Fused piperidinyl bicyclics and related compounds as C5a receptor modulators

Abstract

The present invention relates to fused piperidinyl bicyclic, meta-substituted piperidinyl and related compounds that modulate the activity of mammalian C5a receptors by directly binding to the C5a receptor. The present invention also relates to pharmaceutical compositions containing such compounds and their use in the treatment of diseases or conditions involving pathogenic activation of the C5a receptor.

Description

Field of the Invention

[0001] The present invention relates to fused piperidinyl bicyclic, meta-substituted piperidinyl and related compounds that modulate the activity of mammalian C5a receptors by directly binding to the C5a receptor. The present invention also relates to pharmaceutical compositions containing such compounds and their use in the treatment of diseases or conditions involving pathogenic activation of the C5a receptor. Background of the Invention

[0003] C5a generated by activation of the complement system

[0004] The complement system is an important branch of innate immunity and plays a key role in the host's defense against invading microorganisms. These functions are performed by functionally related proteins that sequentially detect, mark and remove pathogens and cells affected by pathogens. Complement proteins are mainly present in the plasma of circulating blood to exert their immune surveillance functions. These proteins are inactive in the steady state and are activated by enzyme cascades in response to infection, pathogenesis and artificial triggers such as organ transplantation.

[0005] Complement proteins are activated through three typical pathways that differ in their initial activation mechanisms. These three pathways are the classical pathway, the alternative pathway, and the lectin binding pathway. The classical pathway is activated by antibody complexes. The alternative pathway is triggered by foreign surfaces, such as certain molecules present on the membranes of microorganisms, altered host cell surfaces during injury, and artificial surfaces encountered during renal dialysis. The lectin binding pathway is triggered by the binding of mannose-binding lectin proteins or ficolin to microbial carbohydrate structures. After initiation, the progression and amplification of all three pathways utilize the same basic mechanism, which involves a cascade of enzymatic cleavage of complement proteins. All three pathways converge on the formation of the C3 convertase, which results in the hydrolysis of the C3 protein into the biologically active fragments C3a and C3b, which in turn leads to the cleavage of C5 [1].

[0006] C5 is a 190 kDa protein containing an α chain (~120 kDa) and a β chain (~75 kDa). Enzymatic cleavage of the N-terminus of the α chain produces C5a. Human C5a is a 74-amino acid globular protein containing a core structure and a flexible C-terminus. The sugar chain conjugated to the Asn residue at position 64 has a highly variable structure, resulting in a molecular weight of human C5a ranging from 10 kDa to 15 kDa.

[0007] In addition to C5a, proteolysis of C5 also produces C5b, which subsequently forms C5b-9 (MAC, membrane attack complex) with other complement components. C3a, C5a and MAC are the terminal effectors of complement activation. MAC forms transcellular membrane channels on pathogens or damaged host cells to cause cell lysis. Due to their strong pro-inflammatory effects, C3a and C5a are considered anaphylatoxins, with C5a being much more potent than C3a.

[0008] C5a Function

[0009] C5a is a key driver of the rapid innate immune response to infection and injury. C5a induces the release of histamine and TNF-α. C5a activates granulocytes. In particular, C5a stimulates a range of neutrophil activities. At lower concentrations, C5a is a potent chemotactic factor for neutrophils. At higher concentrations, C5a induces the release of granzymes, which generate oxidants by triggering an oxidative burst. C5a stimulates the production and release of proinflammatory cytokines, which in turn cause vasodilation, increase vascular permeability and further enhance neutrophil extravasation. Neutrophils are a double-edged sword. On the one hand, they defend against infection; on the other hand, when there is excessive activity of C5a, they directly cause acute or chronic tissue damage.

[0010] C5a also plays a role in the complex regulation of acquired immunity. C5a participates in the interaction between antigen presenting cells and T cells. C5a can regulate T cell differentiation, survival and proliferation. For example, C5a-mediated activation and differentiation of Th-17 cells and IL-17 production have been proposed as the underlying mechanisms of some autoimmune diseases [2].

[0011] C5a function is largely mediated by C5a receptor 1

[0012] C5a exerts its functions through its cognate receptors, C5a receptor 1 (C5aR1) and the later identified C5a receptor-like 2 (C5aR2). Both receptors consist of seven helical transmembrane domains and share approximately 35% primary sequence homology. C5aR1 is expressed by immune cells, including granulocytes and monocytes, as well as non-myeloid immune cells, such as T cells. C5aR1 is also present in non-immune cells in many organs, such as the kidney, liver, and lung. C5aR1 is a G protein-coupled receptor and is associated with several G protein-coupled downstream signaling pathways, such as cAMP and calcium-mediated pathways. Loss-of-function approaches, including C5aR1-deficient animal models and pharmacological inhibition, have demonstrated that C5aR1 mediates multiple aspects of C5a function in various pathophysiological settings, justifying the use of C5aR1 inhibitors, such as antibodies and antagonists, in the development and clinical use of drugs targeting C5a-related disorders [3].

[0013] C5aR2 is concentrated inside cells and on cell membranes. Since C5aR2 is not associated with G proteins, it has been considered a non-functional decoy receptor in the past and has therefore received much less attention than C5aR1. However, accumulating experimental observations have shown that C5aR2 may have both pro-inflammatory and anti-inflammatory effects, depending on the biological context.

[0014] The C5a-C5aR1 axis is a promising therapeutic target for various pathologies.

[0015] C5a has been implicated in a wide variety of diseases, including but not limited to: kidney-related disorders, cardiovascular disorders, respiratory diseases, skin disorders, arthritis, neurodegenerative disorders (Alzheimer's disease, dementia), ischemia-reperfusion injury, multiple sclerosis, transplant rejection, age-related macular degeneration, neutrophilic dermatoses, and cancer. In line with this view, preclinical and clinical data have highlighted the potential benefits of inhibiting the C5a-C5aR1 interaction in several disease states [4-7].

[0016] Targeting C5a or C5a receptors vs targeting C5 or C3.

[0017] In principle, there are several ways to block pathogenic C5a function. This can be done by directly neutralizing C5a, such as with anti-C5a antibodies, or by blocking C5aR1 inhibitors. It can also be done by inhibiting C5 cleavage to block C5a generation, which can be achieved by targeting C5 itself or its upstream activators such as C3. However, blocking C5a function by targeting its upstream complement molecules is inherently confounded by the existence of the extrinsic pathway. The extrinsic pathway refers to pathways other than the three classic pathways that lead to C5 cleavage and subsequent C5a generation. The extrinsic pathway utilizes a range of proteases outside the complement sphere. These proteases include those released by microorganisms, associated with the coagulation cascade, or activated during inflammatory responses and tissue damage [8].

[0018] Therefore, approaches targeting C3 or C5 do not block C5 cleavage via the extrinsic pathway and therefore do not completely block C5a generation, which may result in impaired therapeutic efficacy.

