group,

provided that when R is²is-B-Q- [ R³]_nAnd R is³Is a 3-to 7-membered heterocyclyl-, the heteroatom directly bonded to Q is not nitrogen.

It is contemplated that the compounds of the present invention may be prepared in hydrate and solvate forms. Any reference herein (including the claims herein) to "a compound to which the invention relates" or "a compound of the invention" or the like, includes reference to salts, hydrates, and solvates of such compounds. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

The individual compounds of the invention may exist in amorphous form and/or in several polymorphic forms and may be obtained in different crystal habits (crystal habit). Any reference herein (including the claims herein) to "a compound to which the invention relates" or "a compound of the invention" etc. includes reference to the compound, whether in amorphous or polymorphic form.

Because the compounds of the present invention have a nitrogen atom in the aromatic ring, they may form N-oxides, and the present invention includes the compounds of the present invention in their N-oxide form.

Definition of

The following definitions shall apply throughout the specification and appended claims unless otherwise indicated or indicated.

The term "C_1-4-alkyl "means a straight or branched chain alkyl group having 1 to 4 carbon atoms. For C_1-4The part of the range of alkyl groups, including all subgroups thereof, e.g. C_1-3Alkyl radical, C_1-2Alkyl radical, C_2-4Alkyl radical, C_2-3-alkyl and C_3-4-an alkyl group. Said C is_1-4Examples of-alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Unless otherwise specified, the term "C_3-7-cycloalkyl "refers to a monocyclic saturated or partially unsaturated hydrocarbon ring system having 3 to 7 carbon atoms. Said C is_3-7Examples of-cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl and cycloheptenyl. For "C_3-7-cycloalkyl "range including all subgroups thereof, e.g. C_3-7-cycloalkyl, C_3-6-RingAlkyl radical, C_3-5-cycloalkyl, C_3-4-cycloalkyl, C_4-7-cycloalkyl, C_4-6-cycloalkyl, C_4-5-cycloalkyl, C_5-7-cycloalkyl, C_5-6-cycloalkyl and C_6-7-a cycloalkyl group.

The term "C_1-4By alkoxy is meant a straight or branched chain C attached to the remainder of the molecule via an oxygen atom_1-4-an alkyl group. For C_1-4Part of the alkoxy range, including all subgroups thereof, e.g. C_1-3-alkoxy, C_1-2-alkoxy, C_2-4-alkoxy, C_2-3-alkoxy and C_3-4-alkoxy groups. Said C is_1-4Examples of the-alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The term "hydroxy-C_1-4-alkyl "means a straight or branched chain C with one or more of its hydrogen atoms replaced by OH_1-4-an alkyl group. The hydroxy group-C_1-4Examples of-alkyl groups include hydroxymethyl, 2-hydroxyethyl and 2, 3-dihydroxypropyl.

The term "halo-C_1-4-alkyl "means a straight or branched chain C with one or more hydrogen atoms replaced by halogen_1-4-an alkyl group. Said halo-C_1-4Examples of-alkyl groups include fluoromethyl, trifluoromethyl, trichloromethyl and 2-fluoroethyl.

The term "cyano-C_1-4-alkyl "means a straight or branched chain C with one or more hydrogen atoms replaced by cyano_1-4-an alkyl group. The cyano group-C_1-4Examples of the-alkyl group include cyanomethyl, 2-cyanoethyl and 3-cyanopropyl.

The term "amino-C_1-4By alkyl is meant a straight or branched chain C substituted by amino_1-4-an alkyl group. Said amino-C_1-4Examples of-alkyl groups include aminomethyl and 2-aminoethyl.

The term "C_1-4-alkylamino-C_1-4-alkyl "means amino-C as defined above_1-4Alkyl, in which the amino group is substituted by a straight or branched chain C_1-4-alkyl substitution. Said C is_1-4-alkylamino-C_1-4Examples of-alkyl groups include methylaminoethyl and ethylaminopropyl.

The term "di (C)_1-4-alkyl) amino-C_1-4-alkyl "means amino-C as defined above_1-4Alkyl, in which the amino groups are substituted by straight-chain or branched C groups which may be the same or different_1-4-alkyl disubstituted. Said two (C)_1-4-alkyl) amino-C_1-4Examples of the-alkyl group include N, N-dimethylaminomethyl group, N-ethyl-N-methylaminoethyl group and N, N-diethylaminomethyl group.

The terms "heteroaryl" and "heteroaromatic ring" refer to monocyclic heteroaromatic rings comprising 5 to 6 ring atoms, wherein one or more of the ring atoms is not carbon, e.g., is nitrogen, sulfur or oxygen. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl,Azolyl radical, isoOxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, tetrazolyl, pyrazolyl, pyridazinyl, pyrazinyl and thiadiazolyl.

The terms "heterocyclyl" and "heterocycle" refer to non-aromatic, fully saturated or partially unsaturated (preferably fully saturated), monocyclic ring systems having 3 to 7 ring atoms (especially 5 or 6 ring atoms), wherein one or more of the ring atoms is other than carbon, for example nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include piperidinyl, morpholinyl, homomorpholinyl, azepanyl, piperazinyl, oxo-piperazinyl, diazaRadical (diazepinyl), tetrahydropyridinyl, tetrahydropyranyl, pyrrolidinyl, tetrahydrofuranyl and dihydropyrrolylAnd (4) a base.

The term "heterocycle-C_1-4-alkyl "means a carbon or nitrogen atom through the ring with a straight or branched chain C_1-4-heterocycles with alkyl groups directly attached. The heterocycle-C_1-4Examples of-alkyl groups include piperidin-4-ylmethyl, piperidin-1-ylmethyl, morpholin-4-ylmethyl, and piperazin-4-ylmethyl. C_1-4-an alkyl moiety (including methylene, ethylene, propylene or butylene) optionally substituted with one or more substituents selected from: halogen, amino, methoxy or hydroxy.

The term "C_1-3-alkylene "means a linear or branched divalent saturated hydrocarbon chain having from 1 to 3 carbon atoms. C_1-3The alkylene chain may be linked to the remainder of the molecule and the remainder of the group by one carbon in the chain or by any two carbons in the chain. C_1-3Examples of the "alkylene group" include methylene [ -CH₂-]1, 2-ethylene [ -CH ]₂-CH₂-]1, 1-ethylene [ -CH (CH)₃)-]1, 2-propylene [ -CH₂-CH(CH₃)-]And 1, 3-propylene [ -CH₂-CH₂-CH₂-]. When referring to "C_1-3When an alkylene group "includes all subgroups thereof, e.g. C_1-2Alkylene and C_2-3-an alkylene group.

"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine, most preferably fluorine.

"hydroxy" means an-OH group.

"cyano" refers to the group-CN.

"oxo" means carbonyl = O.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

"pharmaceutically acceptable" means useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic, and biologically or otherwise undesirable, and which include use in veterinary as well as human pharmaceutical applications.

As used herein, "treatment" includes prophylaxis of the disease or condition, or reduction or elimination of the disease after it has occurred.

An "effective amount" refers to the amount of a compound that imparts a therapeutic effect to a subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels the effect).

"prodrug" refers to a compound that can be converted to the biologically active compounds of the present invention under physiological conditions or by solvolysis. When administered to a subject in need thereof, the prodrug may be inactive, but it converts to the active compound of the invention in vivo. Prodrugs are generally rapidly converted in vivo (e.g., by hydrolysis in blood) to yield the parent compound of the invention. Prodrug compounds generally have The advantage of solubility, histocompatibility or delayed release in mammalian organisms (see Silverman, R.B., The organic chemistry of Drug Design and Drug action, 2 nd edition, Elsevier Academic Press (2004), p.498-549). Prodrugs of a compound of the invention may be prepared by modifying functional groups (e.g., hydroxy, amino, or mercapto) present in a compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Examples of prodrugs include, but are not limited to, acetate, formate and succinate derivatives of hydroxyl functional groups, or phenyl carbamate derivatives of amino functional groups.

Throughout the specification and the appended claims, a given formula or name shall also include all salt, hydrate, solvate, N-oxide and prodrug forms thereof. In addition, a given chemical formula or name shall include all tautomeric and stereoisomeric forms thereof. Tautomers include enol forms and keto forms. Stereoisomers include enantiomers and diastereomers. Enantiomers can exist in their pure form or as a racemic (equal) or unequal mixture of two enantiomers. Diastereomers may exist in their pure forms or as mixtures of diastereomers. Diastereomers also include geometric isomers, which may exist in their pure cis or trans forms, or as mixtures thereof.

The compounds of formula (I) may be used as such or, where appropriate, as pharmaceutically acceptable salts (acid or base addition salts) thereof. The pharmaceutically acceptable addition salts mentioned below are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form. Compounds having basic properties may be converted into their pharmaceutically acceptable acid addition salts by treating the base form with a suitable acid. Exemplary acids include inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid (pamoic acid), benzoic acid, ascorbic acid, and the like. Exemplary base addition salt forms are sodium, potassium, calcium salts and salts with pharmaceutically acceptable amines (e.g., ammonia, alkylamines, benzathine (benzathine)), as well as amino acids (e.g., arginine and lysine). The term addition salt as used herein also includes solvates, such as hydrates, alcoholates and the like, which the compounds and salts thereof are able to form.

Group X

In the compounds of the present invention, X may be selected from any one of the groups of formulas 1-16.

Presently preferred embodiments of the invention include embodiments wherein X is:

formula 1 and R¹、R²Y, Z and W are as defined above, or

Formula 2 and R¹、R²Y, Z and W are as defined above, or

Formula 3 and R¹、R²Y and Z are as defined above, or

Formula 4 and R¹、R²Y and W are as defined above, or

Formula 5 and R¹、R²And Y is as defined above, or

Formula 6 and R¹、R²Y and Z are as defined above.

Group B

In one embodiment of the invention, B is a bond, O, NR⁴(e.g., NH, NCH₃Or NCH₂CH₃) -C (O) -or C_1-3Alkylene (such as methylene, ethylene or propylene). In a presently preferred embodiment, B is a bond, -C (O) -, or methylene. In another preferred embodiment, B is a bond.

Radical Y

In a presently preferred embodiment of the invention, Y is selected from hydrogen, hydroxy, amino (NH)₂)、-NHR⁶(e.g., NHCH)₃Or NHCH₂CH₃) or-OCH₃. In another presently preferred embodiment, Y is H, OH or NH₂. In one presently preferred alternative embodiment, Y is H.

Group Z

Z is selected from hydrogen, fluorine, hydroxyl and C_1-4Alkoxy (e.g. methoxy or ethoxy), halo-C_1-4Alkyl (such as fluoromethoxy, difluoromethoxy or trimethoxy), CONH₂Cyano, SO₂NH₂Amino, -NHR⁶(e.g., NHCH)₃Or NHCH₂CH₃). In a presently preferred embodiment of the invention, Z is hydrogen or hydroxy.

Group W

In a presently preferred embodiment of the invention, W is selected from H, C_1-4Alkyl (e.g. methyl, ethyl, propyl)Alkyl, isopropyl) or halo-C_1-4Alkyl (such as fluoromethyl, difluoromethyl or trifluoromethyl). In another presently preferred embodiment, W is hydrogen.

Radical R¹

In one embodiment of the invention, R¹Is phenyl or 6-membered heteroaryl (e.g. pyridine, pyridazine, pyrimidine, pyrazine), optionally substituted with one or more substituents selected from: halogen (e.g. chlorine or fluorine), cyano, C_1-4Alkyl (such as methyl, ethyl, propyl or isopropyl), halo-C_1-4Alkyl (e.g. fluoromethyl, difluoromethyl or trifluoromethyl), C_1-4alkoxy-C_1-4Alkyl, hydroxy-C_1-4Alkyl (e.g. hydroxymethyl or hydroxyethyl), cyano-C_1-4Alkyl (e.g. cyanomethyl or cyanoethyl), amino-C_1-4Alkyl (e.g. aminomethyl, aminoethyl or aminopropyl), C_1-4-alkylamino-C_1-4Alkyl, di (C)_1-4-alkyl) amino-C_1-4-alkyl, -NR^4AR^4B、-NR⁶C(O)OR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)NR^4AR^4B、-C(O)NR^4AR^4B、-C(O)R⁵、-C(O)OR⁵and-NR⁶S(O)₂R⁵。

In a presently preferred embodiment of the invention, R¹Optionally substituted with one or more substituents selected from: halogen (e.g. fluorine or chlorine), cyano, hydroxy, C_1-4Alkyl (e.g. methyl or ethyl), halo-C_1-4Alkyl (e.g. fluoromethyl, difluoromethyl or trifluoromethyl), C_1-4alkoxy-C_1-4Alkyl, hydroxy-C_1-4-alkyl, cyano-C_1-4Alkyl (e.g. cyanomethyl or cyanoethyl), amino-C_1-4Alkyl radical, C_1-4-alkylamino-C_1-4Alkyl, di (C)_1-4-alkyl) amino-C_1-4-alkyl, -NR^4AR^4B。

In another presently preferred embodimentIn the scheme, R¹Is heteroaryl (e.g. pyridin-2-yl, pyridin-3-yl or pyridin-4-yl), optionally substituted with one or more substituents selected from: fluorine, chlorine and C_1-4Alkyl (such as methyl, ethyl, propyl or isopropyl).

In an alternative embodiment, R¹Is phenyl, optionally substituted at one or more of the para, meta and ortho positions with one or more substituents selected from the group consisting of: hydrogen, fluorine, chlorine, cyano, hydroxy, C_1-4-alkyl (such as methyl, ethyl, propyl or isopropyl), or fluoromethyl, difluoromethyl or trifluoromethyl.

In one presently preferred embodiment, R¹Is phenyl substituted at the para-position with a substituent selected from: fluorine, chlorine, cyano, hydroxy, C_1-4-alkyl (such as methyl, ethyl, propyl or isopropyl), or fluoromethyl, difluoromethyl or trifluoromethyl. In an alternative embodiment which is presently preferred, the para substituent is selected from fluorine, chlorine or methyl.

In another presently preferred embodiment, R¹Is phenyl substituted in the meta position by hydrogen.

In another presently preferred embodiment, R¹Is phenyl substituted at the ortho position with a substituent selected from: hydrogen, fluoro, methyl, fluoromethyl, difluoromethyl or trifluoromethyl. In another preferred embodiment, R¹Is phenyl substituted ortho-position by hydrogen, fluorine or methyl.

In a presently preferred embodiment of the invention, R¹Are mono-, di-, or tri-substituted phenyl rings in which the ortho, meta, and/or para positions may be any combination of the substituents discussed above.

In a preferred embodiment, R¹The length of the optional substituent(s) of (b) is 4 atoms or less, preferably 3 atoms or less, more preferably 2 atoms or less.

Radical R²

In a presently preferred embodiment of the invention, R²is-B-Q- [ R³]_n. n may be 1,2,3 or 4. In another embodiment that is presently preferred, n is 1 or 2.

Ring Q is by R³Substituted saturated or partially unsaturated monocyclic 3-to 7-membered heterocycle or C_3-7-a cycloalkyl ring. In one embodiment that is presently preferred, Q is a 7-membered saturated or partially unsaturated 7-membered heterocyclic ring, such as a homomorpholino ring (homomorpholino ring) or a bridged homomorpholino ring (wherein the bridge is formed from an ethylene or propylene group); or a 7-membered cycloalkyl ring, such as cycloheptane.

In an alternative preferred embodiment, Q is a 5-or 6-membered saturated or partially unsaturated 5-or 6-membered heterocyclic ring (e.g., tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, cyclohexyl, or any of the above rings containing a bridge formed by ethylene or propylene), or a 5-or 6-membered cycloalkyl ring (e.g., cyclopentyl or cyclohexyl). In one embodiment, Q is piperidinyl, piperazinyl, or morpholinyl.