[0019] In addition, targeting C5a or C5a receptors has other potential clinical benefits compared to targeting C5 and C3. For example, inhibiting C5 or C3 not only blocks C5a but also blocks C5b and subsequent MAC formation. Targeting C5a or C5a receptors, however, leaves MAC generation intact, which may be an advantage because MAC plays an important role in the maintenance of homeostasis in vivo through its microbicidal and tumoricidal effects. Clinical interventions targeting C5a or C5a receptors may carry less risk of infectious complications than interventions targeting C5 or C3.

[0020] The technical problem on which the present invention is based

[0021] As explained above, the C5a-C5aR1 axis is a promising therapeutic target for the treatment of various disorders.The inventors have now been able to prepare novel compounds that directly target the C5a receptor, thereby avoiding the disadvantages associated with targeting C5 or C3.

[0022] The present invention describes the synthesis and biological efficacy of novel C5aR1 modulators. The compounds of the present invention exhibit high binding affinity to the C5a receptor and thus high blocking activity on C5a-mediated physiological effects. SUMMARY OF THE INVENTION

[0024] In a first aspect, the present invention relates to a compound having the general formula (XXI)

[0025]

[0026] and pharmaceutically acceptable salts, hydrates and rotamers thereof;

[0027] in

[0028] C 1 is selected from aryl and heteroaryl, wherein the heteroaryl has 1 to 3 heteroatoms selected from N, O and S as ring members; and wherein the aryl and heteroaryl are optionally substituted by 1 to 3 R 1 Substituent substitution;

[0029] C 2 is selected from aryl and heteroaryl, wherein the heteroaryl has 1 to 3 heteroatoms selected from N, O and S as ring members; and wherein the aryl and heteroaryl are optionally substituted by 1 to 3 R 2 Substituent substitution;

[0030] C 3 Selected from C 1-8 Alkyl or heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, heterocycloalkyl or heterocycloalkyl-C 1-4 wherein the heteroalkyl group or moiety has 1-3 heteroatoms selected from N, O and S, wherein the heterocycloalkyl group or moiety has 1-3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has 1-3 heteroatoms selected from N, O and S as ring members, and each C 3 Optional 1 to 3 R 3 Substituent substitution;

[0031] Each R 1 are independently selected from halogen, -CN, -R c、-CO2R a 、-CONR a R b 、-C(O)R a 、-OC(O)NR a R b 、-NR b C(O)R a 、-NR b C(O)2R c 、-NR a -C(O)NR a R b 、-NR a C(O)NR a R b 、-NR a R b 、-OR a and -S(O)2NR a R b ; Each R a and R b are independently selected from hydrogen, C 1-8 Alkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom, may be combined with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms selected from N, O or S as ring members, and is optionally substituted by one or two oxo groups; each R c Independently selected from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein R a , R b and R c The aliphatic and / or cyclic part is optionally further substituted by 1 to 3 halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino; and optionally when two R 1 When the substituents are on adjacent atoms, they combine to form a fused five- or six-membered carbocyclic or heterocyclic ring;

[0032] Each R 2 independently selected from halogen, -CN, -NO2, -R f 、-CO2R d 、-CONR d R e 、-C(O)R d 、-OC(O)NR d R e 、-NR e C(O)R d 、-NR e C(O)2R f 、-NRd C(O)NR d R e 、-NR d R e 、-OR d and -S(O)2NR d R e ; Each R d and R e are independently selected from hydrogen, C 1-8 Alkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom, may be combined with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms selected from N, O or S as ring members, and is optionally substituted by one or two oxo groups; each R f Independently selected from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein R d , R e and R f The aliphatic and / or cyclic part is optionally further substituted by 1 to 3 halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups, and optionally when two R 2 When the groups are on adjacent atoms, they combine to form a five- or six-membered ring;

[0033] Each R 3 are independently selected from halogen, -CN, -R i 、-CO2R g 、-CONR g R h 、-C(O)R g 、-C(O)R i 、-OC(O)NR g R h 、-NR h C(O)R g 、-NR h CO2R i 、-NR g C(O)NR g R h 、-NR g R h 、-OR g 、-OR j 、-S(O)2NR g R h , -X 4 -R j 、-NH-X 4 -R j 、-OX 4 -Rj , -X 4 -NR g R h , -X 4 -NHR j , -X 4 -CONR g R h , -X 4 -NR h C(O)R g , -X 4 -CO2R g 、-OX 4 -CO2R g 、-NH-X 4 -CO2R g , -X 4 -NR h CO2R i 、-OX 4 -NR h CO2R i 、-NHR j and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h are independently selected from hydrogen, C 1-8 Alkyl or heteroalkyl, C 3-6 Cycloalkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom, may be combined with the nitrogen atom to form a four-, five- or six-membered ring having 0 to 2 further heteroatoms selected from N, O or S as ring members and optionally substituted by one or two oxo groups; and each R i Independently selected from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each R j Selected from C 3-6 cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinyl, pyrrolyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and S,S-dioxo-tetrahydrothiopyranyl, and wherein R g , R h , R i and R j The aliphatic and / or cyclic part is optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -C(O)OC 1-8alkyl, amino, alkylamino and dialkylamino, and optionally when two R 3 When the groups are on adjacent atoms, they combine to form a five- or six-membered ring;

[0034] X is hydrogen or CH3; and

[0035] R 8 and R 9 are independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 alkoxy, or R 8 and R 9 Combined to form a fused saturated or unsaturated monocyclic or polycyclic carbocyclic ring, wherein one or more ring carbon atoms may be replaced independently of each other by N, S or O,

[0036] The condition is R 8 and R 9 At least one of them is not hydrogen.

[0037] In a second aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to the first aspect.

[0038] In a third aspect, the invention relates to a compound according to the first aspect for use in medicine.

[0039] In a fourth aspect, the invention relates to a compound according to the first aspect for use in the treatment of a disease or disorder involving pathogenic activation of the C5a receptor.

[0040] This summary of the invention does not necessarily describe all features of the invention. Other embodiments will become apparent upon examination of the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 . General Synthetic Schemes of Compounds of the Invention. In general, compounds according to the invention are prepared by the general synthetic methods outlined in Scheme A.

[0043] Figure 2 . General synthetic schemes for compounds according to formula (I). In general, compounds according to formula (I) are prepared by the general synthetic methods outlined in Scheme A or Scheme B. DETAILED DESCRIPTION OF THE INVENTION

[0045] definition

[0046] Before describing the present invention in detail below, it is to be understood that the present invention is not limited to the specific methods, procedures and reagents described herein, as these are variable. It is also to be understood that the terms used herein are only used to describe specific embodiments and are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0047] Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, HGW, Nagel, B. and Kölbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland.

[0048] In this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising", will be understood to mean the inclusion of a specified integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0049] Several documents (e.g., patents, patent applications, scientific publications, manufacturer's specifications, instructions, GenBank Accession Number sequence submissions, etc.) are referenced throughout the text of this specification. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. Some of the documents cited herein are characterized as " Incorporated by reference ” In the event of a conflict between definitions or teachings in these incorporated references and definitions or teachings set forth in this specification, the text of this specification shall prevail.

[0050] In the context of the present invention, C5a refers in particular to human C5a. The amino acid sequence of human C5 (CO5_HUMAN) can be found in accession number UniProtKB P01031.