In one presently preferred embodiment, R²is-B-Q- [ R³]_nWherein R is³Selected from:

(i) 3-to 7-membered heterocyclyl-, such as 2-or 4-pyrrolidinyl, 2-, 3-or 4-piperidinyl, 2-or 3-piperazinyl, or 2-or 3-morpholinyl; 3-to 7-membered heterocyclyl-C_1-4-alkyl-, such as piperidin-4-ylmethyl, piperidin-1-ylmethyl, morpholin-4-yl-methyl, morpholin-2-yl-methyl, morpholin-3-yl-methyl and piperazin-4-ylmethyl, piperazin-2-ylmethyl or piperazin-3-ylmethyl, or piperidin-4-ylethyl, piperidin-1-ylethyl, morpholin-4-yl-ethyl, morpholin-2-yl-ethyl and morpholin-3-yl-ethyl, and piperazin-4-ylethyl, piperazin-2-ylethyl or piperazin-3-ylethyl, or piperidin-4-ylpropyl, piperidin-1-ylpropyl, di-n-propylmethyl, morpholin-4-yl-propyl, morpholin-2-yl-propyl and morpholin-3-yl-propyl and piperazin-4-ylpropyl, piperazin-2-ylpropyl or piperazin-3-ylpropyl, or piperidin-4-ylbutyl, piperidine-1-ylbutyl, morpholin-4-ylbutyl, morpholin-2-ylbutyl and morpholin-3-ylbutyl and piperazin-4-ylbutyl, piperazin-2-ylbutyl or piperazin-3-ylbutyl; (3-7 membered heterocyclyl-C)_1-4-alkyl) -amino-C_1-4-alkyl-, such as (piperidin-4-ylmethyl) aminomethyl; amino-C_1-4-alkoxy-C_1-4-alkyl-; (amino-C)_1-4-alkyl) -amino-C_1-4-alkyl) -; -C_1-4-alkyl-NR⁶C(O)OR⁵；-C_1-4-alkyl-NR⁶C(O)NR^4AR^4B；-C_1-4alkyl-C (O) NR^4AR^4B(ii) a (3-to 7-membered heterocyclyl-C)_1-4-alkyl) -c (o) -; -C_1-4alkyl-C (O) OR⁵；-OC(O)R⁵(ii) a Or

(ii)-C(O)NR^9AR^9BWherein R is^9AAnd R^9BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, which is substituted with one or more substituents selected from: c_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl-, C_3-7-a cycloalkyl group. In a preferred embodiment, the cyclic amino group is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each of which is substituted on a ring carbon or nitrogen atom with one or more substituents selected from: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, methoxyethyl, cyclopropyl or cyclobutyl. In one embodiment that is presently preferred, the cyclic amino group is piperazinyl substituted at the 4-position with methyl, ethyl, propyl, isopropyl, sec-butyl or cyclopropyl; or

(iii)-C(O)NR⁶R^10BWherein R is^10BIs, for example, a 3-to 7-membered heterocyclic radical as defined above, or a 3-to 7-membered heterocyclic radical-C as defined above_1-4-alkyl-, or-C_1-4-alkyl-NR⁶C(O)R⁵(ii) a Or

R^10BIs 5-or 6-membered heteroaryl-C_1-4-alkyl-, such as tetrazolylmethyl, wherein the heteroaryl ring is optionally selected from C_1-4-alkyl or halo-C_1-4-alkyl substituted with one or more substituents, and wherein heteroaryl-C_1-4C of an-alkyl-group_1-4-alkyl moieties optionally substituted by one or more C_1-4-alkyl substitution, or C_1-4Alkyl moieties by two C_1-4-alkyl substitution, said two C_1-4-alkyl groups taken together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl spirocycle. In a preferred embodiment, R^10BIs tetrazolylmethyl-, wherein the tetrazolyl group is optionally selected from C_1-4-alkyl or halo-C_1-4-one or more substituents of an alkyl group, and wherein the methyl group of the tetrazolylmethyl group is substituted with two C_1-4-alkyl substitution, said two C_1-4-alkyl groups taken together with the carbon atom to which they are attached form a spirocyclopropyl, cyclobutyl or cyclopentyl group.

Radical R^4A、R^4BAnd R⁵Each independently selected from hydrogen and C_1-4Alkyl (such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl), 3-to 7-membered heterocyclyl-C as defined previously_1-4-alkyl-, amino-C_1-4Alkyl (e.g. aminomethyl, aminoethyl), 3-to 7-membered heterocyclyl-, -C as defined previously_1-4-alkyl-NR⁶C(O)OR⁵Or C_3-7Cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl);

or R^4AAnd R^4BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group (e.g. pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or morpholinyl) optionally substituted with one or more substituents selected from: c_1-4Alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl), -NR^4AR^4B(e.g., -NH)₂、-NHCH₃、NHCH₂CH₃Or NH (CH)₃)₂)。

In some embodiments that are presently preferred, 3-to 7-membered heterocyclyl (other than ring Q), or 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocycle)radical-C_1-4-alkyl) -amino-C_1-4-alkyl-or (3 to 7 membered heterocyclyl-C)_1-4-the heterocyclyl part of the-alkyl) -c (o) -group is optionally substituted with one or more substituents selected from: oxo, C_1-4Alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl), -C (O) OR⁵、-C(O)R⁵、-C(O)NR^4AR^4B、-NR^4AR^4B(e.g., -NH)₂、-NHCH₃、NHCH₂CH₃Or N (CH)₃)₂)、-C_1-4alkyl-C (O) NR^4AR^4BOr C_1-4alkoxy-C_1-4Alkyl (e.g., methoxyethyl).

In one presently preferred embodiment, R³The group comprising a divalent group-C directly attached to the Q ring_1-4-alkyl-, such that R³May be, for example, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-, amino-C_1-4-alkoxy-C_1-4-alkyl-, (amino-C)_1-4-alkyl) -amino-C_1-4-alkyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、-C_1-4-alkyl-NR⁶C(O)NR^4AR^4Bor-C_1-4alkyl-C (O) NR^4AR^4B. In a preferred embodiment, -C_1-4-the alkyl-group is optionally substituted with one or more groups independently selected from: halogen, amino, methoxy and hydroxy. In one embodiment, -C_1-4-an alkyl-group is selected from methylene, ethylene, propylene or butylene, any of which is optionally substituted with one or more groups independently selected from: halogen, amino, methoxy and hydroxy. For example, R³The group comprising-CH₂-C(O)NR^4AR^4B、-(CH₂)₂-C(O)NR^4AR^4B、-(CH₂)₃-C(O)NR^4AR^4BOr 3 to 7 membered heterocyclyl-CH₂-, 3-to 7-membered heterocyclyl- (CH)₂)₂-or 3 to 7 membered heterocyclyl- (CH)₂)₃-。

R⁴And R⁶Each independently selected from hydrogen or C_1-4Alkyl radicals such as the methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl radicals; and is

In another embodiment, R²is-B-R³And R is³is-NR⁶R^11BWherein R is^11BIs a 3-to 7-membered heterocyclyl-C as previously defined_1-4-alkyl-and R⁶As previously defined;

in one alternative embodiment, which is presently preferred, R²is-B-Q- [ R³]_nAnd R is³The method comprises the following steps: (i) -C (O) NR⁶R^10BWherein R is⁶Is methyl or hydrogen, and R^10BIs a 3-to 7-membered heterocyclyl-, such as piperidinyl (including piperidin-4-yl and 1-methylpiperidin-4-yl), or R^10BIs a 3-to 7-membered heterocyclyl-C_1-4-alkyl-, including morpholin-4-ylmethyl, morpholin-4-ylethyl, morpholin-4-ylpropyl, piperidin-4-ylmethyl, piperidin-4-ylethyl, piperidin-4-ylpropyl, piperazin-1-ylmethyl, or piperazin-1-ylethyl, wherein the nitrogen atom in the piperidine 1-position or the piperazine 4-position is substituted with a substituent selected from: hydrogen, methyl, ethyl, isopropyl, methoxyethyl-.

In one presently preferred embodiment, R³is-C_1-4alkyl-C (O) NR^4AR^4BWherein R is^4AIs hydrogen and R^4BIs aminoethyl, or R^4AAnd R^4BTogether with the nitrogen to which they are attached form a pyrrolidinyl or piperidinyl ring, said ring being optionally substituted with one or more substituents selected from: -NH₂、-NHCH₃、NHCH₂CH₃Or N (CH)₃)₂。

In a preferred embodiment, R²The method comprises the following steps:

wherein

T is a trivalent nitrogen atom or methine (i.e., CH);

R⁶is hydrogen or C_1-4-alkyl (such as methyl);

R^10Bis 3-to 7-membered heterocyclyl- (e.g. morpholine or piperidine) or 3-to 7-membered heterocyclyl-C_1-4-alkyl (e.g. morpholinylmethyl, morpholinylethyl, morpholinylpropyl, piperidinylmethyl, piperidinylethyl, piperidinylpropyl, piperazinylmethyl, piperazinylethyl or piperazinylpropyl), any of said heterocyclyl rings being optionally substituted with one or more substituents selected from: c_1-4-alkyl-and C_1-4alkoxy-C_1-4An alkyl group.

In another embodiment, R²The method comprises the following steps:

wherein

T is a trivalent nitrogen atom or methine (i.e., CH);

p is a direct bond or a diradical selected from methylene, ethylene or propylene;

R⁶is hydrogen or C_1-4-an alkyl group;

R¹²selected from hydrogen, C_1-4Alkyl (e.g. methyl, ethyl, propyl, butyl, isopropyl) and C_1-4alkoxy-C_1-4Alkyl (such as methoxyethyl-).

In another embodiment, R²The method comprises the following steps:

wherein

T is a trivalent nitrogen atom or methine (i.e., CH);

p is a diradical selected from methylene, ethylene or propylene;

R⁶is hydrogen or C_1-4-an alkyl group;

R¹²selected from hydrogen, C_1-4Alkyl (e.g. methyl, ethyl, propyl, butyl, isopropyl) and C_1-4alkoxy-C_1-4Alkyl (such as methoxyethyl-).

In another embodiment, R²The method comprises the following steps:

wherein

R³is-C_1-4alkyl-C (O) NR^4AR^4B(e.g., -CH)₂-C(O)NR^4AR^4B、-(CH₂)₂-C(O)NR^4AR^4BOr- (CH)₂)₃-C(O)NR^4AR^4B) Wherein R is^4AAnd R^4BEach independently selected from hydrogen and C_1-4Alkyl (e.g. methyl, ethyl, propyl) and amino-C_1-4-alkyl-, or R^4AAnd R^4BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, for example pyrrolidine, piperidine, piperazine or morpholine, any of which is optionally substituted with one or more substituents selected from: c_1-4-alkyl or-NR^4AR^4B。

In any of the compounds of the invention, R¹The group may be a specific R at the corresponding position in any of the examples described herein¹Radical ofIt is one way.

In any of the compounds of the invention, R²The group may be a specific R at the corresponding position in any of the examples described herein²Any one of the groups.

In any of the compounds of the invention, R³The group may be a specific R at the corresponding position in any of the examples described herein³Any one of the groups.

Some of the presently particularly preferred embodiments of the present invention include:

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- (piperidin-4-ylmethyl) piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- (1-methylpiperidin-4-yl) piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [ (1-methylpiperidin-4-yl) methyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [ (1-ethylpiperidin-4-yl) methyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N-methyl-N- [ (1-methylpiperidin-4-yl) methyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [2- (piperazin-1-yl) ethyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [2- (1-methylpiperidin-4-yl) ethyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [3- (morpholin-4-yl) propyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- { [1- (prop-2-yl) piperidin-4-yl ] methyl } piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- { [1- (2-methoxyethyl) piperidin-4-yl ] methyl } piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -N- [ (1-methylpiperidin-4-yl) methyl ] piperazine-1-carboxamide

N- (2-aminoethyl) -2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } acetamide

2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } -1- [ (3S) -3- (dimethylamino) pyrrolidin-1-yl ] ethan-1-one,

or a pharmaceutically acceptable salt or N-oxide thereof.

In one aspect, the invention relates to compounds of formula (I) for use in therapy. The compounds as defined above are useful as inhibitors of SSAO activity. Thus, they are useful for the treatment or prevention of conditions and diseases in which inhibition of SSAO activity is beneficial. More specifically, they are useful for the treatment or prevention of inflammation, inflammatory diseases, immune or autoimmune disorders, cystic fibrosis, or for the inhibition of tumor growth.

In particular, the compounds of formula (I) are believed to be useful in the treatment or prevention of arthritis (such as rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis and psoriatic arthritis), synovitis, vasculitis, conditions associated with intestinal inflammation (such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and irritable bowel syndrome), atherosclerosis, multiple sclerosis, Alzheimer's disease, vascular dementia, inflammatory diseases of the lung (such as asthma, chronic obstructive pulmonary disease and acute respiratory distress syndrome), fibrotic diseases (including idiopathic pulmonary fibrosis, myocardial fibrosis and systemic sclerosis (scleroderma)), inflammatory diseases of the skin (such as contact dermatitis, atopic dermatitis and psoriasis), systemic inflammatory response syndrome, sepsis, inflammation of the liver and/or autoimmune conditions (such as autoimmune hepatitis, Primary biliary cirrhosis, alcoholic liver disease, sclerosing cholangitis, and autoimmune cholangitis), diabetes (type I or type II) and/or its complications, chronic heart failure, congestive heart failure, ischemic diseases (such as stroke and ischemia-reperfusion injury), and myocardial infarction and/or its complications.

It is believed that the compounds of the invention are particularly useful for treating or preventing vasculitis, including, but not limited to, giant cell arteritis, Takayasu's arteritis, polyarteritis nodosa, Kawasaki disease, Wegener's granulomatosis, Churg-Strauss syndrome, microvascular vasculitis, hensche purpura (Henschel-Schoenoprasis), and Henschel purpurapurpura), cryoglobulinemia (cryoglobulinemia), cutaneous leukocytoclastic vasculitis (cutaneouseukocytic angiitis) and primary vasculitis of the central nervous system.

It is also believed that the compounds of the invention are particularly useful in the treatment of rheumatoid arthritis, chronic obstructive pulmonary disease or atopic dermatitis.

In view of the evidence cited in the introduction above (VAP-1 is upregulated in several cancers including gastric, melanoma, liver and head and neck tumors, and melanoma growth is more slow in mice with enzymatically inactive VAP-1), and in view of the association between VAP-1 and angiogenesis, the compounds of the invention are also expected to be anti-angiogenic and therefore useful in the treatment of cancer by inhibiting tumor growth.

Accordingly, the present invention includes compounds of formula (I) above for use in the treatment or prevention of the above-mentioned conditions and diseases. The invention also includes the use of the compounds in the manufacture of medicaments for the treatment or prevention of the above-mentioned conditions and diseases. The invention also includes methods for the treatment or prevention of such conditions and diseases which comprise administering to a mammal (including man) in need of such treatment an effective amount of a compound as defined above.

The methods described herein include those in which the subject is identified as in need of a treatment as specifically described. Identifying a subject in need of such treatment can be made at the discretion of the subject or a healthcare professional, and can be subjective (e.g., opinion) or objective (e.g., measurable by testing or diagnostic methods).

In other aspects, the methods herein include methods further comprising monitoring the subject's response to the administration of the treatment. Such monitoring may include periodic sampling of subject tissues, fluids, samples, cells, proteins, chemical markers, genetic material, etc. as markers or indicators of a treatment regimen. In other methods, a subject in need of such treatment is pre-screened or identified by assessing relevant markers or indicators appropriate for the treatment.