[0051] In the context of the present invention, the expression "C5a receptor" refers to any potential C5a binding ligand on the cell surface, in particular to any receptor protein to which C5a can bind and cause a response on the receptor (e.g., activation or inhibition of the receptor). The term "C5a receptor" particularly encompasses two receptors, C5aR and C5L2. Other names for C5aR are C5aR1 and CD88. Another name for C5L2 is C5aR2. Certain embodiments of the present invention relate to compounds that modulate the activity of the C5a receptor (e.g., by binding to the C5a receptor). In these contexts, the term "C5a receptor" may refer to (i) C5aR or to (ii) C5L2 or to (iii) C5aR and C5L2. This means that some compounds modulate the activity of only one C5a receptor (i.e., C5aR or C5L2), while other compounds modulate the activity of both C5a receptors (i.e., C5aR and C5L2).

[0052] As used herein, a first compound (e.g., a compound of the present invention) is considered to be a compound if it has an OD of 1 mM or less, preferably 100 μM or less, preferably 50 μM or less, preferably 30 μM or less, preferably 20 μM or less, preferably 10 μM or less, preferably 5 μM or less, more preferably 1 μM or less, more preferably 900 nM or less, more preferably 800 nM or less, more preferably 700 nM or less, more preferably 600 nM or less, more preferably 500 nM or less, more preferably 400 nM or less, more preferably 300 nM or less, more preferably 200 nM or less, still more preferably 100 nM or less, still more preferably 90 nM or less, still more preferably 80 nM or less, still more preferably 70 nM or less, still more preferably 60 nM or less, still more preferably 50 nM or less, still more preferably 40 nM or less, still more preferably 30 nM or less, still more preferably 20 nM or less, still more preferably 100 nM or less, still more preferably 90 nM or less, still more preferably 80 nM or less, still more preferably 70 nM or less, still more preferably 60 nM or less, still more preferably 50 nM or less, still more preferably 40 nM or less, still more preferably 30 nM or less, still more preferably 20 nM or less, still more preferably 10 Dissociation constant K with a second compound (e.g., target protein) of nM or less d , which is said to be "bound" to the second compound.

[0053] The term "binding" according to the present invention preferably refers to specific binding. "Specific binding" means that a compound (e.g. a protein ligand or a nucleic acid aptamer) binds more strongly to its specific target (e.g. a target protein or a target epitope) than to another target. If the dissociation constant (K d ) is lower than the dissociation constant for the second target, then the compound binds more strongly to the first target than to the second target. Preferably, the dissociation constant (K) for the target to which the compound specifically binds is d ) is the dissociation constant (K) for the target nonspecifically bound to the compound d) is less than 1 / 10, preferably less than 1 / 20, more preferably less than 1 / 50, and even more preferably less than 1 / 100, 1 / 200, 1 / 500 or 1 / 1000.

[0054] The term "K d ” (usually measured in “mol / L” and sometimes abbreviated as “M”) is intended to represent the dissociation equilibrium constant for a particular interaction between a compound (eg, a compound of the invention) and a target molecule.

[0055] Used to determine the binding affinity of a compound, i.e., to determine the dissociation constant K d The methods for determining the dissociation constant K are known to those of ordinary skill in the art and can be selected, for example, from the following methods known in the art: techniques based on surface plasmon resonance (SPR), biolayer interferometry (BLI), enzyme-linked immunosorbent assay (ELISA), flow cytometry, isothermal titration calorimetry (ITC), analytical ultracentrifugation, radioimmunoassay (RIA or IRMA) and enhanced chemiluminescence (ECL). Typically, the dissociation constant K is determined at 20°C, 25°C, 30°C or 37°C. d If not otherwise specified, the K d The values ​​were determined by SPR at 20 °C.

[0056] As used herein, the term "naturally occurring" when applied to an object refers to the fact that an object can be found in nature. For example, a polypeptide or polynucleotide sequence present in an organism (including viruses) that can be isolated from a source in nature and has not been intentionally modified by man in the laboratory is naturally occurring.

[0057] As used herein, "patient" refers to any mammal or bird that can benefit from treatment with a compound described herein (i.e., with an inhibitor of C5a receptor activity described herein). Preferably, the "patient" is selected from experimental animals (e.g., mice or rats), domestic animals (including, for example, guinea pigs, rabbits, chickens, turkeys, pigs, sheep, goats, camels, cows, horses, donkeys, cats or dogs) or primates, including monkeys and apes (e.g., African green monkeys, chimpanzees, bonobos, gorillas) and humans. The "patient" is particularly preferably a human. The terms "patient" and "subject to be treated" (or simply "subject") are used interchangeably herein.

[0058] As used herein, "treating" or "treatment" of a disease or condition means achieving one or more of the following: (a) lessening the severity and / or reducing the duration of the condition; (b) limiting or preventing the development of symptoms characteristic of the condition being treated; (c) inhibiting the worsening of symptoms characteristic of the condition being treated; (d) limiting or preventing the recurrence of the condition in a patient who previously had the condition; and (e) limiting or preventing the recurrence of symptoms in a patient who previously had symptoms of the condition.

[0059] As used herein, "prevention" or "prevention" of a disease or condition refers to preventing a subject from developing a condition for a certain amount of time. For example, if a compound of the present invention (or a pharmaceutical composition comprising the compound) is administered to a subject for the purpose of preventing a disease or condition, the disease or condition is prevented from occurring at least on the day of administration and preferably also on one or more days (e.g., 1 to 30 days; or 2 to 28 days; or 3 to 21 days; or 4 to 14 days; or 5 to 10 days) after the day of administration.

[0060] As used herein, "administration" includes in vivo administration, as well as direct administration to ex vivo tissue, such as a vein graft.

[0061] The "pharmaceutical composition" according to the present invention may be in the form of a composition in which different active ingredients and diluents and / or carriers are mixed with each other, or may be in the form of a combined preparation in which the active ingredients are present in a partially or completely separated form. An example of such a combination or combined preparation is a kit-of-parts.

[0062] An "effective amount" is an amount of a therapeutic agent sufficient to achieve the intended purpose. The effective amount of a given therapeutic agent varies with factors such as the nature of the agent, the route of administration, the size and species of the animal to receive the therapeutic agent, and the purpose of the administration. The effective amount in each individual case can be determined empirically by a skilled artisan according to established methods in the art.

[0063] Unless otherwise indicated, the term "alkyl", alone or as part of another substituent, refers to a straight or branched hydrocarbon group having a specified number of carbon atoms (i.e., C1-C8 refers to 1 to 8 carbons). The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. The term "cycloalkyl" refers to a hydrocarbon ring having the number of ring atoms shown (e.g., C3-6 cycloalkyl) and being fully saturated or having no more than 1 double bond between the ring vertices. "Cycloalkyl" is also intended to represent a bicyclic or polycyclic hydrocarbon ring. The term "heterocycloalkyl" refers to a cycloalkyl group containing 1 to 5 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heterocycloalkyl group can be a monocyclic, bicyclic or polycyclic ring system. The heterocycloalkyl group can be connected to the rest of the molecule via a ring carbon or heteroatom.