In one embodiment, the invention provides a method of monitoring the progress of a treatment. The method comprises the following steps: determining the level of a diagnostic Marker (Marker) (e.g., any target or cell type described herein that is modulated by a compound herein) or performing a diagnostic measurement (e.g., screening, assay) in a subject having or susceptible to a disease or symptom thereof described herein, wherein the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptom thereof. Marker levels determined in the methods can be compared to known levels of the marker in healthy normal controls or other diseased patients to establish the disease state of the subject. In some preferred embodiments, a second level of the marker in the subject is determined at a time point after the first level is determined, and the two levels are compared to monitor the course of the disease or the efficacy of the treatment. In certain preferred embodiments, the pre-treatment level of the marker in the subject is determined prior to initiation of treatment according to the present invention; the pre-treatment level of such a marker can then be compared to the level of the marker in the subject after treatment has begun to determine the efficacy of the treatment.

In certain method embodiments, the level of a marker or the activity of a marker in a subject is determined at least once. Comparison of the marker level with another measurement of the marker level, e.g., previously or subsequently obtained from the same patient, another patient, or a normal subject, can be used to determine whether the therapy of the invention has the desired effect, and thus the dosage level can be adjusted as needed. Determination of marker levels can be performed using any suitable sampling/expression assay known in the art or described herein. Preferably, a tissue or fluid sample is first taken from the subject. Examples of suitable samples include blood, urine, tissue, mouth or cheek cells, and hair samples including roots. Other suitable samples are known to those skilled in the art. Protein levels and/or mRNA levels (e.g., marker levels) in a sample can be determined using any suitable technique known in the art, including but not limited to enzyme immunoassay, ELISA, radiolabelling/assay techniques, blotting/chemiluminescence, real-time PCR, and the like.

Composition comprising a metal oxide and a metal oxide

One presently preferred embodiment of the present invention is a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and/or excipients.

For clinical use, the compounds of the present invention are formulated into pharmaceutical formulations for a variety of modes of administration. It is understood that the compounds of the present invention may be administered with a physiologically acceptable carrier, excipient or diluent. The pharmaceutical compositions of the present invention may be administered by any suitable route, preferably by oral, rectal, nasal, topical (including buccal and sublingual), sublingual, transdermal, intrathecal, transmucosal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.

Other formulations may conveniently be presented in unit dosage form (e.g., tablets and sustained release capsules) and liposomes, and may be prepared by any of the methods well known in the art of pharmacy. Pharmaceutical formulations are generally prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutically acceptable carriers, diluents or excipients. Examples of excipients are water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, and the like. These preparations may also contain additional pharmaceutically active agents and conventional additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers and the like. Typically, the amount of active compound is from 0.1% to 95% by weight of the formulation, preferably from 0.2% to 20% by weight of the formulation for parenteral application, more preferably from 1% to 50% by weight of the formulation for oral administration.

The formulations may also be prepared by known methods (e.g., granulation, compression, microencapsulation, spray coating, etc.). The preparation can also be prepared into dosage forms of tablets, capsules, granules, powder, syrup, suspension, suppository or injection by a conventional method. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable medium. Tablets and granules may be coated in a conventional manner. To maintain therapeutically effective plasma concentrations for extended periods of time, the compounds of the present invention may be incorporated into slow release formulations.

The dose level and frequency of dosage for a particular compound will vary with a variety of factors including the potency of the particular compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition being treated, and the ongoing treatment of the patient. The daily dose may be, for example, from about 0.001mg to about 100mg per kg of body weight, which is administered in single or multiple doses, each dose being, for example, from about 0.01mg to about 25 mg. Typically, the dose is administered orally, but parenteral administration is also an option.

Preparation of the Compounds of the invention

The compounds of formula (I) above may be prepared by conventional methods or by methods analogous thereto. In particular, the preparation of intermediates and compounds according to the examples of the invention can be illustrated by the following schemes. The definitions of structural variables in the schemes herein are the same as those of the corresponding positions in the formulae described herein.

Scheme 1 general synthetic route for the preparation of Compounds of formula (Ia)

W, Y, Z, Q, R therein¹And R³As defined for formula (I);

by introducing the Q ring (or protected Q ring) and then the R¹Or by reversing these steps to give an intermediate of formula (IIIa), from 1H-pyrrolo [2, 3-c]Pyridine (IIa) produces compounds of general formula (Ia). The compound of formula (IIIa) can then be converted to a compound of formula (Ia) by standard synthetic methods. For example, 1H-pyrrolo [2, 3-c ]]Pyridine (IIa) and 4-oxo piperidine-1-carboxylic acid tert-butyl ester are condensed, reduced and R is introduced through arylation reaction¹And Boc deprotection can be used to obtain compounds of general formula (IVa). Functionalization of a compound of formula (IVa) by, for example, urea formation, amide coupling or reductive amination gives a compound of formula (Ia).

Scheme 2. general synthetic route for the preparation of Compounds of formula (Ib)

W, Y, Z, R therein¹And R²As defined for formula (I);

by introducing R²(e.g. by nucleophilic substitution) followed by introduction of R¹Compounds of general formula (Ib) can be readily prepared from bromoindoles (IIb) (e.g. by Suzuki reactions) or by reversing these steps (with appropriate group protection strategies).

Scheme 3. general synthetic route for the preparation of Compounds of formula (Ic)

Y, Z, R therein¹And R²As defined for formula (I);

the compounds of formula (Ic) can be readily prepared by reductive amination of 3-amino-pyridine-4-carbaldehyde of formula (IIc) to give a compound of formula (IIIc), followed by cyclization to give pyrrolo [3, 4-c ] pyridine of formula (IVc). Alternatively, pyrrolo [3, 4-c ] pyridines of formula (IVc) can be prepared by cyclizing a (3-fluoropyridin-4-yl) carbonyl compound of formula (Vc) with hydrazine. The compounds of formula (Ic) can be prepared from compounds of formula (IVc) by standard N-arylation reactions.

Scheme 4. general synthetic route for preparing Compounds of formula (Id)

W, Y, R therein¹And R²As defined for formula (I);

according to standard methods known in the scientific literature, e.g. by 7-bromo-4-chloro-5H-pyrrolo [3, 2-d]Lithiation of pyrimidines (IId) and reaction with aldehydes, followed by reduction and subsequent introduction of R¹The compounds of formula (Id) can be readily prepared (e.g., by arylation). Such methods are known to the person skilled in the art, for example in WO2008070507 and antrella et al, JOC, 69,5578,2004.

Scheme 5. general synthetic route for the preparation of Compounds of formula (Ie)

Y, R therein¹And R²As defined for formula (I);

the compounds of general formula (Ie) can be readily prepared according to standard procedures known in the scientific literature, for example by condensation of 5-chloropyrimidine (IIe) with Weinreb amide followed by reaction with hydrazine. Such methods are known to those skilled in the art, for example in WO2003039469 and Verma et al, tet.

Scheme 6. general synthetic route for the preparation of Compounds of formula (If)

Y, Z, R therein¹And R²As defined for formula (I);

the compounds of general formula (If) can be readily prepared by condensing pyrazine-2-carbonitrile with a Grignard reagent to give an amine intermediate (IIf). Functionalization of the amine (IIf) to give an amide or urea of formula (IIIf), cyclization with phosphorus oxychloride to give the compound of formula (If).

Scheme 7 general synthetic routes for the preparation of Compounds of formula (Ig)

W, Z, R therein¹And R²As defined for formula (I);

by bromination with CuBr (e.g., as described in Gallou et al, Syn. Lett., 2,211-214, 2007), followed by introduction of R¹(e.g. by arylation) and R²(e.g., by Buchwald-Hartwig reaction), can be readily prepared from 1H-pyrrolo [2, 3-d]Pyridazine (IIg) Compounds of the general formula (Ig) are prepared.

Scheme 8 general synthetic route for the preparation of Compounds of formula (Ih)

Y, Z, R therein¹And R²As defined for formula (I);

the compounds of formula (Ih) may be prepared by sequential alkylation of 1H,2H, 3H-imidazo [4, 5-c ] pyridin-2-one (IIh), for example as described in WO 2008054749.

Scheme 9 general synthetic routes for the preparation of Compounds of formula (Ii)

W, Y, Z, R therein¹And R²As defined for formula (I);

by bromination with CuBr (e.g., as described in Gallou et al, Syn. Lett., 2,211-214, 2007), followed by introduction of R²(e.g. by nucleophilic substitution) followed by introduction of R¹(e.g.by Suzuki reaction) or by reversing these steps (with appropriate protecting group strategy), can be prepared from 1H-pyrrolo [2, 3-d]Pyridazine (IIi) Compounds of the formula (Ii) are prepared.

Scheme 10 general synthetic route for the preparation of Compounds of formula (Ij)

W, Z, R therein¹And R²As defined for formula (I);

by bromination with CuBr (e.g., as described in Gallou et al, Syn. Lett., 2,211-214, 2007), followed by introduction of R²(e.g. by nucleophilic substitution) followed by introduction of R¹(e.g.by Suzuki reaction) or by reversing these steps (with appropriate protecting group strategy), can be prepared from 1H-pyrrolo [2, 3-d]Pyridazine(IIj) preparation of the compound of formula (Ij).

Scheme 11 general synthetic route for the preparation of Compounds of formula (Ik)

Y, Z, R therein¹And R²As defined for formula (I);

compounds of formula (Ik) may be prepared by cyclization of compounds of formula (IIk) with hydrazine, for example, as described by Deeb et al, Journal of the Chinese Chemical Society,37(3), 287-94; 1990.

Scheme 12 general synthetic route for the preparation of Compounds of formula (II)

Z, R therein¹And R²As defined for formula (I);

compounds of formula (II) may be prepared by cyclisation of a compound of formula (III) with hydrazine, for example as described in Haider et al, Journal of the Chemical Society, Perkin transformations 1: organic and Bio-Organic Chemistry,1, 169-72; 1986.

Scheme 13 general synthetic route for the preparation of compounds of formula (Im)

W, Y, R therein¹And R²As defined for formula (I);

the compounds of general formula (Im) may be prepared by sequential alkylation/arylation of 7H-pyrrolo [2, 3-d ] pyridazine (IIm), for example as described in WO 2009080682.

Scheme 14 general synthetic routes for the preparation of Compounds of formula (In)

Y, Z, R therein¹And R²As defined for formula (I);

compounds of formula (In) can be prepared by cyclisation of a compound of formula (IIn) with hydrazine, for example as described In Filaok et al, Journal of Organic Chemistry,73(10), 3900-.

Scheme 15 general synthetic route for the preparation of compounds of formula (Io)

Z, R therein¹And R²As defined for formula (I);

compounds of general formula (Io) may be prepared according to scheme 15, for example, as in Haider et al, journal of the Chemical Society, Perkin Transactions 1: organic and Bio-Organic chemistry,1,169-72; 1986.

Scheme 16 general synthetic route to Compounds of formula (Ip)

Wherein R is¹And R²As defined for formula (I);

compounds of general formula (Ip) may be prepared according to scheme 16, for example, as described in WO 2007134828.

Optionally, a compound of formula (I) may also be converted to another compound of formula (I) in one or more synthetic steps.

The following abbreviations have been used:

ac acetyl group

Ac₂O acetic anhydride

AcOH acetic acid

aq solution of aq

Ar aryl radical

Boc tert-butyloxycarbonyl group

nBuLi n-butyllithium

calcd calculated

CDI carbonyl diimidazole

conc concentrated

d days

DCE Dichloroethane

DCM dichloromethane

DIBALH diisobutyl aluminum hydride

DIPEA diisopropylethylamine

DMAP 4-dimethylaminopyridine

DMF dimethyl formamide

EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

ES + electrospray ionization

EtOAc ethyl acetate

EtOH ethanol

Ex examples

h hours

HBTU O-benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate

HOBt 1-hydroxybenzotriazole hydrate

HPLC high performance liquid chromatography

HRMS high resolution mass spectrum

Int intermediates

LCMS liquid chromatography-mass spectrometry

LDA lithium diisopropylamide

M mol

Me methyl group

mCPBA m-chloroperbenzoic acid

MeCN acetonitrile

MeOH methanol

min for

Ms mesylate

MS Mass Spectrometry

NaBH(OAc)₃Sodium triacetoxyborohydride

NIS N-iodosuccinimide

NMP N-methylpyrrolidone

Rf Retention time

RT Room temperature

sat is saturated

SCX Strong cation exchange

SM raw material

TFA trifluoroacetic acid

THF tetrahydrofuran

Examples and intermediate Compounds

Experimental methods

Unless otherwise specified, the reaction is carried out at room temperature. The microwave reaction was carried out using a Biotage microwave reactor using a process vial equipped with an aluminum cap and a septum. Hydrogenation was carried out using ThalesH-Cube. Preparative Flash chromatography was performed on Merck silica gel 60 (230-400 mesh) using either a Flash Master Personal system equipped with a Strata SI-1 silica giga tube (gigatube) or a Combiflash company system equipped with a RediSep silica column. Reversed phase column chromatography in a Merck configurationRP-18 (40-63 μm) column on a Gilson system (Gilson321 pump and Gilson FC204 fraction collector). Reverse phase HPLC was performed on a Gilson system equipped with a UV detector with a Phenomenex Synergi Hydro RP150mm X10 mm column or a YMC ODS-A100/150mm X20 mm column. The purest fractions were collected, concentrated and dried under vacuum. Before the purity analysis, the compounds are usually dried at 40 ℃ in a vacuum oven. Agilent1100HPLC System/Waters ZQ Mass Spectroscopy by HPL connected to Agilent1100HPLC SystemC/LCMS for compound analysis, Agilent1100HPLC system with Phenomenex Synergi, RP-Hydro column (150 mm. times.4.6 mm, 4 μm, 1.5 mL/min, 30 ℃ C., gradient 5% to 100% MeCN (+ 0.085% TFA) in water (+ 0.1% TFA) for 7 min, 200nm to 300 nm). Accurate mass (HRMS) was measured using Thermo Scientific LTQ Orbitrap XL equipped with an Advio TriVersa NanoMate electrospray ion source (calibration by three mass checks during analysis. spectra were obtained in positive electrospray mode. the resulting mass range was m/z 100-2000. before analysis, the sample was dissolved in DMSO to give a10 mM solution, which was then further treated with MeOH or 10mM NH in MeOH₄OAc dilution to 0.1M solution). The values reported correspond to protonated molecular ion [ MH]⁺. The compounds prepared were named using ACD name6.0, 7.0 and 10.0.

Intermediate 1

4- { 1H-pyrrolo [2, 3-c ] pyridin-3-yl } -1,2,3, 6-tetrahydropyridine-1-carboxylic acid tert-butyl ester

6-azaindole (4.48g, 37.9mmol) was dissolved in MeOH (70mL) and KOH (4.68g, 83.4mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (8.31g, 41.7mmol) were added. The reaction mixture was heated at 70 ℃ for 18 hours. The residue was partitioned between water (250mL) and DCM (250mL) and the aqueous phase was extracted with DCM (2X 250 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum to give the title compound as a yellow foam (11.3g, 99%). LCMS (ES +): 300.1[ MH]+。

Intermediate 2

4- { 1H-pyrrolo [2, 3-c ] pyridin-3-yl } piperidine-1-carboxylic acid tert-butyl ester

Intermediate 1(11.3g, 37.7mmol) was dissolved in EtOH (200mL) and hydrogenated over 10% Pd/C in H-cube at 90 ℃ and 90 bar (bar). The reaction mixture was concentrated in vacuo to give the title compound as a yellow solid (11.1g, 97%). LCMS (ES +): 302.1[ MH ] +.