[0064] The term "alkylene", alone or as part of another substituent, refers to a divalent group derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. "Lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, typically having 4 or fewer carbon atoms. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double or triple bonds, respectively.

[0065] The term "heteroalkyl", alone or in combination with another term, refers to a stable straight or branched chain or cyclic hydrocarbon radical consisting of the specified number of carbon atoms and 1 to 3 heteroatoms selected from O, N and S, or a combination thereof, and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatoms O, N and S may be located at any interior position of the heteroalkyl radical. Similarly, the terms "heteroalkenyl" and "heteroalkynyl", alone or in combination with another term, refer to alkenyl or alkynyl radicals, respectively, containing the specified number of carbons and having 1 to 3 heteroatoms selected from O, N and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, unless otherwise indicated. The heteroatoms O, N and S may be located at any interior position of the heteroalkyl radical.

[0066] The term "heteroalkylene", by itself or as part of another substituent, refers to a divalent radical, saturated or unsaturated or polyunsaturated, derived from a heteroalkyl group. For heteroalkylene, heteroatoms may also occupy either or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.).

[0067] The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl moieties may be the same or different and may also be combined with the nitrogen atom to which they are attached to form a 3-7 membered ring.

[0068] Unless otherwise indicated, the term "halo" or "halogen", alone or as part of another substituent, refers to a fluorine, chlorine, bromine or iodine atom. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-4 haloalkyl" is intended to include trifluoromethyl and the like.

[0069] Unless otherwise indicated, the term "aryl" refers to a polyunsaturated, usually aromatic hydrocarbon group, which can be a single ring or multiple rings (up to 3 rings) fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group can be connected to the rest of the molecule via a heteroatom. Non-limiting examples of aryl include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl include quinolinyl, quinolyl, isoquinolinyl, etc. The substituents of each of the above-mentioned aryl and heteroaryl ring systems are selected from the following acceptable substituents.

[0070] For brevity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is intended to include those groups in which an aryl group is attached to an alkyl group.

[0071] The above terms (e.g., "alkyl," "aryl," and "heteroaryl") include, in some embodiments, substituted and unsubstituted forms of the indicated groups. Preferred substituents for each type of group are provided below. For brevity, the terms aryl and heteroaryl refer to substituted or unsubstituted forms as provided below, while the term "alkyl" and related aliphatic groups are intended to represent the unsubstituted form unless substitution is indicated.

[0072] Substituents for alkyl groups (including those groups commonly referred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be various groups selected from: -halogen, -OR', -NR'R", -SR', -OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN and -NO2, in an amount ranging from 0 to (2m'+1), where m' is the total number of carbon atoms in such groups. R', R" and R'" each independently refer to hydrogen, unsubstituted C 1-6 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1 to 3 halogens, unsubstituted C 1-6 Alkyl, C 1-8 Alkoxy or C 1-6 Alkylthio, or unsubstituted aryl-C 1-4Alkyl. When R' and R" are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. The term "acyl" used alone or as part of another group refers to an alkyl group in which both substituents on the carbon closest to the point of attachment of the group are replaced by substituents =0.

[0073] Similarly, substituents for aryl and heteroaryl groups vary and are typically selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R"', -NH- C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, in an amount from 0 to the total number of open valences on the aromatic ring system; and wherein R', R" and R'" are independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-8 Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Alkyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom via an alkylene tether of 1 to 4 carbon atoms.

[0074] Two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally replaced by groups of the formula -TC(O)-(CH2) q -U-, wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -A-(CH2) r -B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 3. One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a substituent of the formula -(CH2) s -X-(CH2) twherein s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2- or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C 1-6 alkyl.

[0075] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), and sulfur (S).

[0076] As used herein, the term "CYCLE" refers to a saturated or unsaturated monocyclic or polycyclic carbocyclic ring, wherein one or more (e.g., 1, 2, 3, or 4) ring carbon atoms may be independently replaced by N, S, or O. The term "CYCLE" refers to fully saturated and unsaturated ring systems as well as partially unsaturated ring systems and is intended to include all possible isomeric forms of the carbocyclic ring (e.g., pyrrolyl includes 1H-pyrrolyl and 2H-pyrrolyl). - Examples of CYCLE being a monocyclic or bicyclic aromatic group include phenyl and naphthyl. Examples of CYCLE being a monocyclic or bicyclic cycloalkyl group include, but are not limited to, cyclopentyl and cyclohexyl. Examples of CYCLE being a monocyclic or bicyclic saturated heterocycle include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like. Examples of partially saturated heterocycles in which CYCLE is a monocyclic, bicyclic or tricyclic group include, but are not limited to, pyrrolinyl, imidazolinyl, pyrazolinyl, and the like. Examples of aromatic heterocycles in which CYCLE is a monocyclic, bicyclic or tricyclic group include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, and the like.

[0077] Throughout this specification, indices are used to distinguish different substituents in the compounds of the present invention. These indices are used as superscript numbers or as subscript numbers without indicating any specific meaning for the use of superscripts or subscripts. In other words, superscript indices and subscript indices can be used interchangeably. For example, formulas (I), (XI) and (XXI) all contain substituents C1, C2 and C3. In some formulas and reaction schemes, these substituents are shown as C1, C2 and C3; in other formulas and reaction schemes, these substituents are shown as C1, C2 and C3. 1 , C 2 and C 3 But C 1 and C1 are the same substituents; C 2 and C2 are the same substituents; and C 3 and C3 are the same substituents.

[0078] "Pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0079] The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending upon the particular substituents present on the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferrous, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and those derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galactunoronic acid (see, e.g., Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain basic and acidic functional groups so that the compounds can be converted into base addition salts or acid addition salts.

[0080] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of the present invention.

[0081] In addition to the salt form, the present invention also provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are those compounds that are susceptible to chemical changes under physiological conditions to provide compounds of the present invention. In addition, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted into compounds of the present invention when placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent.

[0082] Some compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally speaking, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of the present invention. Some compounds of the present invention may exist in a variety of crystalline or amorphous forms. Generally speaking, all physical forms are equivalent to the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0083] Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) are intended to be encompassed within the scope of the invention. The compounds of the invention may also contain unnatural proportions of atomic isotopes (e.g., 2 H (i.e. deuterium, D) instead 1 H). The compound can also be used with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Radiolabeled. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0084] Embodiments of the present invention

[0085] The present invention is now further described. Different aspects of the present invention are defined in more detail in the following paragraphs. Each aspect defined below can be combined with any other aspect, unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous can be combined with any other feature indicated as being preferred or advantageous.