Intermediate 3

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] piperidine-1-carboxylic acid tert-butyl ester

Intermediate 2(11.1g, 36.7mmol) was dissolved in DMF (60mL) and 1-chloro-4-iodo-benzene (10.5g, 44.0mmol), N' -dimethylethylenediamine (789 μ L, 7.33mmol), K, were added under nitrogen₃PO₄(16.3g, 77.0mmol) and CuI (698mg, 3.67 mmol). The reaction mixture was heated under microwave at 160 ℃ for 20 min and concentrated under vacuum. The residue was partitioned between water (250mL) and DCM (250mL) and the aqueous phase was extracted with DCM (2X 250 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography to give the title compound (6.86g, 45%) as a yellow solid. LCMS (ES +): 411.9[ MH]And (2) HPLC: rt5.91 min, 76% purity.

Intermediate 4

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] piperidine

Intermediate 3(6.86g, 16.6mmol) was dissolved in DCM (200mL) and TFA (50mL) and stirred for 2 h. The solvent was removed in vacuo and the residue was dissolved in 1M Na₂CO₃Aqueous (200mL) and extracted with DCM (3X 200 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography to give the title compound as a red gum (3.18g, 61%). LCMS (ES +): 312.1[ MH]+. HPLC: rt3.61 min, 96% purity.

Intermediate 5

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- (piperidin-4-ylmethyl) piperidine-1-carboxamide

CDI (936mg, 5.77mmol) was dissolved in DCM (50mL), a solution of tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (1.24g, 5.77mmol) and DIPEA (1.25mL, 7.22mmol) in DCM (10mL) was added and the reaction mixture was stirred for 18 h. A solution of intermediate 4(1.50g, 4.81mmol) and DIPEA (1.25mL, 7.22mmol) in DCM (10mL) was added and the reaction mixture was stirred for 24h with 1M Na₂CO₃Aqueous solution (100mL) was diluted and extracted with DCM (3X 100 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography, dissolved in DCM (10mL) and TFA (2.5mL) and stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in 1M Na₂CO₃Aqueous (50mL) and extracted with DCM (3X 50 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography to give the title compound (1.41g, 65%) as a light yellow solid. LCMS (ES +): 452.0[ MH]+. HPLC: rt3.98 min, 97% purity.

Intermediate 6

N- (3-aminopropyl) -4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] piperidine-1-carboxamide

Intermediate 6(178mg, 8%) was prepared similarly to intermediate 5 using tert-butyl N- (3-aminopropyl) carbamate instead of tert-butyl 4- (aminomethyl) piperidine-1-carboxylate. LCMS (ES +): 412.3[ MH ] +. HPLC: rt3.82 min, 100% purity.

Intermediate 7

N- ({4- [ (3-Aminopyridin-4-yl) methyl ] morpholin-2-yl } methyl) carbamic acid tert-butyl ester

3-amino-pyridine-4-carbaldehyde (513mg, 4.20mmol) was dissolved in DCE (7.3mL) and tert-butyl (morpholin-2-ylmethyl) carbamate (999mg, 4.62mmol) and NaBH (OAc) were added₃(1.07g, 5.04 mmol). The reaction mixture was heated at 60 ℃ for 5 min using microwave, diluted with DCM (10mL) and saturated Na₂CO₃Aqueous solution (5mL) was quenched.

The aqueous phase was extracted with DCM (3X 20mL) and the combined organic fractions were dried (MgSO)₄) And concentrated in vacuo to give the crude title compound as a yellow gum (1.37g, 100%). LCMS (ES +): 323.1[ MH]+。

Intermediate 8

N- [ (4- { 1H-pyrazolo [3, 4-c ] pyridin-3-yl } morpholin-2-yl) methyl ] carbamic acid tert-butyl ester

Intermediate 7(1.35g, 4.20mmol) was dissolved in AcOH (55mL) and NaNO was added₂(290mg, 4.20mmol) in water (438. mu.L). Mixing the reaction mixtureStir 5 min and concentrate under vacuum. The residue was dissolved in EtOAc (40mL) and saturated Na₂CO₃Aqueous (2X 20mL) wash. The organic fraction was dried (MgSO)₄) And concentrated in vacuo to give the crude title compound as a yellow gum (999mg, 71%). LCMS (ES +): 334.0[ MH]+。

Intermediate 9

N- ({4- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) carbamic acid tert-butyl ester

Intermediate 8(999mg, 3.00mmol) was dissolved in DMF (4mL) and 1-methyl-4-iodo-benzene (784mg, 3.60mmol), N' -dimethylethylenediamine (64.5. mu.L, 0.60mmol), K, and added₃PO₄(1.34g, 6.29mmol) and CuI (57.1mg, 0.30 mmol). The reaction mixture was heated at 140 ℃ for 20 minutes using microwaves. The solvent was removed in vacuo and the residue was purified by column chromatography to give the crude title compound as a yellow gum (438mg, 35%). LCMS (ES +): 424.0[ MH]+。

Intermediate 10

{4- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methylamine dihydrochloride

Intermediate 9(438mg, 1.03mmol) was dissolved in 1.25M HCl in EtOH (10mL) and stirred overnight. The solvent was removed in vacuo to give the crude title compound as an orange gum (400mg, 98%). LCMS (ES +): 324.0[ MH ] +.

Intermediate 11

2- [ (Acetyloxy) methyl ] morpholine-4-carboxylic acid tert-butyl ester

Ac is added₂O (5.17mL, 54.7mmol) was dissolved in DCM (200mL), DMAP (611mg, 5.00mmol), DIPEA (9.52mL, 54.7mmol) and tert-butyl 2- (hydroxymethyl) morpholine-4-carboxylate (10.0g, 49.7mmol) were added and the reaction mixture was stirred for 1 h. With saturated NH₄The reaction mixture was washed with aqueous Cl (3X 100mL) and the aqueous fraction was extracted with DCM (2X 100 mL). The combined organic fractions were dried (MgSO)₄) And concentrated in vacuo to give the crude title compound (14.1g) as an off-white solid. LCMS (ES +): 282.1 MNa]+。

Intermediate 12

{4- [ (3-Aminopyridin-4-yl) methyl ] morpholin-2-yl } methyl acetate

Intermediate 11(12.8g, 49.5mmol) was dissolved in TFA (20mL) and DCM (80mL), the reaction mixture was stirred overnight and concentrated in vacuo. The residue was dissolved in DCE (80mL), cooled to 0 ℃ and Et was added dropwise₃N (6.90mL, 49.5 mmol). 3-amino-pyridine-4-carbaldehyde (6.04g, 49.5mmol) and MeOH (50mL) were added and the reaction mixture was stirred for 30 min. Add NaBH (OAc) portionwise₃(12.6g, 59.4mmol) and the reaction mixture was stirred overnight. Additional 3-amino-pyridine-4-carbaldehyde (6.04g, 49.5mmol) and NaBH (OAc) were added portionwise over 2 days₃(25.2g, 119 mmol). The reaction mixture was stirred at 60 ℃ for 30 hours, cooled to 0 ℃ and saturated Na₂CO₃Aqueous solution (50mL) was quenched and diluted with DCM (100 mL). Organic fraction saturated with Na₂CO₃Aqueous solution (20mL) and saturated NH₄Cl waterThe solution (2X 20mL) was washed and dried (MgSO)₄) And concentrated under vacuum. The residue was purified by filtration through a pad of silica gel to give the crude title compound as a yellow gum (5.77g, 44%). LCMS (ES +): 266.1[ MH]+。

Intermediate 13

(4- { 1H-pyrazolo [3, 4-c ] pyridin-3-yl } morpholin-2-yl) methyl acetate

Intermediate 12(5.77g, 21.8mmol) was dissolved in AcOH (282mL), cooled to 0 deg.C, and NaNO was added₂(1.50g, 21.8mmol) in water (2.29 mL). The reaction mixture was stirred for 5 minutes and concentrated under vacuum. The residue was dissolved in EtOAc (200mL) and saturated Na₂CO₃Washed with aqueous solution (2X 100mL) and dried (MgSO)₄) And concentrated in vacuo to give the title compound as a dark yellow gum (3.85g, 64%). LCMS (ES +): 277.1[ MH]+。

Intermediate 14

{4- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl acetate

Intermediate 13(3.85g, 13.9mmol) was dissolved in DMF (20mL) and 1-methyl-4-iodo-benzene (3.64g, 16.7mmol), N' -dimethylethylenediamine (300. mu.L, 2.78mmol), K, were added₃PO₄(6.21g, 29.2mmol) and CuI (265mg, 1.39 mmol). The reaction mixture was heated in a microwave reactor at 140 ℃ for 1 hour and concentrated under vacuum. The residue was purified by column chromatography to give the title compound (260mg, 5%) as a yellow gum. LCMS (ES +): 367.0[ MH]+。HPLC：Rt5.07 min, 97.4%.

Intermediate 15

{4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl acetate

Intermediate 13(200mg, 0.72mmol), 4-chlorophenylboronic acid (226mg, 1.45mmol), Cu (OAc)₂(263mg, 1.45mmol) and pyridine (292. mu.L, 3.62mmol) were suspended in DCM (10mL) and stirred for 36 h. The reaction mixture was concentrated in vacuo and purified by column chromatography to give the crude title compound as a yellow solid (80.0mg, 29%). LCMS (ES +): 387.0[ MH]+。

Intermediate 16

{4- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methanol

Intermediate 14(200mg, 0.55mmol) was dissolved in MeOH (4mL) and K was added₂CO₃(302mg, 2.18 mmol). The reaction mixture was stirred for 30 minutes and concentrated under vacuum. The residue was dissolved in DCM (20mL) and water (10mL) and the aqueous phase was extracted with DCM (3X 50 mL). The combined organic fractions were dried (MgSO)₄) And concentrated in vacuo to give the title compound as a dark brown gum (168mg, 95%). LCMS (ES +): 325.1[ MH]+。

Intermediate 17

{4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methanol

Intermediate 17(65.0mg, 91%) was prepared similarly to intermediate 16, using intermediate 15 instead of intermediate 14. LCMS (ES +): 345.0[ MH ] +.

Intermediate 18

{4- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl methanesulfonate

Intermediate 16(292mg, 0.90mmol) was dissolved in DCM (7mL), cooled to 0 deg.C and Et was added₃N (138. mu.L, 0.99mmol) and methanesulfonyl chloride (76.6. mu.L, 0.99 mmol). The reaction mixture was stirred for 1 hour, diluted with DCM (10mL) and saturated NH₄Aqueous Cl (2X 5mL) and saturated Na₂CO₃Aqueous (2X 5mL) wash. The organic fraction was dried (MgSO)₄) And concentrated in vacuo to give the title compound as a brown gum (277mg, 77%). LCMS (ES +): 403.0[ MH]+。

Intermediate 19

{4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl methanesulfonate

Intermediate 19(60.0mg, 75%) was prepared similarly to intermediate 18, using intermediate 17 instead of intermediate 16. LCMS (ES +): 422.9[ MH ] +.

Intermediate 20

4- ({4- [ (3-Aminopyridin-4-yl) methyl ] morpholin-2-yl } methyl) piperazine-1-carboxylic acid tert-butyl ester

3-amino-pyridine-4-carbaldehyde (584mg, 4.78mmol) was dissolved in DCM (10mL) and tert-butyl 4- (morpholin-2-ylmethyl) piperazine-1-carboxylate (1.50g, 5.26mmol) and NaBH (OAc) were added₃(1.11g, 5.26 mmol). The reaction mixture was heated under microwave at 60 ℃ for 2.5 min, diluted with DCM (20mL) and saturated Na₂CO₃Aqueous solution (10mL) was quenched. With saturated NH₄The organic fraction was washed with aqueous Cl (10 mL). The combined aqueous fractions were extracted with DCM (2X 20mL) and the combined organic fractions were dried (MgSO)₄) And concentrated in vacuo to give the crude title compound (2.46g) as a yellow gum. LCMS (ES +): 392.1[ MH]+。

Intermediate 21

4- [ (4- { 1H-pyrazolo [3, 4-c ] pyridin-3-yl } morpholin-2-yl) methyl ] piperazine-1-carboxylic acid tert-butyl ester

Intermediate 20(1.87g, 4.76mmol) was dissolved in AcOH (62mL), cooled to 0 deg.C and NaNO added₂(330mg, 4.76mmol) in water (502. mu.L). The reaction mixture was stirred for 5 minutes and concentrated under vacuum. The residue was dissolved in EtOAc (100mL) and saturated Na₂CO₃Aqueous (2X 50mL) wash. The organic fraction was dried (MgSO)₄) And concentrated in vacuo to give the title compound as a brown gum (1.80g, 93%). LCMS (ES +): 403.1[ MH]+。

Intermediate 22

4- ({4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) piperazine-1-carboxylic acid tert-butyl ester

Intermediate 21(1.08g, 2.69mmol), 4-chlorophenylboronic acid (840mg, 5.37mmol), Cu (OAc)₂(976mg, 5.37mmol) and pyridine (1.08mL, 13.4mmol) were suspended in DCE (19mL) and stirred overnight. The solvent was removed under vacuum and the residue was purified by column chromatography to give the title compound as a light yellow solid (58.0mg, 4%). LCMS (ES +): 513.0[ MH]+. HPLC: rt4.81 min, 97.1% purity.

Intermediates 23 to 30

Intermediates 23 to 30 were prepared similarly to intermediate 20 by reductive amination of 3-amino-pyridine-4-carbaldehyde with the appropriate amine; see table 1 below.

Table 1: reductive amination of 3-amino-pyridine-4-carbaldehyde

Intermediate 31

N- [ (3-Aminopyridin-4-yl) methyl ] -N- [2- (morpholin-4-yl) ethyl ] carbamic acid tert-butyl ester

Intermediate 25(341mg, 1.44mmol) was dissolved in DCM (15mL) and Boc was added₂O (346mg, 1.59mmol) and the reaction mixture was stirred for 1.5 h. With saturated Na₂CO₃The reaction mixture was quenched with aqueous solution (40mL) and the aqueous fraction was extracted with DCM (2X 20 mL). The combined organic fractions were washed with brine (30mL) and dried (MgSO)₄) And concentrated in vacuo to give the crude title compound (329mg) as a brown oil. LCMS (ES +): 337.0[ MH]+。

Intermediate 32

4- (2- { [ (3-Aminopyridin-4-yl) methyl ] [ (tert-butoxy) carbonyl ] amino } ethyl) piperazine-1-carboxylic acid tert-butyl ester

Intermediate 32 was prepared similarly to intermediate 31, using intermediate 26 instead of intermediate 25, to give the title compound (409mg, 54%) as a brown oil. LCMS (ES +): 436.1[ MH ] +. HPLC: rt4.18 min, 93% purity.

Intermediates 33 to 40

By reacting 3-aminopyridines 23 to 24 and 27 to 32 with NaNO₂Cyclization produced intermediates 33 to 30 in analogy to intermediate 21. See table 2 below.

Table 2: cyclization of 3-aminopyridines

Intermediates 41 to 43

Intermediates 41 to 43 were prepared in analogy to intermediate 22 by N-arylation of 1H-pyrazolo [3, 4-c ] pyridine; see table 3 below.