[0086] In a first aspect, the present invention relates to a compound having the general formula (XXI)

[0087]

[0088] and pharmaceutically acceptable salts, hydrates and rotamers thereof;

[0089] in

[0090] C 1is selected from aryl and heteroaryl, wherein the heteroaryl has 1 to 3 heteroatoms selected from N, O and S as ring members; and wherein the aryl and heteroaryl are optionally substituted by 1 to 3 R 1 Substituent substitution;

[0091] C 2 is selected from aryl and heteroaryl, wherein the heteroaryl has 1 to 3 heteroatoms selected from N, O and S as ring members; and wherein the aryl and heteroaryl are optionally substituted by 1 to 3 R 2 Substituent substitution;

[0092] C 3 Selected from C 1-8 Alkyl or heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-4 Alkyl, Aryl, Aryl-C 1-4 Alkyl, Heteroaryl, Heteroaryl-C 1-4 Alkyl, heterocycloalkyl or heterocycloalkyl-C 1-4 wherein the heteroalkyl group or moiety has 1-3 heteroatoms selected from N, O and S, wherein the heterocycloalkyl group or moiety has 1-3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has 1-3 heteroatoms selected from N, O and S as ring members, and each C 3 Optional 1 to 3 R 3 Substituent substitution;

[0093] Each R 1 are independently selected from halogen, -CN, -R c 、-CO2R a 、-CONR a R b 、-C(O)R a 、-OC(O)NR a R b 、-NR b C(O)R a 、-NR b C(O)2R c 、-NR a -C(O)NR a R b 、-NR a C(O)NR a R b 、-NR a R b 、-OR a and -S(O)2NR a R b ; Each R a and R b are independently selected from hydrogen, C 1-8Alkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom, may be combined with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms selected from N, O or S as ring members, and is optionally substituted by one or two oxo groups; each R c Independently selected from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein R a , R b and R c The aliphatic and / or cyclic part is optionally further substituted by 1 to 3 halogen, hydroxyl, methyl, amino, alkylamino and dialkylamino; and optionally when two R 1 When the substituents are on adjacent atoms, they combine to form a fused five- or six-membered carbocyclic or heterocyclic ring;

[0094] Each R 2 independently selected from halogen, -CN, -NO2, -R f 、-CO2R d 、-CONR d R e 、-C(O)R d 、-OC(O)NR d R e 、-NR e C(O)R d 、-NR e C(O)2R f 、-NR d C(O)NR d R e 、-NR d R e 、-OR d and -S(O)2NR d R e ; Each R d and R e are independently selected from hydrogen, C 1-8 Alkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom, may be combined with the nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms selected from N, O or S as ring members, and is optionally substituted by one or two oxo groups; each R f Independently selected from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein R d , R e and R fThe aliphatic and / or cyclic part is optionally further substituted by 1 to 3 halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups, and optionally when two R 2 When the groups are on adjacent atoms, they combine to form a five- or six-membered ring;

[0095] Each R 3 are independently selected from halogen, -CN, -R i 、-CO2R g 、-CONR g R h 、-C(O)R g 、-C(O)R i 、-OC(O)NR g R h 、-NR h C(O)R g 、-NR h CO2R i 、-NR g C(O)NR g R h 、-NR g R h 、-OR g 、-OR j 、-S(O)2NR g R h , -X 4 -R j 、-NH-X 4 -R j 、-OX 4 -R j , -X 4 -NR g R h , -X 4 -NHR j , -X 4 -CONR g R h , -X 4 -NR h C(O)R g , -X 4 -CO2R g 、-OX 4 -CO2R g 、-NH-X 4 -CO2R g , -X 4 -NR h CO2R i 、-OX 4 -NR h CO2R i 、-NHRj and -NHCH2R j , where X 4 It is C 1-4 Alkylene; each R g and R h are independently selected from hydrogen, C 1-8 Alkyl or heteroalkyl, C 3-6 Cycloalkyl and C 1-8 haloalkyl, or when attached to the same nitrogen atom, may be combined with the nitrogen atom to form a four-, five- or six-membered ring having 0 to 2 further heteroatoms selected from N, O or S as ring members and optionally substituted by one or two oxo groups; each R i Independently selected from C 1-8 Alkyl or heteroalkyl, C 1-8 Haloalkyl, C 3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and each R j Selected from C 3-6 cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinyl, pyrrolyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and S,S-dioxo-tetrahydrothiopyranyl, and wherein R g , R h , R i and R j The aliphatic and / or cyclic part is optionally further substituted with 1 to 3 halogen, methyl, CF3, hydroxyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -C(O)OC 1-8 alkyl, amino, alkylamino and dialkylamino, and optionally when two R 3 When the groups are on adjacent atoms, they combine to form a five- or six-membered ring;

[0096] X is hydrogen or CH3; and

[0097] R 8 and R 9 are independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl and C1-C8 alkoxy, or R 8 and R 9 Combined to form a fused saturated or unsaturated monocyclic or polycyclic carbocyclic ring, wherein one or more ring carbon atoms may be replaced independently of each other by N, S or O,

[0098] The condition is R 8 and R 9 At least one of them is not hydrogen.

[0099] In some embodiments of the first aspect, X is hydrogen.

[0100] In some embodiments of the first aspect, the compound has formula (XXIa)

[0101] .

[0102] In some embodiments of the first aspect, the compound has Formula (Ia) or Formula (XI):

[0103] or

[0104] in

[0105] X, C 1 , C 2 and C 3 As defined above;

[0106] R in formula (XI) 8 As defined above [This means that R 8 Selected from halogen, C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl and C 1 -C 8 Alkoxy, because in formula (XI) R 9 is hydrogen and is therefore not explicitly shown, so that due to the above condition R 8 It cannot be hydrogen And so that R 8 and R 9 cannot combine to form a fused saturated or unsaturated monocyclic or polycyclic carbocyclic ring] ;

[0107] R 4 Selected from cyano, halogen, nitro, hydroxyl, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkyl-OH, (C1-C6)-alkyl-NR 5 R 6 , trifluoromethyl, (C1-C6) alkoxy, (C1-C6) alkylthio, phenoxy, COR 7 NR 5 R 6 , NHCO(C1-C6)alkyl, SO3H, SO2(C1-C6)alkyl and SO2NR 5 R 6 ;

[0108] R 5 and R 6are each independently selected from hydrogen, (C1-C6)alkyl and (C3-C6)cycloalkyl;

[0109] R 7 are independently hydroxy, (C1-C6) alkoxy, phenoxy or -NR 5 R 6 ;

[0110] m is 0-4; and

[0111] CYCLE is a saturated or unsaturated monocyclic or polycyclic carbocycle, wherein one or more ring carbon atoms may be replaced independently of one another by N, S or O.

[0112] In a further embodiment of the first aspect, the compound has Formula (Ia) or Formula (XIa):

[0113] or .

[0114] In some embodiments of the first aspect, CYCLE is a saturated or unsaturated monocyclic or polycyclic carbocycle, wherein 1 to 4 (preferably 1 to 3, more preferably 1 or 2, even more preferably 1) ring carbon atoms can be replaced by N, S or O independently of each other.

[0115] In some embodiments of the first aspect, the compound has formula (II):

[0116] .

[0117] In a further embodiment of the first aspect, the compound has formula (IIa):

[0118] .

[0119] In some embodiments of the first aspect, the compound has a formula selected from (IIIa), (IIIb), (IIIc), and (IIId):

[0120]

[0121] and .

[0122] In further embodiments, the integer m is 0. In these embodiments, the substituent R is absent. 4 .

[0123] In a further embodiment of the first aspect, the compound has a formula selected from (IIIe), (IIIf), (IIIg) and (IIIh):

[0124] and .

[0125] In further embodiments, the integer m is 0, i.e., in these embodiments, the substituent R is absent. 4 .

[0126] In some embodiments of the first aspect, C 1 yes

[0127]

[0128] in

[0129] R 1 As defined above, and

[0130] n is an integer selected from 0, 1, 2 or 3, preferably 2.

[0131] In a further embodiment, each R 1 independently selected from -OH, halogen, C 1-6 Alkyl, hydroxyl (C 1-6 ) alkyl and halogen (C 1-6 In a preferred embodiment, each R 1 Independently selected from -OH, chloro, methyl, -CH2-OH and CF3.

[0132] In some embodiments of the first aspect, C 2 yes

[0133]

[0134] in

[0135] R 2 As defined above, and

[0136] o is an integer selected from 0, 1, 2 or 3.

[0137] In a further embodiment, each R 2 Independently selected from C 1-6 In a preferred embodiment, each R 2 Independently selected from methyl, fluoro and chloro.

[0138] In some embodiments of the first aspect, C 3 yes

[0139]

[0140] in

[0141] R 3 As defined above, and

[0142] p is an integer selected from 0, 1, 2 or 3.

[0143] In a preferred embodiment, p is 1 and R 3 It is C 1- C8 hydroxyalkyl (preferably hydroxypentyl), C1-C8 hydroxyalkoxy (preferably hydroxybutoxy) or NHR as defined above j In a further preferred embodiment, R j is selected from C1-C8 alkyl, C1-C8 hydroxyalkyl, C3-C6 cycloalkyl and tetrahydropyranyl. j Selected from isopropyl, hydroxybutyl, cyclobutyl, cyclopentyl and tetrahydropyranyl.

[0144] In some embodiments of the first aspect, R8 is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy. In preferred embodiments, R8 is selected from fluorine, chlorine, methyl, trifluoromethyl and methoxy.

[0145] In some embodiments of the first aspect, the compound is selected from INF004, INF011, INF014, INF015, INF022, INF023, INF024, INF025, INF030, INF033, INF034, INF035, INF038, INF039, INF040, INF041, INF045, INF046, INF047, INF048, INF049, INF050, INF051, INF052, INF053, INF055, INF056, INF058, INF067, INF068, INF069, INF070, INF071, INF072, INF075, INF077 and INF080. The structural formulas and chemical names of these compounds are shown below in section "C. Results" of the Examples section.

[0146] Preferably, the compound according to the first aspect of the present invention is in the Ca 2+ Flow detection (Ca 2+ mobilization assay) with an IC of 1 µM or less 50 .Ca 2+ Flow detection is well known in the art. Preferred Ca 2+ Flow assays use human mononuclear cells, such as U-937 (ATCC® CRL-1593.2 TM ). Suitable for determination of IC 50 Ca 2+ Flow detection is described in the Examples. Preferably, the compound is in the Ca2+ The IC values ​​of the present invention are 500 nM or less, more preferably 200 nM or less, and even more preferably 100 nM or less in a flow assay. 50 .

[0147] In a second aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to the first aspect.

[0148] In some embodiments of the second aspect, the pharmaceutical composition further comprises one or more pharmaceutically acceptable diluents, excipients, fillers, binders, lubricants, glidants, disintegrants, adsorbents and / or preservatives.

[0149] In a third aspect, the invention relates to a compound according to the first aspect for use in medicine.

[0150] In a fourth aspect, the invention relates to a compound according to the first aspect for use in the treatment of a disease or disorder involving pathogenic activation of the C5a receptor.

[0151] In other words, the fourth aspect of the present invention relates to the use of a compound according to the first aspect for the preparation of a pharmaceutical composition for the treatment of a disease or disorder involving pathogenic activation of the C5a receptor.

[0152] In other words, the fourth aspect of the present invention relates to a method of treating a disease or condition involving pathogenic activation of the C5a receptor, wherein said method comprises the step of administering a therapeutic amount of a compound according to the first aspect to a subject in need of such treatment.

[0153] In some embodiments of the fourth aspect, the disease or disorder involving pathogenic activation of the C5a receptor is selected from

[0154] - Autoimmune disorders,

[0155] - Inflammatory disorders or related conditions,

[0156] - cardiovascular or cerebrovascular disease,

[0157] - HIV infection or AIDS,

[0158] - Neurodegenerative disorders or related diseases, and

[0159] - Cancer or precancerous conditions.

[0160] Pharmaceutical composition and mode of administration

[0161] In the practice of any aspect of the present invention, the compound described herein or a pharmaceutical composition comprising the compound can be administered to a patient by any route established in the art to provide a sufficient amount of the compound to the patient. It can be administered systemically or topically. Such administration can be parenteral, transmucosal, such as oral, nasal, rectal, intravaginal, sublingual, submucosal, transdermal or by inhalation. Preferably, administration is parenteral, such as by intravenous or intraperitoneal injection, and also includes but is not limited to intra-arterial, intramuscular, intradermal and subcutaneous administration. If the compound described herein or a pharmaceutical composition comprising the compound is administered topically, it can be directly injected into the organ or tissue to be treated.

[0162] Pharmaceutical compositions suitable for oral administration may be provided as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids); as edible foams or whips; or as emulsions. Tablets or hard gelatin capsules may contain lactose, starch or its derivatives, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, stearic acid or its salts. Soft gelatin capsules may contain vegetable oils, waxes, fats, semisolid or liquid polyols, etc. Solutions and syrups may contain water, polyols and sugars.

[0163] Active agents intended for oral administration may be coated or mixed with materials that delay disintegration and / or absorption of the active agent in the gastrointestinal tract (e.g., glyceryl monostearate or glyceryl distearate may be used). Thus, sustained release of the active agent may be achieved over many hours and, if necessary, may be prevented from degradation in the stomach. Pharmaceutical compositions for oral administration may be formulated to promote release of the active agent at specific gastrointestinal locations due to specific pH or enzyme conditions.

[0164] Pharmaceutical compositions suitable for transdermal administration can be provided as independent patches intended to maintain close contact with the epidermis of the recipient for a long period of time. Pharmaceutical compositions suitable for topical administration can be provided as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For topical administration to the skin, oral cavity, eyes or other external tissues, topical ointments or creams are preferably used. When formulated as an ointment, the active ingredient can be used together with a paraffin-type or water-miscible ointment base. Alternatively, the active ingredient can be formulated in an emulsion with an oil-in-water base or an oil-in-water base. Pharmaceutical compositions suitable for topical administration to the eyes include eye drops. In these compositions, the active ingredient can be dissolved or suspended in a suitable carrier, such as an aqueous solvent. Pharmaceutical compositions suitable for topical administration in the oral cavity include lozenges, pastilles and mouthwashes.

[0165] Pharmaceutical compositions suitable for nasal administration may include a solid carrier, such as a powder (preferably having a particle size of 20 to 500 microns). Powders can be administered by sniffing, i.e., by rapid inhalation through the nose from a powder container placed near the nose. Alternatively, compositions suitable for nasal administration may include a liquid carrier, such as a nasal spray or nasal drops. These compositions may include aqueous or oily solutions of the active ingredient. Compositions for inhalation administration may be supplied in specially adapted devices, including but not limited to pressurized sprayers, nebulizers, or insufflators, which may be configured to provide a predetermined dose of the active ingredient. Pharmaceutical compositions may also be administered to the lungs through the nasal cavity.