Table 3: n-arylation of 1H-pyrazolo [3, 4-c ] pyridines

Intermediate 44

1- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] piperidine-4-carboxylic acid hydrochloride

Intermediate 41(834mg, 2.17mmol) was dissolved in 1: 1 THF/water (16mL), LiOH. H was added₂O (200mg, 4.77mmol) and the reaction mixture was stirred for 3 hours. THF was removed under vacuum and the reaction mixture was acidified to pH1 with 1M aqueous Cl solution (5 mL). The precipitate was collected by filtration and washed with water to give the title compound (450mg, 53%) as an orange solid. LCMS (ES +): 357.0[ MH]+. HPLC: rt4.92 min, 99.6% purity.

Intermediate 45

4- ({1- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] piperidin-4-yl } carbonyl) morpholine

Intermediate 44(200mg, 0.51mmol) was dissolved in DMF (2mL), HBTU (231mg, 0.61mmol) was added and the reaction mixture was stirred for 30 min. Morpholine (53.4. mu.L, 0.61mmol) and DIPEA (266. mu.L, 1.53mmol) were added and the reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue diluted with EtOAc (25mL) and saturated NH₄Washed with aqueous Cl (4X 25mL) and dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography to give the title compound (78.7mg, 36%) as a pale yellow solid. HRMS (ESI +) calculated C22H24CIN5O2426.1691, found 426.1691. HPLC: rt4.96 min, 100% purity.

Intermediate 46

4- ({1- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] piperidin-4-yl } carbonyl) piperazine-1-carboxylic acid tert-butyl ester

Intermediate 46 was prepared in analogy to intermediate 45, using tert-butyl 1-piperazinecarboxylate instead of morpholine, to give the title compound (260mg, 97%) as a yellow gum. LCMS (ES +): 525.1[ MH ] +. HPLC: rt6.14 min, 100% purity.

Intermediate 47

1- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] piperidine-2-carboxylic acid hydrochloride

Intermediate 47 was prepared similarly to intermediate 44 using intermediate 43 instead of intermediate 41 to give the crude title compound (332mg) as a brown solid. LCMS (ES +): 357.0[ MH ] +.

Intermediate 48

2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } ethan-1-ol

Example 40(50.0mg, 0.13mmol) was dissolved in DCM (1mL), cooled to 0 deg.C and DIBALH (0.78mL, 1.0M in heptane, 0.78mmol) was added portionwise over 6 days. The reaction mixture was stirred for 1 week, cooled to 0 ℃ and quenched with water (1 mL). The reaction mixture was filtered and concentrated in vacuo to give the crude title compound (51.0mg) as a yellow gum. LCMS (ES +): 359.0[ MH ] +.

Intermediate 49

2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } ethyl methanesulfonate

Intermediate 48(50.0mg, 0.14mmol) was dissolved in DCM (1.5mL), cooled to 0 ℃ and Et was added₃N (42.7. mu.L, 0.31mmol) and methanesulfonyl chloride (11.9. mu.L, 0.15 mmol). The reaction mixture was stirred for 20h, diluted with DCM (5mL) and saturated NH₄Aqueous Cl (3X 5mL) and saturated Na₂CO₃Washed with aqueous solution (5mL) and dried (MgSO)₄) And concentrated in vacuo to give the title compound as a dark yellow gum (60.0mg, 99%). LCMS (ES +): 437.0[ MH]+。

Intermediate 50

1- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] piperazine dihydrochloride

Intermediate 42(80.0mg, 0.19mmol) was dissolved in HCl (1.25M in EtOH, 10mL) and the reaction mixture was stirred for 18 hours. The solvent was removed under vacuum to give the title compound (76.0mg, 100%) as an orange solid. LCMS (ES +): 314.0[ MH ] +. HPLC: rt3.83 min, 90.0% purity.

Intermediate 51

N- ({4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) carbamic acid tert-butyl ester

Intermediate 8(290mg, 0.87mmol), 4-chlorophenylboronic acid (272mg, 1.74mmol), anhydrous copper (II) acetate (316mg, 1.74mmol) and pyridine (350. mu.L, 4.35mmol) were suspended in DCM (12mL) and stirred for 24 h. The residue was dissolved in MeOH (15mL), purified by column chromatography using an SCX-2 cartridge to give the title compound as a pale yellow solid (100mg, 26%). LCMS (ES +): 444.1[ MH ] +. HPLC: rt6.01 min, 84% purity.

Intermediate body 52

{4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methylamine dihydrochloride

Intermediate 52 was prepared similarly to intermediate 10, using intermediate 51 instead of intermediate 9, to give the title compound (62.0mg) as an orange solid. LCMS (ES +): 344.1[ MH ] +.

Intermediate 53

N- [ (3-Aminopyridin-4-yl) methyl ] -N- [2- (2-oxoimidazolidin-1-yl) ethyl ] carbamic acid tert-butyl ester

3-amino-pyridine-4-carbaldehyde (0.86g, 7.04mmol), 1- (2-aminoethyl) imidazolidin-2-one (1.00g, 7.74mmol), and AcOH (0.44mL, 7.75mmol) were dissolved in DCM (20mL) and stirred for 1 hour. Addition of NaBH (OAc)₃(2.24g, 10.6mmol), the reaction mixture was stirred for 3 hours and diluted with DCM (10mL) and water (20 mL). Adding Na₂CO₃(2.24g, 21.1mmol) and di-tert-butyl dicarbonate (1.84g, 8.45mmol) and the reaction mixture is stirred for 20 hours. The aqueous fraction was extracted with DCM (50mL) and saturated NaHCO₃The combined organic fractions were washed with aqueous solution (40mL) and dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography to give the title compound (539mg, 23%) as a yellow gum. LCMS (ES +): 336.2[ MH]+。

Intermediate body 54

N- [2- (2-oxoimidazolidin-1-yl) ethyl ] -N- { 1H-pyrazolo [3, 4-c ] pyridin-3-yl } carbamic acid tert-butyl ester

Intermediate 54 was prepared similarly to intermediate 21, using intermediate 53 instead of intermediate 20, to give the title compound (432mg, 78%) as a light brown solid. LCMS (ES +): 347.2[ MH ] +.

Intermediate 55

N- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -N- [2- (2-oxoimidazolidin-1-yl) ethyl ] carbamic acid tert-butyl ester

Intermediate 55 was prepared similarly to intermediate 22, using intermediate 54 instead of intermediate 21, to give the title compound (74.0mg, 13%) as a yellow solid. LCMS (ES +): 457.0[ MH ] +. HPLC: rt5.33 min, 100% purity.

Example 1

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -1- (pyrrolidin-3-yl) piperidine

Intermediate 4(205mg, 0.66mmol) and tert-butyl 3-oxopyrrolidine-1-carboxylate (229. mu.L, 243mg) were dissolved in DCM (5mL) and NaBH (OAc) added₃(348mg, 1.64 mmol). The reaction mixture was stirred for 18 hours with 1M Na₂CO₃Aqueous solution (50mL) was diluted and extracted with DCM (2X 50 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography, dissolved in DCM (10mL) and TFA (2.5mL) and stirred for 2 h. The reaction mixture was concentrated under vacuum and the residue was dissolved in 1MNa₂CO₃Aqueous (50mL) and extracted with DCM (2X 50 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by reverse phase HPLC to give the title compound as a colourless gum (67.0mg, 27%). HRMS (ESI +) calculated as C22H25ClN4381.184, found 381.1846. HPLC: rt3.36 min, 98% purity.

Example 2

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -1- (piperidin-4-yl) piperidine

Example 2(72.0mg, 19%) was prepared in analogy to example 1 using tert-butyl 4-oxopiperidine-1-carboxylate instead of tert-butyl 3-oxopyrrolidine-1-carboxylate. HRMS (ESI +) calculated C23H27CIN4395.1997, found 395.1998. HPLC: rt3.52 min, 99% purity.

Example 3

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -1- (piperidin-4-ylmethyl) piperidine

Example 3(39.0mg, 20%) was prepared in analogy to example 1 using tert-butyl 4-formylpiperidine-1-carboxylate instead of tert-butyl 3-oxopyrrolidine-1-carboxylate. HRMS (ESI +) calculated C24H29ClN4409.2153 and found 409.2155. HPLC: rt3.55 min, 99% purity.

Example 4

1- {4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] piperidin-1-yl } -2- (piperidin-4-yl) ethan-1-one

Intermediate 4(200mg, 0.64mmol), 2- {1- [ (tert-butoxy) carbonyl]Piperidin-4-yl } acetic acid (203mg, 0.83mmol), HOBt (113mg, 0.83mmol) and DIPEA (290. mu.L, 1.67mmol) were dissolved in DMF (5mL) and EDC (160mg, 0.83mmol) was added. The reaction mixture was stirred for 18 hours and concentrated under vacuum. The residue was dissolved in EtOAc (25mL) and washed with 10% aqueous citric acid (25mL), 1M Na₂CO₃The aqueous solution (25mL) and water (25mL) were washed and dried (MgSO₄) And concentrated under vacuum. The residue was purified by column chromatography, dissolved in DCM (10mL) and TFA (2mL) and stirred for 2 h. The reaction mixture was concentrated in vacuo and dissolved in 1M Na₂CO₃Aqueous (25mL) and extracted with DCM (3X 25 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography to give the title compound (20.5mg, 7%) as a colourless gum. HRMS (ESI +) calculated C25H29ClN40437.2103 and found 437.21. HPLC: rt3.92 min, 96% purity.

Example 5

1- ({4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] piperidin-1-yl } carbonyl) -4-methylpiperazine

Intermediate 4(200mg, 0.64mmol), DIPEA (245 μ L, 1.41mmol) and DMAP (7.80mg, 0.06mmol) were dissolved in DCM (10mL) and 4-methylpiperazine-1-carbonyl chloride hydrochloride (140mg, 0.70mmol) was added. The reaction mixture was stirred for 18 hours with 1M Na₂CO₃Aqueous solution (50mL) was diluted and extracted with DCM (3X 50 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum.The residue was purified by column chromatography and reverse phase HPLC to give the title compound as a white solid (84.0mg, 30%). HRMS (ESI +) calculated C24H28ClN5O438.2055 and found 438.2057. HPLC: rt3.92 min, 100% purity.

Example 6

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- (piperidin-4-ylmethyl) piperidine-1-carboxamide

CDI (187mg, 1.15mmol) was dissolved in DCM (10mL), a solution of tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (247mg, 1.15mmol) and DIPEA (251. mu.L, 1.15mmol) in DCM (2mL) was added and the reaction mixture was stirred for 18 h. A solution of intermediate 4(300mg, 0.96mmol) and DIPEA (251. mu.L, 1.15mmol) in DCM (2mL) was added and the reaction mixture was stirred for 24h with 1M Na₂CO₃Aqueous solutions (50mL) were combined and extracted with DCM (3X 50 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography, dissolved in DCM (10mL) and TFA (2.5mL) and stirred for 1 h. The reaction mixture was concentrated in vacuo and dissolved in 1M Na₂CO₃Aqueous (50mL) and extracted with DCM (3X 50 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by reverse phase HPLC to give the title compound as a colourless gum (52.0mg, 12%). HRMS (ESI +) calculated as C25H30ClN5O452.2212 and found 452.2213. HPLC: rt3.92 min, 100% purity.

Examples 7 to 26

Examples 7 to 26 were prepared similarly to example 6 by CDI (or triphosgene) coupling of intermediate 4 with the appropriate amine followed by Boc deprotection (if required); see table 4 below.

Table 4: urea coupling of intermediate 4 and subsequent Boc deprotection if desired

Example 27

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- { [1- (propan-2-yl) piperidin-4-yl ] methyl } piperidine-1-carboxamide; formic acid

Intermediate 5(250mg, 0.55mmol) and acetone (81.1 μ L, 1.11mmol) were dissolved in DCM (200mL) and stirred for 1 h. Addition of NaBH (OAc)₃(293mg, 1.38mmol) and the reactionThe mixture was stirred for 18 hours with 1M Na₂CO₃Aqueous solution (50mL) was diluted and extracted with DCM (3X 50 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by reverse phase HPLC (formic acid buffered) to give the title compound as a white solid (20.5mg, 7%). LCMS (ES +): 494.1[ MH]+. HPLC: rt4.16 min, 98% purity.

Example 28

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- { [1- (2-methoxyethyl) piperidin-4-yl ] methyl } piperidine-1-carboxamide; formic acid

Intermediate 5(250mg, 0.55mmol) was dissolved in MeCN (3mL) and K was added₂CO₃(229mg, 1.66mmol) and 1-bromo-2-methoxyethane (52.0. mu.L, 0.55 mmol). The reaction mixture was heated in a microwave reactor at 100 ℃ for 30 min, diluted with water (50mL) and extracted with DCM (3X 50 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by reverse phase HPLC (formic acid buffered) to give the title compound as a white solid (11.3mg, 4%). LCMS (ES +): 510.0[ MH]+. HPLC: rt4.08 min, 94% purity.

Example 29

N- [3- ({4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] piperidin-1-yl } carbonylamino) propyl ] acetamide

Will be inIntermediate 6(64.0mg, 0.16mmol) was dissolved in DCM (5mL) and Et was added₃N (22.8. mu.L, 0.16mmol) and Ac₂O (15.4. mu.L, 0.16 mmol). The reaction mixture was stirred for 18 hours and then saturated Na was used₂CO₃Aqueous solution (25mL) was diluted and extracted with DCM (3X 25 mL). The combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by reverse phase HPLC to give the title compound (63.0mg, 89%) as a white solid. HRMS (ESI +) calculated c24h28clny5o2454.2004, found 454.2004. HPLC: rt4.34 min, 98% purity.

Example 30

Propan-2-yl N- ({4- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) carbamate

Intermediate 10(100mg, 0.25mmol) and isopropyl chloride (278. mu.L, 0.28mmol) were added to DCM (2mL) and saturated K₂CO₃Aqueous solution (3.5mL) and the reaction mixture was stirred for 1 hour. The aqueous fraction was extracted with DCM (2X 50mL) and the combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography to give the title compound (18.9mg, 18%) as a white solid. HRMS (ESI +) calculated as C₂₂H₂₇N₅O₃410.2187, found 410.2188. HPLC: rt5.31 min, 98% purity.

Example 31

3-cyclopropyl-1- ({4- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) urea

Cyclopropylamine (17.5. mu.L, 0.25mmol) and CDI (40.9mg, 0.25mmol) were dissolved in DMF (1mL) and stirred for 6 h. A solution of intermediate 10(100mg, 0.25mmol) in DMF (1mL) and DIPEA (92.6. mu.L, 0.56mmol) were added and the reaction mixture was stirred at 50 ℃ overnight. The solvent was removed in vacuo, the residue dissolved in DCM (10mL) and saturated Na₂CO₃Aqueous (5mL) wash. The aqueous fraction was extracted with DCM (10mL) and the combined organic fractions were dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography to give the title compound (32.7mg, 32%) as a pale yellow solid. HRMS (ESI +) calculated as C₂₂H₂₆N₆O₂407.2190, found 407.2192. HPLC: rt4.59 min, 98% purity.

Example 32

2- ({4- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methoxy) ethan-1-amine

Tert-butyl N- (2-hydroxyethyl) carbamate (159. mu.L, 1.03mmol) was dissolved in DMF (0.50mL), NaH (49.2mg, 60% dispersion in mineral oil, 1.03mmol) was added and the reaction mixture was stirred at 50 ℃ for 30 min. A solution of intermediate 18(92.0mg, 0.23mmol) in DMF (0.5mL) was added dropwise and the reaction mixture was stirred at 65 ℃ for 18h and 80 ℃ for 4 h. The reaction mixture was cooled to 0 ℃ and quenched with water (1 mL). The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give the title compound as an orange gum (3.05mg, 4%). HRMS (ESI +) calculated C20H25N5O2368.2081, found 368.2084. HPLC: rt3.96 min, 97.4% purity.

Example 33

(2-aminoethyl) ({4- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) amine trihydrochloride

Intermediate 18(92.0mg, 0.23mmol), N- (2-aminoethyl) carbamic acid tert-butyl ester (110mg, 0.69mmol), K₂CO₃(126mg, 0.91mmol) and Cs₂CO₃(100mg, 0.31mmol) was suspended in MeCN (2mL) and DMF (1mL) and the reaction mixture was heated at 90 ℃ for 20 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography, dissolved in 1.25M HCl in EtOH (2.5mL) and stirred for 18 h. The reaction mixture was concentrated in vacuo to give the title compound (1.52mg, 30%) as a dark yellow solid. LCMS (ES +): 367.0[ MH]+. HPLC: rt3.57 min, 98.2% purity.

Example 34

4- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -2- (morpholin-4-ylmethyl) morpholine

Intermediate 18(92.0mg, 0.23mmol), morpholine (60.0. mu.L, 0.69mmol), K₂CO₃(126mg, 0.91mmol) and Cs₂CO₃(100mg, 0.31mmol) was suspended in MeCN (2mL) and DMF (1mL) and the reaction mixture was heated at 90 ℃ for 20 h. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography to give as a yellow solidThe title compound (7.46mg, 8%). HRMS (ESI +) calculated C22H27N5O2394.2238, found 394.2239. HPLC: rt3.94 min, 94.5% purity.

Example 35

4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -2- [ (4-methylpiperazin-1-yl) methyl ] morpholine

Example 35(1.23mg, 2%) was prepared similarly to example 34, using intermediate 19 instead of intermediate 18 and 1-methylpiperazine instead of morpholine. LCMS (ES +): 427.0[ MH]⁺。

HPLC: rt3.85 min, 97.1% purity.

Example 36

4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -2- (piperazin-1-ylmethyl) morpholine trihydrochloride

Intermediate 22(75.0mg, 0.15mmol) was dissolved in 1.25M HCl in EtOH (15mL) and the reaction mixture was stirred for 18 hours and concentrated in vacuo to give the title compound (74.6mg, 97%) as an orange solid. HRMS (ESI +) calculated as C21H25ClN6O413.1851 and found 413.1853. HPLC: rt3.76 min, 97.8% purity.

Example 37

3-aminopropyl 4- ({4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) piperazine-1-carboxylic acid trihydrochloride

Triphosgene (14.2mg, 0.05mmol) was dissolved in DCM (1mL) and a solution of tert-butyl N- (3-hydroxypropyl) carbamate (25.2mg, 0.14mmol) and DIPEA (25.0. mu.L, 0.14mmol) in DCM (1mL) was added. The reaction mixture was stirred for 1h, a solution of example 36(50.0mg, 0.10mmol) and DIPEA (25.0. mu.L, 0.14mmol) in DCM (1mL) was added and the reaction mixture was stirred for 4 days. The reaction mixture was diluted with DCM (10mL) and saturated NH₄Aqueous Cl (5X 10 mL). The organic fraction was dried (MgSO)₄) And concentrated under vacuum. The residue was purified by reverse phase chromatography, dissolved in 1.25M HCl in EtOH (5mL) and stirred for 16 h. The solvent was removed under vacuum to give the title compound as an orange solid (19.5mg, 35%). HRMS (ESI +) calculated as C25H32ClN7O3514.2328 and found 514.2326. HPLC: rt3.79 min, 98.3% purity.

Example 38

N- (3-aminopropyl) -4- ({4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) piperazine-1-carboxamide trihydrochloride

Example 38(24.6mg, 41%) was prepared in analogy to example 37, using tert-butyl N- (3-aminopropyl) carbamate instead of tert-butyl N- (3-hydroxypropyl) carbamate. HRMS (ESI +) calculated as C25H33ClN8O2513.2488 and found 513.2486. HPLC: rt3.73 min, 100% purity.

Example 39

4- ({4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) -N-ethylpiperazine-1-carboxamide

Triphosgene (14.2mg, 0.05mmol) was dissolved in DCM (1mL) and a solution of ethylamine (9.52. mu.L, 0.14mmol) and DIPEA (25.0. mu.L, 0.14mmol) in DCM (1mL) was added. The reaction mixture was stirred for 1h and a solution of example 36(50.0mg, 0.10mmol) and DIPEA (25.0. mu.L, 0.14mmol) in DCM (1mL) was added. The reaction mixture was stirred for 4 days, diluted with DCM (10mL) and saturated NH₄Aqueous Cl (5X 10 mL). The organic fraction was dried (MgSO)₄) And concentrated under vacuum. The residue was purified by reverse phase chromatography to give the title compound (18.6mg, 40%) as a pale yellow solid. HRMS (ESI +) calculated as C24H30ClN7O2484.2222 and found 484.2219. HPLC: rt4.15 min, 99.3% purity.

Example 40

2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } acetic acid methyl ester

Intermediate 33(1.64g, 5.94mmol), 4-chlorophenylboronic acid (1.86g, 11.9mmol), Cu (OAc)₂(2.16g, 11.9mmol) and pyridine (2.39mL, 29.7mmol) were suspended in DCE (41mL) and stirred overnight. The reaction mixture was purified by column chromatography to give the title compound (866mg, 38%) as a yellow gum. HRMS (ESI +) calculated as C19H19ClN4O3387.1218, and the measurement was carried outThe value is 387.1218. HPLC: rt5.32 min, 100% purity.

EXAMPLE 41

4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -3- (morpholin-4-ylmethyl) morpholine

Example 41 was prepared in analogy to example 40 by N-arylation of intermediate 38 to give the title compound (6.00mg, 5%) as a yellow gum. HRMS (ESI +) calculated as c21h24cln5o2414.1691 and found 414.1693. HPLC: rt4.04 min, 97.6% purity.

Example 42

4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -3- [2- (4-methylpiperazin-1-yl) ethyl ] morpholine

Intermediate 49(60.0mg, 0.14mmol), 1-methyl-piperazine (45.7 μ L, o.41mmol) and K₂CO₃(75.9mg, 0.55mmol) was suspended in MeCN (1mL) and the reaction mixture was heated at 50 ℃ for 4 hours and 75 ℃ for 4 hours. The reaction mixture was filtered, concentrated under vacuum and the residue was purified by column chromatography to give the title compound as a dark yellow colloid (3.47mg, 6%). HRMS (ESI +) calculated as C23H29ClN6O441.2164 with a measurement of 441.2164. HPLC: rt3.89 min, 99.1% purity.

Example 43

1- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -N- [ (1-methylpiperidin-4-yl) methyl ] piperidine-2-carboxamide

Intermediate 47(66.0mg, 0.17mmol) was dissolved in DMF (2mL), cooled to 0 deg.C and HBTU (63.3mg, 0.17mmol), (1-methyl-4-piperidinyl) methylamine (25.7mg, 0.20mmol) and DIPEA (58.2. mu.L, 0.33mmol) were added. The reaction mixture was stirred at 0 ℃ for 1 hour and at room temperature for 18 hours, diluted with DCM (10mL) and saturated NH₄Aqueous Cl (3X 5 mL). The organic fraction was dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography to give the title compound (8.62mg, 11%) as a yellow solid. LCMS (ES +): 467.0[ MH]+. HPLC: rt4.19 min, 100% purity.

Example 44

1- (4-chlorophenyl) -N- [2- (morpholin-4-yl) ethyl ] -1H-pyrazolo [3, 4-c ] pyridin-3-amine

Example 44 was prepared similarly to example 40 by N-arylation of intermediate 35 followed by Boc deprotection (HCl in EtOH) to give the title compound as a light brown gum (2.27mg, 1%). HRMS (ESI +) calculated as C18H20ClN5O358.1429, found 358.1434. HPLC: rt4.00 min, 97% purity.

Example 45

1- (4-chlorophenyl) -N- [2- (piperazin-1-yl) ethyl ] -1H-pyrazolo [3, 4-c ] pyridin-3-amine

By N-arylation of intermediate 36 and subsequent Boc deprotection (Et)₂HCl in O), example 45 was prepared in analogy to example 40 to yield the title compound (9.98mg, 10%) as a pale green gum. HRMS (ESI +) calculated as c18h21clnj6357.1589 and found 357.1592. HPLC: rt3.57 min, 99.5% purity.

Example 46

1- (4-chlorophenyl) -N- [2- (4-methylpiperazin-1-yl) ethyl ] -1H-pyrazolo [3, 4-c ] pyridin-3-amine

Example 45(24.6mg, 0.07mmol) was dissolved in MeOH (2mL), formaldehyde (55.9mg, 37% in water, 0.69mmol) was added and the reaction mixture was stirred for 30 min. Addition of NaBH (OAc)₃(17.5mg, 0.08mmol) and the reaction mixture was stirred overnight and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound as a pale green gum (16.0mg, 63%). HRMS (ESI +) calculated as C19H23ClN6371.1745 and found 371.1751. HPLC: rt3.54 min, 100% purity.

Example 47

1- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -N- (piperidin-4-ylmethyl) piperidine-4-carboxamide dihydrochloride

Intermediate 44(200mg, 0.51mmol) was dissolved in DMF (2mL) and HBTU (231mg, 0.61mmol) was added. The reaction mixture was stirred for 30 min, tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (131mg, 0.61mmol) and DIPEA (266. mu.L, 1.53mmol) were added and the reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue diluted with EtOAc (25mL) and saturated NH₄Washed with aqueous Cl (4X 25mL) and dried (MgSO)₄) And concentrated under vacuum. The residue was purified by column chromatography, half of the product was dissolved in 1.25M HCl in EtOH (10mL) and stirred for 18 hours. The reaction mixture was concentrated in vacuo to give the title compound as an orange solid (77.9mg, 58%). HRMS (ESI +) calculated as C24H29ClN6O453.2164 and found 453.2163. HPLC: rt4.07 min, 98.1% purity.

Example 48

4- ({1- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] piperidin-4-yl } methyl) morpholine dihydrochloride

Intermediate 45(100mg, 0.23mmol) was dissolved in THF (1mL) and 1.0M BH in THF was added portionwise₃(1.88mL, 1.88mmol) and heated at 67 ℃ for 2 days. The reaction mixture was cooled to 0 ℃, quenched with cold water (2mL) and concentrated in vacuo. The residue was purified by column chromatography, dissolved in 1.25M HCl in EtOH (5mL), stirred for 4 hours and concentrated in vacuo to give the title compound as an orange solid (5.68mg, 5%). HRMS (ESI +) calculated as cz22h26clny5o412.1899 and found 412.1896. HPLC: rt4.13 min, 98.1% purity.

Examples 49 to 50

Examples 49 to 50 were prepared similarly to example 48 by intermediate 46 and Boc protected borane reduction of example 47, followed by Boc deprotection; see table 5 below.

Table 5: borane reduction and subsequent Boc deprotection

Example 51

4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -N- [ (1-methylpiperidin-4-yl) methyl ] piperazine-1-carboxamide

Triphosgene (14.2mg, 0.05mmol) was dissolved in DCM (1mL) and a solution of (1-methyl-4-piperidinyl) methylamine (18.4mg, 0.14mmol) and DIPEA (25.0. mu.L, 0.14mmol) in DCM (1mL) was added. The reaction mixture was stirred for 1 hour and a solution of intermediate 50(37.0mg, 0.10mmol) and DIPEA (25.0 μ L,0.14mmol) in DCM (1mL) was added. The reaction mixture was stirred for 18h, diluted with DCM (10mL) and saturated NH₄Washed with aqueous Cl (5X 10mL) and dried (MgSO)₄) And concentrated under vacuum. The residue was purified by reverse phase chromatography to give the title compound (17.0mg, 38%) as a yellow solid. LCMS (ES +): 468.0[ MH]+. HPLC: rt4.13 min, 98.7% purity.

Example 52

1- [1- (4-methylphenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] piperidin-4-yl acetate

Intermediate 37(618mg, 2.37mmol) was dissolved in DMF (3.5mL) and 1-methyl-4-iodo-benzene (621mg, 2.85mmol), N' -dimethylethylenediamine (51.1. mu.L, 0.42mmol), K, were added₃PO₄(1.06g, 4.99mmol) and CuI (45.2mg, 0.24 mmol). The reaction mixture was heated at 60 ℃ for 10 minutes using a microwave reactor. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give the title compound as a yellow gum (248mg, 30%). HRMS (ESI +) calculated C20H22N4O2351.1816, found 351.1819. HPLC: rt5.44 min, 100% purity.

Example 53

2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } acetate hydrochloride

Example 40(1.00g, 2.84mmol) was dissolved in 1: 1 THF/water (16mL), LiOH. H was added₂O (262mg, 6.24mmol) and the reaction mixture was stirred for 3 hours. The THF was removed under vacuum and the reaction mixture was acidified to pH1 with 1M aqueous HCl (5 mL). The precipitate was collected by filtration and washed with water to give the title compound (28.3mg, 3%) as an orange solid. The calculated HRMS (ESI +) value was C18H17ClN4O3373.1062, and the measured value was 373.1062. HPLC: rt4.40 min, 97% purity.

Example 54

N- (2-aminoethyl) -2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } acetamide dihydrochloride

Example 53(180mg, 0.44mmol) was dissolved in DMF (2.1mL) and cooled to 0 deg.C, HBTU (167mg, 0.44mmol), tert-butyl N- (2-aminoethyl) carbamate (84.6mg, 0.53mmol) and DIPEA (76.6. mu.L, 0.44mmol) were added. The reaction mixture was stirred at 0 ℃ for 2.5 hours and purified by column chromatography. The residue was dissolved in 1.25M HCl in EtOH (2.5mL) and stirred for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound as an orange solid (46.4mg, 22%). HRMS (ESI +) calculated as C20H23ClN6O2415.1644, found 415.1638. HPLC: rt3.97 min, 99% purity.

Examples 55 to 58

Examples 55 to 58 were prepared in analogy to example 54 by amide coupling with example 53 (without the HCl salt formation step); see table 6 below.

Table 6: amide coupling with example 53

Example 59

({4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) urea

Intermediate 52(50.0mg, 0.12mmol) and DIPEA (41.8. mu.L, 0.24mmol) were dissolved in DMF (2 mL). Trimethylsilyl isocyanate (29.2 μ L, 0.22mmol) was added and the reaction mixture was stirred for 48 hours. The reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc (10mL) and washed with water (2X 5 mL). The organic fraction was concentrated in vacuo and purified by reverse phase HPLC to give the title compound as a white solid (16.5mg, 35%). LCMS (ES +): 387.2[ MH ] +. HPLC: rt4.40 min, 96.8% purity.

Example 60

1- ({4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-2-yl } methyl) -3-methylurea

Intermediate 52(50.0mg, 0.12mmol) and DIPEA (62.7. mu.L, 0.36mmol) were dissolved in THF (2 mL). N-methylcarbamoyl chloride (12.3mg, 0.132mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc (10mL) and washed with water (2X 5 mL). The organic fraction was concentrated in vacuo and purified by reverse phase HPLC to give the title compound as an off-white solid (11.1mg, 23%). LCMS (ES +): 401.1[ MH ] +. HPLC: rt4.55 min, 99.7% purity.