[0166] Pharmaceutical compositions suitable for rectal administration may be provided as suppositories or enemas. Pharmaceutical compositions suitable for vaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0167] The pharmaceutical composition that is suitable for parenteral administration comprises aqueous and non-aqueous sterile injection solution or suspension, and it can contain antioxidant, buffer, antibacterial agent and solute so that said composition is substantially isotonic with the blood of expected recipient.Other components that may be present in such composition comprise for example water, alcohol, polyol, glycerine and vegetable oil.The composition that is suitable for parenteral administration can be present in single dose or multi-dose container, for example in sealed ampoule and vial, and can be stored with freeze drying (lyophilization) state, only need to add sterile liquid carrier before using, for example sterile saline solution for injection.Extemporary injection solution and suspension can be prepared by sterile powder, granule and tablet.

[0168] In a preferred embodiment, the compounds described herein are formulated according to conventional procedures as pharmaceutical compositions suitable for intravenous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffers. If necessary, the composition may also include a solubilizer and a local anesthetic such as lidocaine to relieve pain at the injection site. Typically, these components are supplied separately or mixed together in a unit dosage form, for example as a lyophilized powder or anhydrous concentrate in an airtight sealed container such as an ampoule or sachette indicating the amount of active agent. If the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. If the composition is administered by injection, an ampoule of sterile saline may be provided to mix these components before administration.

[0169] In another embodiment, for example, a compound described herein or a pharmaceutical composition comprising the compound can be delivered in a controlled release system. For example, the compound can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In one embodiment, a pump (see Sefton (1987) CRC Crit. Ref. Biomed. Eng. 14: 201; Buchwald et al. (1980) Surgery 88:507; Saudek et al. (1989) N. Eng. J. Med. 321: 574). In another embodiment, the compound may be delivered in a vesicle, particularly a liposome (see Langer (1990) Science 249:1527-1533; Treat et al. (1989), Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, NY, 353-365; WO 91 / 04014; US 4,704,355). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release (1974) Langer and Wise (eds.), CRC Press: Boca Raton, Fla.; Controlled Drug Bioavailability, Drug Product Design and Performance, (1984) Smolen and Ball (eds.), Wiley: NY; Ranger and Peppas (1953) J. Macromol. Sci. Rev. Macromol. Chem. 23: 61; see also Levy et al. (1985) Science 228:190; During et al. (1989) Ann. Neurol. 25: 351; Howard et al. (1989) J. Neurosurg. 71: 105).

[0170] In yet another embodiment, the controlled release system can be positioned near the therapeutic target, i.e., the target cell, tissue, or organ, thereby requiring only a fraction of the systemic dose (see, e.g., Goodson (1984) 115-138, Medical Applications of Controlled Release, vol. 2). Other controlled release systems are discussed in the review by Langer (1990, Science 249: 1527-1533).

[0171] In a specific embodiment, it may be desirable to administer a compound described herein or a pharmaceutical composition comprising the compound locally to the area in need of treatment. For example and not by way of limitation, this may be achieved by local infusion during surgery, local application (e.g., in conjunction with a wound dressing after surgery), by injection, by catheter, by suppository, or by implant, the implant being a porous, non-porous or gelling material, including membranes, such as silastic™ membranes, or fibers.

[0172] The technician will determine the selection of the preferred effective dose based on consideration of several factors known to those of ordinary skill in the art. Such factors include specific forms of pharmaceutical compositions, such as polypeptides or vectors, and pharmacokinetic parameters thereof, such as bioavailability, metabolism, half-life, etc., which have been established in the common development procedures commonly used to obtain registration approval for pharmaceutical compounds. Other factors when considering dosage include the condition or disease to be prevented and / or treated or the benefit to be achieved in a normal individual, the patient's weight, route of administration, whether the administration is acute or chronic, combined medication, and other factors that are well known to affect the efficacy of the administered agent. Therefore, the precise dosage should be determined according to the judgment of the practitioner and the situation of each patient, for example, according to the condition and immune status of the individual patient, according to standard clinical techniques.

[0173] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredients are known to those skilled in the art. For examples of methods for preparing pharmaceutical compositions, see Remington: The Science and Practice of Pharmacy , Lippincott, Williams & Wilkins, 21 st ed. (2005).

[0174] In one embodiment of the invention, the compounds of the invention may also be combined with at least one additional therapeutic agent.

[0175] Description of general chemical process procedures and drawings

[0176] In general, the compounds of the present invention are prepared by the general synthetic methods outlined in Scheme A (see Figure 1 ).

[0177] Regarding route A, the corresponding acid can be coupled to the amine using a coupling agent such as HATU and a base such as diisopropylethylamine in a solvent such as dichloromethane, or using thionyl chloride and a base such as diisopropylamine. The coupling at the 2-position of the pyridine ring can be achieved using transition metal catalysis and a base such as potassium carbonate in a solvent such as DMF or aqueous toluene via a Suzuki-type coupling reaction using a suitably substituted halopyridine derivative and a suitably substituted boronic acid. Hydrogenation with a reducing agent such as hydrogen and a platinum catalyst in a solvent such as ethanol produces the desired piperidine. Absolute stereochemistry can be established by various methods, by using chiral ligands or chiral auxiliary agents, separating chiral diastereomers, using chiral raw materials or classical resolution. Acylation of piperidine can be achieved using suitably substituted acyl derivatives, wherein X can be selected from a suitable group such as OH, Cl and F, or from any group capable of activating a carbonyl group for addition of an amine (e.g., imidazole). Such coupling can be assisted by inorganic or organic bases, activators such as HBTU, and catalysts such as DMAP, HOBT, etc. The final compounds can be separated using chiral chromatography techniques such as supercritical fluid chromatography (SFC), where the mobile phase is a supercritical fluid such as carbon dioxide, with a co-solvent such as methanol, ethanol or isopropanol.

[0178] Compounds according to general formula (I) can be prepared by the general synthetic methods outlined in Schemes A or B (see Figure 2 ).

[0179] Figure 2 Route A shown in Figure 1 is almost identical to Route A shown in . However, Figure 2 The hydrogenation step in can also be carried out in solvents such as THF and methanol with a reducing agent such as sodium cyanoborohydride to produce the desired 2,3-cis-piperidine.