Example 61

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- (2H-1,2,3, 4-tetrazol-5-ylmethyl) piperidine-1-carboxamide; trifluoroacetic acid

CDI (172mg, 1.06mmol) was dissolved in DCM (10mL) and a suspension of 1H-1,2,3, 4-tetrazol-5-ylmethylamine hydrochloride (143mg, 1.06mmol) and DIPEA (368. mu.L, 2.12mmol) in DCM was added. The reaction mixture was stirred for 6 hours and a solution of intermediate 4(300mg, 0.96mmol) and DIPEA (368 μ L, 2.12mmol) in DCM (2mL) was added. The reaction mixture was stirred for 3 days and concentrated under vacuum. The residue was purified by reverse phase HPLC to give the title compound as a white solid (134mg, 25%). LCMS (ES +): 437.0[ MH ] +. HPLC: rt4.29 min, 100% purity.

Example 62

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [ cyclopropyl (2H-1,2,3, 4-tetrazol-5-yl) methyl ] piperidine-1-carboxamide; trifluoroacetic acid

Example 62(252mg, 53%) was prepared in analogy to example 61 using cyclopropyl (1H-1,2,3, 4-tetrazol-5-yl) methylamine instead of 1H-1,2,3, 4-tetrazol-5-ylmethylamine hydrochloride. LCMS (ES +): 477.1[ MH ] +. HPLC: rt4.69 min, 99% purity.

Example 63

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [1- (2H-1,2,3, 4-tetrazol-5-yl) cyclobutyl ] piperidine-1-carboxamide; trifluoroacetic acid

Example 63(92.0mg, 19%) was prepared in analogy to example 61 using 1- (1H-1,2,3, 4-tetrazol-5-yl) cyclobutan-1-amine instead of 1H-1,2,3, 4-tetrazol-5-ylmethylamine hydrochloride. LCMS (ES +): 477.1[ MH ] +. HPLC: rt4.57 min, 99% purity.

Example 64

1- (2- { [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] amino } ethyl) imidazolidin-2-one

Intermediate 55(70.0mg, 0.15mmol) was dissolved in HCl in EtOH (1.25M, 20mL) and stirred for 5 days. The reaction mixture was concentrated in vacuo, taken up in DCM (15mL) and saturated NaHCO₃Partition between aqueous solutions (10mL) and dry the organic fraction (MgSO)₄) And concentrated in vacuo to give the title compound as a white solid (47.5mg, 87%). LCMS (ES +): 357.1[ MH]+. HPLC: rt4.89 min, 99.6% purity.

Biological assay

Biological assays for SSAO enzyme inhibitors

All preliminary assays were performed at room temperature using purified samplesIs performed by the recombinantly expressed human SSAO. Substantially as followsEtc. (Protein Expression and Purification46(2006) 321-331). In addition, secondary and selective assays were performed using SSAO prepared from various tissues or purified rat recombinant SSAO. Using benzylamine as substrate by using¹⁴C-labeled substrates measure benzaldehyde production or enzyme activity is determined by using hydrogen peroxide production in a horseradish peroxidase (HRP) coupling reaction. Briefly, test compounds were dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mM. By performing a 1: 10 to generate a 7-point curve or by performing a 1: 3 to generate an 11-point curve to determine dose-response measurements. The highest concentration is adjusted according to the potency of the compound and then diluted in reaction buffer to obtain a final DMSO concentration of less than or equal to 2%.

And (3) detecting hydrogen peroxide:

in the horseradish peroxidase (HRP) coupling reaction, the 10-acetyl-3, 7-dihydroxythiopheneOxidation of oxazines by hydrogen peroxide produces resorufin (resorufin), a highly efficient fluorescent compound (Zhout and Panchuk-Voloshina. analytical Biochemistry253(1997) 169-174;red hydrogen peroxide/peroxidase assay kit, invitrogen a 22188). The enzyme and compound in 50mM sodium phosphate (ph7.4) were set to pre-incubation in flat-bottom microtiter plates for about 15 minutes before starting the reaction by adding a mixture of HRP, benzylamine and Amplex reagents. The concentration of benzylamine was fixed at a concentration corresponding to the mie constant, which was determined using standard procedures. Fluorescence intensity was then measured at several time points over a period of 1 to 2 hours, with excitation at 544nm and reading of emission at 590 nm. Assay wellFinal concentrations of human SSAO for medium reagent were: SSAO enzyme 1. mu.g/mL, benzylamine 100. mu.M, Amplex reagent 20. mu.M, HRP0.1U/mL and various concentrations of test compound. Inhibition was measured as the percentage reduction in signal compared to the control without inhibitor (diluted DMSO only). The background signal from the sample without SSAO enzyme was subtracted from all data points. Data were fit to a four parameter logistic model and IC's were calculated using GraphPad Prism4 or XLFit4 programs₅₀The value is obtained.

And (3) aldehyde detection:

SSAO activity was determined using 14C-labeled benzylamine and analyzed by measuring radioactive benzaldehyde. 20 μ L of diluted test compound was preincubated with 20 μ L of SSAO enzyme in a white 96-well light-transmitting plate (Packard) for about 15 minutes at room temperature while stirring was continued. All dilutions were performed with PBS. The reaction was initiated by the addition of 20. mu.L of benzylamine substrate solution containing [7-14C ] benzylamine hydrochloride (CFA589, GEHealthcare). Plates were incubated for 1 hour as described above, and the reaction was then stopped by acidification (10 μ L1M HCl). Then, 90 μ L of a micro scintillation-E solution (Perkin-Elmer) was added to each well and the plates were mixed continuously for 15 minutes. Phase separation was immediately performed and activity was read in a Topcount scintillation counter (Perkin-Elmer). In the final reaction wells, the concentration of human recombinant SSAO was 10. mu.g/ml. To optimize sensitivity, substrate concentration was reduced compared to HRP-conjugated assay to get a higher fraction of radioactive product. In the human SSAO assay, the benzylamine concentration was 40. mu.M (0.2. mu. Ci/mL). The data was analyzed as described above.

IC for SSAO of all compounds exemplified in the present invention₅₀Values were 1 to 2500nM (see Table 7).

Table 7: SSAO inhibitory Activity

(A：＜100nM，B：100-500nM，C：500-2500nM)

Compound (I)	IC50(nM)	Compound (I)	IC50(nM)	Compound (I)	IC50(nM)
						1	A	23	A	45	B
2	B	24	A	46	B
						3	B	25	A	47	B
4	A	26	A	48	A
						5	A	27	A	49	B
6	A	28	A	50	B
						7	A	29	A	51	A
8	A	30	A	52	A
						9	A	31	A	53	C
10	A	32	B	54	A
						11	A	33	B	55	A
12	A	34	B	56	A
						13	A	35	B	57	B
14	A	36	A	58	B
						15	A	37	B	59	A
16	A	38	B	60	A
						17	A	39	B	61	A
18	A	40	A	62	A
						19	A	41	B	63	A
20	A	42	A	64	A
						21	A	43	B
22	A	44	C

The claims (modification according to treaty clause 19)

1. A compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof:

R¹-X-R²

(I)

wherein

R¹Is phenyl or 6-membered heteroaryl, optionally substituted with one or more substituents selected from: halogen, cyano, C_1-4-alkyl, halo-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl, hydroxy-C_1-4-alkyl, cyano-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-4-alkylamino-C_1-4Alkyl, di (C)_1-4-alkyl) amino-C_1-4-alkyl, -NR^4AR^4B、-NR⁶C(O)OR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)NR^4AR^4B、-C(O)NR^4AR^4B、-C(O)R⁵、-C(O)OR⁵and-NR⁶S(O)₂R⁵；

R²is-B-Q- [ R³]_nor-B-R³；

Wherein n =1, 2,3 or 4,

b is a bond, O, NR⁴-C (O) -or C_1-3-an alkylene group;

q is a saturated or partially unsaturated monocyclic ring 3 to 7Membered heterocyclic ring or C_3-7-a cycloalkyl ring;

when R is²is-B-Q- [ R³]_nWhen R is³Independently selected from: 3-to 7-membered heterocyclyl-, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-, amino-C_1-4-alkoxy-C_1-4-alkyl-, (amino-C)_1-4-alkyl) -amino-C_1-4-alkyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、-C_1-4-alkyl-NR⁶C(O)NR^4AR^4B、-C_1-4alkyl-C (O) NR^4AR^4B(3-to 7-membered heterocyclic group-C)_1-4-alkyl) -C (O) -, -C_1-4alkyl-C (O) OR⁵、-OC(O)R⁵Or is or

-C(O)NR^9AR^9BWherein R is^9AAnd R^9BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, which is substituted with one or more substituents selected from: c_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl-, C_3-7-cycloalkyl, or

-C(O)NR⁶R^10BWherein R is^10BIs 3-to 7-membered heterocyclyl-or 3-to 7-membered heterocyclyl-C_1-4-alkyl-or-C_1-4-alkyl-NR⁶C(O)R⁵(ii) a Or

When R is²is-B-R³When R is³is-NR⁶R^11BWherein R is^11BIs a 3-to 7-membered heterocyclyl-C_1-4-alkyl-;

R^4A、R^4Band R⁵Each independently selected from hydrogen and C_1-4-alkyl-, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, amino-C_1-4-alkyl-, 3-to 7-membered heterocyclyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、C_3-7-a cycloalkyl group,

or R^4AAnd R^4BWith themThe attached nitrogens taken together form a 3 to 7 membered cyclic amino group, which is optionally substituted with one or more substituents selected from the group consisting of: c_1-4-alkyl, -NR^4AR^4B；

Unless otherwise specified, a 3-to 7-membered heterocyclyl group, or a 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-or (3 to 7 membered heterocyclyl-C)_1-4-the heterocyclyl part of the-alkyl) -c (o) -group is optionally substituted with one or more substituents selected from: c_1-4Alkyl-, -C (O) OR⁵、-C(O)R⁵、-C(O)NR^4AR^4B、-NR^4AR^4B、-C_1-4alkyl-C (O) NR^4AR^4BOr C_1-4alkoxy-C_1-4An alkyl group; and is

When present, diradical-C directly attached to Q_1-4-the alkyl-group is optionally substituted with one or more groups independently selected from: halogen, amino, methoxy, hydroxy;

R⁴and R⁶Each independently selected from hydrogen or C_1-4-an alkyl group; and is

X is selected from the group of formula (1-16) wherein the bond marked with < i > ANGSTROM </i > and R¹-a bond linked and labelled with < ANGSTROM > and-R²And (3) connection:

wherein Y is selected from hydrogen, hydroxy, amino, -NHR⁶、-OCH₃；

Z is selected from hydrogen, fluorine, hydroxyl and C_1-4-alkoxy, halo-C_1-4Alkyl, CONH₂Cyano, SO₂NH₂Amino, -NHR⁶；

W is selected from H, C_1-4-alkyl, halo-C_1-4-an alkyl group,

provided that when R is²is-B-Q- [ R³]_nAnd R is³Is a 3-to 7-membered heterocyclyl-, the heteroatom directly bonded to Q is not nitrogen, and

with the proviso that the compound of formula (I) is not:

2. the compound of claim 1, wherein X is selected from the group of formula 1 or 3.

3. The compound of claim 1 or 2, wherein R¹Is phenyl optionally substituted by one or more substituents as defined in claim 1.

4. A compound according to any one of claims 1 to 3, wherein R¹Optionally substituted by halogen, cyano, C_1-4-alkyl, halo-C_1-4-alkyl substitution.

5. The compound according to any one of claims 1 to 4, wherein B is a bond.

6. A compound according to any one of claims 1 to 5, wherein R²is-B-Q- [ R³]_nAnd Q is a saturated or partially unsaturated 5 or 6 membered heterocyclic or cycloalkyl ring.

7. A compound according to claim 7, wherein Q is selected from tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, cyclohexyl, or any of the above rings containing a bridge formed by an ethylene or propylene group.

8. A compound according to any one of claims 1 to 6, wherein R²The method comprises the following steps:

wherein

T is N or CH;

R⁶is hydrogen or C_1-4-an alkyl group;

R^10Bis 3-to 7-membered heterocyclyl-or 3-to 7-membered heterocyclyl-C_1-4-alkyl-, any of said heterocyclyl rings being optionally substituted with one or more substituents selected from: c_1-4-Alkyl-and C_1-4alkoxy-C_1-4An alkyl group.

9. The compound of claim 8, wherein R²The method comprises the following steps:

wherein

T is N or CH;

p is a direct bond or a diradical selected from methylene, ethylene or propylene;

R⁶is hydrogen or C_1-4-an alkyl group;

R¹²selected from hydrogen, C_1-4-alkyl-and C_1-4alkoxy-C_1-4An alkyl group-.

10. The compound of claim 8, wherein R²The method comprises the following steps:

wherein

T is N or CH;

p is a diradical selected from methylene, ethylene or propylene;

R⁶is hydrogen or C_1-4-an alkyl group;

R¹²selected from hydrogen, C_1-4-alkyl and C_1-4alkoxy-C_1-4An alkyl group-.

11. A compound according to any one of claims 1 to 6, wherein R²The method comprises the following steps:

wherein

R³is-C_1-4Alkyl C (O) NR^4AR^4BWherein

R^4AAnd R^4BEach independently selected from hydrogen and C_1-4-alkyl-and amino-C_1-4-alkyl-, or

R^4AAnd R^4BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, optionally substituted with one or more substituents selected from: c_1-4-alkyl or-NR^4AR^4B(ii) a Or

12. The compound of claim 1, which is:

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- (piperidin-4-ylmethyl) piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- (1-methylpiperidin-4-yl) piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [ (1-methylpiperidin-4-yl) methyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [ (1-ethylpiperidin-4-yl) methyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N-methyl-N- [ (1-methylpiperidin-4-yl) methyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [2- (piperazin-1-yl) ethyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [2- (1-methylpiperidin-4-yl) ethyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [3- (morpholin-4-yl) propyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- { [1- (prop-2-yl) piperidin-4-yl ] methyl } piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- { [1- (2-methoxyethyl) piperidin-4-yl ] methyl } piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -N- [ (1-methylpiperidin-4-yl) methyl ] piperazine-1-carboxamide

N- (2-aminoethyl) -2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } acetamide

2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } -1- [ (3S) -3- (dimethylamino) pyrrolidin-1-yl ] ethan-1-one,

or a pharmaceutically acceptable salt or N-oxide thereof.

13. A pharmaceutical composition comprising a compound according to any one of the preceding claims, and one or more pharmaceutically acceptable carriers and/or excipients.

14. A compound according to any one of claims 1 to 12 for use in the treatment of inflammation, inflammatory diseases, immune or autoimmune diseases, or for inhibiting tumor growth.

15. Use of a compound according to any one of claims 1 to 12 in the manufacture of a composition for the treatment of inflammation, inflammatory disease, immune or autoimmune disease or for inhibiting tumor growth.

16. A method for the treatment of inflammation, inflammatory diseases, immune or autoimmune diseases or for inhibiting tumor growth, which comprises administering to a subject suffering from said diseases an effective amount of a compound of formula (I) according to any one of claims 1 to 12.

17. A compound according to any one of claims 1 to 12, or a use according to claim 15, or a method according to claim 16, wherein the inflammatory or inflammatory disease or immune or autoimmune disease is arthritis (including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis and psoriatic arthritis), synovitis, vasculitis, conditions associated with inflammation of the gut (including crohn's disease, ulcerative colitis, inflammatory bowel disease and irritable bowel syndrome), atherosclerosis, multiple sclerosis, alzheimer's disease, vascular dementia, inflammatory diseases of the lung (including asthma, chronic obstructive pulmonary disease and acute respiratory distress syndrome), fibrotic diseases (including cystic fibrosis, idiopathic pulmonary fibrosis, myocardial fibrosis and systemic sclerosis (scleroderma)), inflammatory diseases of the skin (including contact dermatitis, chronic obstructive pulmonary fibrosis, myocardial fibrosis and systemic sclerosis (scleroderma), Atopic dermatitis and psoriasis), systemic inflammatory response syndrome, sepsis, inflammatory and/or autoimmune conditions of the liver (including autoimmune hepatitis, primary biliary cirrhosis, alcoholic liver disease, sclerosing cholangitis, and autoimmune cholangitis), diabetes (type I or type II) and/or its complications, chronic heart failure, congestive heart failure, ischemic diseases (including stroke and ischemia-reperfusion injury), or myocardial infarction and/or its complications.

18. A compound according to any one of claims 1 to 12, or a use according to claim 15, or a method according to claim 16, wherein the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease or atopic dermatitis.

19. A compound according to any one of claims 1 to 12, or the use according to claim 15, or the method according to claim 16, for use in inhibiting tumor growth.

Claims (20)

1. A compound of formula (I), or a pharmaceutically acceptable salt or N-oxide thereof:

R¹-X-R²

(I)

wherein

R¹Is phenyl or 6-membered heteroaryl, optionally substituted with one or more substituents selected from: halogen, cyano, C_1-4-alkyl, halo-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl, hydroxy-C_1-4-alkyl, cyano-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-4-alkylamino-C_1-4Alkyl, di (C)_1-4-alkyl) amino-C_1-4-alkyl, -NR^4AR^4B、-NR⁶C(O)OR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)NR^4AR^4B、-C(O)NR^4AR^4B、-C(O)R⁵、-C(O)OR⁵and-NR⁶S(O)₂R⁵；

R²is-B-Q- [ R³]_nor-B-R³；

Wherein n =1, 2,3 or 4,

b is a bond, O, NR⁴-C (O) -or C_1-3-an alkylene group;

q is a saturated or partially unsaturated monocyclic 3-to 7-membered heterocycle or C_3-7-a cycloalkyl ring;

when R is²is-B-Q- [ R³]_nWhen R is³Independently selected from: 3-to 7-membered heterocyclyl-, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-, amino-C_1-4-alkoxy-C_1-4-alkyl-, (amino-C)_1-4-alkyl) -amino-C_1-4-alkyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、-C_1-4-alkyl-NR⁶C(O)NR^4AR^4B、-C_1-4alkyl-C (O) NR^4AR^4B(3-to 7-membered heterocyclic group-C)_1-4-alkyl) -C (O) -, -C_1-4alkyl-C (O) OR⁵、-OC(O)R⁵Or is or

-C(O)NR^9AR^9BWherein R is^9AAnd R^9BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, which is substituted with one or more substituents selected from: c_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl-, C_3-7-cycloalkyl, or

-C(O)NR⁶R^10BWherein R is^10BThe method comprises the following steps:

(i) 3-to 7-membered heterocyclyl-or 3-to 7-membered heterocyclyl-C_1-4-alkyl-or-C_1-4-alkyl-NR⁶C(O)R⁵(ii) a Or

(ii) 5-or 6-membered heteroaryl-C_1-4-alkyl-, wherein the heteroaryl ring is optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, C_1-4-alkyl, halo-C_1-4-alkyl, and wherein said C_1-4-alkyl moieties optionally substituted by one or more C_1-4-alkyl-group substitution, or said C_1-4Alkyl moieties by two C_1-4-alkyl substitution, said two C_1-4-alkyl groups taken together with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl spirocycle; and wherein

When R is²is-B-R³When R is³is-NR⁶R^11BAnd R is^11BIs a 3-to 7-membered heterocyclyl-C_1-4-alkyl-;

R^4A、R^4Band R⁵Each independently selected from hydrogen and C_1-4-alkyl-, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, amino-C_1-4-alkyl-, 3-to 7-membered heterocyclyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、C_3-7-cycloalkyl, or

R^4AAnd R^4BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, optionally substituted with one or more substituents selected from: c_1-4-alkyl, -NR^4AR^4B(ii) a And wherein

Unless otherwise specified, a 3-to 7-membered heterocyclyl group, or a 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-or (3 to 7 membered heterocyclyl-C)_1-4-the heterocyclyl part of the-alkyl) -c (o) -group is optionally substituted with one or more substituents selected from: oxo, C_1-4Alkyl-, -C (O) OR⁵、-C(O)R⁵、-C(O)NR^4AR^4B、-NR^4AR^4B、-C_1-4alkyl-C (O) NR^4AR^4BOr C_1-4alkoxy-C_1-4An alkyl group; and is

When present, directly connected to Qdiradical-C_1-4-the alkyl-group is optionally substituted with one or more groups independently selected from: halogen, amino, methoxy, hydroxy; and wherein

R⁴And R⁶Each independently selected from hydrogen or C_1-4-an alkyl group; and is

X is selected from the group of formula (1-16) wherein the bond marked with < i > ANGSTROM </i > and R¹-a bond linked and labelled with < ANGSTROM > and-R²And (3) connection:

wherein Y is selected from hydrogen, hydroxy, amino, -NHR⁶、-OCH₃；

Z is selected from hydrogen, fluorine, hydroxyl and C_1-4-alkoxy, halo-C_1-4Alkyl, CONH₂Cyano, SO₂NH₂Amino, -NHR⁶；

W is selected from H, C_1-4-alkyl, halo-C_1-4-an alkyl group,

provided that when R is²is-B-Q- [ R³]_nAnd R is³R directly bonded to Q when it is a 3-to 7-membered heterocyclyl-group³The heterocyclic atom is not nitrogen.

2. A compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof:

R¹-X-R²

(I)

wherein

R¹Is phenyl or 6-membered heteroaryl, optionally substituted with one or more substituents selected from: halogen, cyano, C_1-4-alkyl, halo-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl, hydroxy-C_1-4-alkyl, cyano-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-4-alkylamino-C_1-4Alkyl, di (C)_1-4-alkyl) amino-C_1-4-alkyl, -NR^4AR^4B、-NR⁶C(O)OR⁵、-NR⁶C(O)R⁵、-NR⁶C(O)NR^4AR^4B、-C(O)NR^4AR^4B、-C(O)R⁵、-C(O)OR⁵and-NR⁶S(O)₂R⁵；

R²is-B-Q- [ R³]_nor-B-R³；

Wherein n =1, 2,3 or 4,

b is a bond, O, NR⁴-C (O) -or C_1-3-an alkylene group;

q is a saturated or partially unsaturated monocyclic 3-to 7-membered heterocycle or C_3-7-a cycloalkyl ring;

when R is²is-B-Q- [ R³]_nWhen R is³Independently selected from: 3-to 7-membered heterocyclyl-, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-, amino-C_1-4-alkoxy-C_1-4-alkyl-, (amino-C)_1-4-alkyl) -amino-C_1-4-alkyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、-C_1-4-alkyl-NR⁶C(O)NR^4AR^4B、-C_1-4alkyl-C (O) NR^4AR^4B(3-to 7-membered heterocyclic group-C)_1-4-alkyl) -C (O) -, -C_1-4alkyl-C (O) OR⁵、-OC(O)R⁵Or is or

-C(O)NR^9AR^9BWherein R is^9AAnd R^9BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, which is substituted with one or more substituents selected from: c_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl-, C_3-7-cycloalkyl, or

-C(O)NR⁶R^10BWherein R is^10BIs 3-to 7-membered heterocyclyl-or 3-to 7-membered heterocyclyl-C_1-4-alkyl-or-C_1-4-alkyl-NR⁶C(O)R⁵(ii) a Or

When R is²is-B-R³When R is³is-NR⁶R^11BWherein R is^11BIs 3 to 7Cyclic radical-C_1-4-alkyl-;

R^4A、R^4Band R⁵Each independently selected from hydrogen and C_1-4-alkyl-, 3-to 7-membered heterocyclyl-C_1-4-alkyl-, amino-C_1-4-alkyl-, 3-to 7-membered heterocyclyl-, -C_1-4-alkyl-NR⁶C(O)OR⁵、C_3-7-a cycloalkyl group,

or R^4AAnd R^4BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, optionally substituted with one or more substituents selected from: c_1-4-alkyl, -NR^4AR^4B；

Unless otherwise specified, a 3-to 7-membered heterocyclyl group, or a 3-to 7-membered heterocyclyl-C_1-4-alkyl-, (3-to 7-membered heterocyclyl-C_1-4-alkyl) -amino-C_1-4-alkyl-or (3 to 7 membered heterocyclyl-C)_1-4-the heterocyclyl part of the-alkyl) -c (o) -group is optionally substituted with one or more substituents selected from: c_1-4Alkyl-, -C (O) OR⁵、-C(O)R⁵、-C(O)NR^4AR^4B、-NR^4AR^4B、-C_1-4alkyl-C (O) NR^4AR^4BOr C_1-4alkoxy-C_1-4An alkyl group; and is

When present, diradical-C directly attached to Q_1-4-the alkyl-group is optionally substituted with one or more groups independently selected from: halogen, amino, methoxy, hydroxy;

R⁴and R⁶Each independently selected from hydrogen or C_1-4-an alkyl group; and is

X is selected from the group of formula (1-16) wherein the bond marked with < i > ANGSTROM </i > and R¹-a bond linked and labelled with < ANGSTROM > and-R²And (3) connection:

wherein Y is selected from hydrogen, hydroxy, amino, -NHR⁶、-OCH₃；

Z is selected from hydrogen, fluorine, hydroxyl and C_1-4-alkoxy, halo-C_1-4Alkyl, CONH₂Cyano, SO₂NH₂Amino, -NHR⁶；

W is selected from H, C_1-4-alkyl, halo-C_1-4-an alkyl group,

provided that when R is²is-B-Q- [ R³]_nAnd R is³Is a 3-to 7-membered heterocyclyl-, the heteroatom directly bonded to Q is not nitrogen.

3. The compound of claim 1 or 2, wherein X is selected from the group of formula 1 or 3.

4. A compound according to any one of claims 1 to 3, wherein R¹Is phenyl optionally substituted by one or more substituents as defined in claim 1.

5. A compound according to any one of claims 1 to 4, wherein R¹Optionally substituted by halogen, cyano, C_1-4-alkyl, halo-C_1-4-alkyl substitution.

6. The compound according to any one of claims 1 to 5, wherein B is a bond.

7. A compound according to any one of claims 1 to 6, wherein R²is-B-Q- [ R³]_nAnd Q is a saturated or partially unsaturated 5 or 6 membered heterocyclic or cycloalkyl ring.

8. A compound according to claim 7, wherein Q is selected from tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, cyclohexyl, or any of the above rings containing a bridge formed by an ethylene or propylene group.

9. A compound according to any one of claims 1 to 7, wherein R²The method comprises the following steps:

wherein

T is N or CH;

R⁶is hydrogen or C_1-4-an alkyl group;

R^10Bis 3-to 7-membered heterocyclyl-or 3-to 7-membered heterocyclyl-C_1-4-alkyl-, any of said heterocyclyl rings being optionally substituted with one or more substituents selected from: c_1-4-alkyl-and C_1-4alkoxy-C_1-4An alkyl group.

10. The compound of claim 9, wherein R²The method comprises the following steps:

wherein

T is N or CH;

p is a direct bond or a diradical selected from methylene, ethylene or propylene;

R⁶is hydrogen or C_1-4-an alkyl group;

R¹²selected from hydrogen, C_1-4-alkyl-and C_1-4alkoxy-C_1-4An alkyl group-.

11. The compound of claim 9, wherein R²The method comprises the following steps:

wherein

T is N or CH;

p is a diradical selected from methylene, ethylene or propylene;

R⁶is hydrogen or C_1-4-an alkyl group;

R¹²selected from hydrogen, C_1-4-alkyl and C_1-4alkoxy-C_1-4An alkyl group-.

12. A compound according to any one of claims 1 to 7, wherein R²The method comprises the following steps:

wherein

R³is-C_1-4Alkyl C (O) NR^4AR^4BWherein

R^4AAnd R^4BEach independently selected from hydrogen and C_1-4-alkyl-and amino-C_1-4-alkyl-, or

R^4AAnd R^4BTogether with the nitrogen to which they are attached form a 3 to 7 membered cyclic amino group, optionally substituted with one or more substituents selected from: c_1-4-alkyl or-NR^4AR^4B(ii) a Or

13. The compound of claim 1, which is:

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- (piperidin-4-ylmethyl) piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- (1-methylpiperidin-4-yl) piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [ (1-methylpiperidin-4-yl) methyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [ (1-ethylpiperidin-4-yl) methyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N-methyl-N- [ (1-methylpiperidin-4-yl) methyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [2- (piperazin-1-yl) ethyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [2- (1-methylpiperidin-4-yl) ethyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- [3- (morpholin-4-yl) propyl ] piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- { [1- (prop-2-yl) piperidin-4-yl ] methyl } piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrrolo [2, 3-c ] pyridin-3-yl ] -N- { [1- (2-methoxyethyl) piperidin-4-yl ] methyl } piperidine-1-carboxamide

4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] -N- [ (1-methylpiperidin-4-yl) methyl ] piperazine-1-carboxamide

N- (2-aminoethyl) -2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } acetamide

2- {4- [1- (4-chlorophenyl) -1H-pyrazolo [3, 4-c ] pyridin-3-yl ] morpholin-3-yl } -1- [ (3S) -3- (dimethylamino) pyrrolidin-1-yl ] ethan-1-one,

or a pharmaceutically acceptable salt or N-oxide thereof.

14. A pharmaceutical composition comprising a compound according to any one of the preceding claims, and one or more pharmaceutically acceptable carriers and/or excipients.

15. A compound according to any one of claims 1 to 13 for use in the treatment of inflammation, inflammatory diseases, immune or autoimmune diseases, or for inhibiting tumor growth.

16. Use of a compound according to any one of claims 1 to 13 in the manufacture of a composition for the treatment of inflammation, inflammatory disease, immune or autoimmune disease or for inhibiting tumor growth.

17. A method for the treatment of inflammation, inflammatory diseases, immune or autoimmune diseases or for inhibiting tumor growth, which comprises administering to a subject suffering from said diseases an effective amount of a compound of formula (I) according to any one of claims 1 to 13.

18. A compound according to any one of claims 1 to 13, or a use according to claim 15, or a method according to claim 17, wherein the inflammatory or inflammatory disease or immune or autoimmune disease is arthritis (including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis and psoriatic arthritis), synovitis, vasculitis, conditions associated with inflammation of the gut (including crohn's disease, ulcerative colitis, inflammatory bowel disease and irritable bowel syndrome), atherosclerosis, multiple sclerosis, alzheimer's disease, vascular dementia, inflammatory diseases of the lung (including asthma, chronic obstructive pulmonary disease and acute respiratory distress syndrome), fibrotic diseases (including cystic fibrosis, idiopathic pulmonary fibrosis, myocardial fibrosis and systemic sclerosis (scleroderma)), inflammatory diseases of the skin (including contact dermatitis, chronic obstructive pulmonary fibrosis, myocardial fibrosis and systemic sclerosis (scleroderma), Atopic dermatitis and psoriasis), systemic inflammatory response syndrome, sepsis, inflammatory and/or autoimmune conditions of the liver (including autoimmune hepatitis, primary biliary cirrhosis, alcoholic liver disease, sclerosing cholangitis, and autoimmune cholangitis), diabetes (type I or type II) and/or its complications, chronic heart failure, congestive heart failure, ischemic diseases (including stroke and ischemia-reperfusion injury), or myocardial infarction and/or its complications.

19. A compound according to any one of claims 1 to 13, or a use according to claim 16, or a method according to claim 17, wherein the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease or atopic dermatitis.

20. A compound according to any one of claims 1 to 13, or the use according to claim 15, or the method according to claim 17, for use in inhibiting tumor growth.