[0180] With respect to route B, coupling at the 2-position of the pyridine ring can be achieved via a Suzuki-type coupling reaction using an appropriately substituted halopyridine derivative and an appropriately substituted boronic acid using transition metal catalysis and a base such as sodium carbonate in a solvent such as DMF or aqueous toluene. The resulting ester is hydrolyzed with a base such as lithium hydroxide in a solvent such as aqueous THF to produce the corresponding acid, which can then be coupled with an amine using a coupling agent such as HATU and a base such as diisopropylethylamine or NMM in a solvent such as DMF. Hydrogenation with a reducing agent such as sodium cyanoborohydride in a solvent such as THF and methanol produces the desired 2,3-cis-piperidine. The absolute stereochemistry can also be established by various methods, by using chiral ligands or chiral auxiliaries, by separating chiral diastereomers, by using chiral starting materials, or by classical resolution. Acylation of the piperidine can be achieved using an appropriately substituted acyl derivative, wherein X can be selected from appropriate groups such as OH, Cl, and F, or from any group capable of activating the carbonyl group for the addition of an amine (e.g., imidazole). Such coupling can be assisted by inorganic or organic bases, activators such as HBTU, and by catalysts such as DMAP, HOBT, etc. Those skilled in the art will recognize that there are other possible combinations that will also produce the desired product. The final compounds can be separated using chiral chromatographic techniques such as supercritical fluid chromatography (SFC), wherein the mobile phase is a supercritical fluid such as carbon dioxide, containing a cosolvent such as methanol, ethanol or isopropanol. Example

[0181] The following examples are provided to illustrate but not limit the claimed invention. Compounds within the scope of the present invention can be synthesized using various reactions known to the skilled person as described below. It is also recognized by those skilled in the art that alternative methods can be used to synthesize the target compound of the present invention and the methods described herein are not exhaustive, but provide widely applicable and practical routes for obtaining related compounds. Certain molecules claimed in this patent can exist in different enantiomers and diastereoisomers, and all such variants of these compounds are claimed. The detailed description of the experimental procedures used to synthesize key compounds in this article yields molecules described by identifying their physical data and depicting structures associated with them. It is also recognized by those skilled in the art that acids and bases are often used during standard post-processing procedures. Sometimes salts of the parent compound are generated.

[0182] A. Chemical synthesis procedures

[0183] Example 1

[0184] Synthesis of (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (INF004)

[0185]

[0186] a) HATU (3.66 g, 9.63 mmol) was added to a solution of 2-chloroquinoline-3-carboxylic acid (1.00 g, 4.82 mmol), 4-methyl-3-(trifluoromethyl)aniline (1.27 g, 7.22 mmol, 1.04 mL) and NMM (1.46 g, 14.5 mmol, 1.59 mL) in DMF (10.0 mL). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL×2). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: EtOAc = 8:1~2:1) to give 2-chloro-N-(4-methyl-3-(trifluoromethyl)phenyl)quinoline-3-carboxamide (1.95 g, 4.12 mmol, 85.5% yield) as a white solid.

[0187]

[0188] b) To a mixture of compound 2-chloro-N-(4-methyl-3-(trifluoromethyl)phenyl)quinoline-3-carboxamide (550 mg, 1.51 mmol), (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (530 mg, 2.24 mmol) and K2CO3 (625 mg, 4.52 mmol) in H2O (2.00 mL) and toluene (20.0 mL) was added Pd(dppf)Cl2 (221 mg, 302 µmol). The reaction mixture was stirred at 100 °C for 10 hours. The reaction was diluted with EtOAc (200 mL) and filtered through a pad of celite. The filtrate was concentrated in vacuo to give tert-butyl (4-(3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)quinolin-2-yl)phenyl)carbamate (2.90 g, crude) as a grey solid which was used directly in the next step. LCMS: R t = 1.130min, MS+1 =522.2.

[0189] c) To a solution of tert-butyl (4-(3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)-quinolin-2-yl)phenyl)carbamate (2.20 g, 4.22 mmol) in THF (7.00 mL) and MeOH (3.50 mL) was added NaBH3CN (3.92 g, 62.4 mmol). The reaction mixture was adjusted to pH = 4-6 with 4 N HCl / dioxane and the mixture was stirred at 20 °C for 0.5 h. TLC (petroleum ether: EtOAc = 3: 1) indicated that the reaction was complete and two spots (R f = 0.6, 0.65). The reaction mixture was adjusted to pH = 7~8 with saturated NaHCO3, diluted with water (200 mL), and extracted with EtOAc (120 mL×2). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with petroleum ether: EtOAc = 10:1 (15.0 mL) at 0°C to give the cis product (350 mg, 666 µmol, 15.8% yield) as a white solid, which was used directly in the next step.

[0190] d) To a solution of the product obtained above (350 mg, 666 µmol), DIEA (522 mg, 4.04 mmol, 704 µL) and DMAP (10 mg, 81.9 µmol) in DCM (10.0 mL) and THF (2.00 mL) was added 2-fluoro-6-methylbenzoyl chloride (350 mg, 2.03 mmol) at 20°C. The reaction mixture was stirred at 20°C for 2 hours. Then more 2-fluoro-6-methylbenzoyl chloride (350 mg, 2.03 mmol) and DIEA (522 mg, 4.04 mmol, 704 µL) were added and the mixture was stirred at 20°C for another hour. LCMS showed the same as the desired compound (MS (R t = 0.996 min, MS-56+1 = 606.2)) together with ~19.0% of the cis compound (R t = 0.953 min, MS+1 = 526.1). The reaction was quenched with water (20.0 mL) and extracted with EtOAc (20.0 mL×2). The organic phase was washed with brine (50.0 mL), separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (0.1% TFA) to give the desired compound (151 mg, 33.9% yield) as a yellow solid, which was purified by HPLC R t = 2.799 min and LCMS R t= 0.996 min, MS-55 =606.0 inspection.

[0191] e) To a solution of the compound obtained in step d) (150 mg, 227 µmol) in EtOAc (2.00 mL) was added HCl / dioxane (4 M, 8.57 mL). The reaction mixture was stirred at 20-25 °C for 0.5 h. LCMS indicated that the reaction was complete and the desired MS (R t = 0.836 min, MS+1 = 562.0). The reaction was concentrated in vacuo. The residue was dissolved in water (20.0 mL), adjusted to pH = 8 with saturated NaHCO3, and extracted with EtOAc (25.0 mL×2). The organic phase was separated, washed with brine (50.0 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the desired compound (129 mg, crude) as a yellow solid, which was purified by HPLC R t = 2.134 min. and supercritical fluid chromatography (SFC) (two peaks at 1.231 and 1.521 min).

[0192] f) To a mixture of the compound obtained in step e) (60 mg, 107 µmol) and cyclopentanone (60 mg, 713 µmol, 63.2 µL) in MeOH (1.50 mL) was added AcOH (8 mg, 133 µmol, 7.62 µL). The reaction mixture was stirred at 30°C for 1 hour. Then NaBH3CN (35 mg, 557 µmol) was added and the mixture was stirred at 30°C for 1 hour. LCMS showed that the desired compound (R t = 0.893 min, MS+1 = 630.1). The reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (30.0 mL) and washed with water (50.0 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: EtOAc = 2:1) to give the desired compound (40 mg, 60.9 µmol, 57.0% yield, 95.8% purity) as a white solid, which was analyzed by HPLC R t = 2.422 min. and supercritical fluid chromatography (SFC) (two peaks at 1.780 min. and 2.581 min.).

[0193] g) The compound obtained above (60 mg, 95.29 µmol) was purified by preparative SFC (column: REGIS (s,s) WHELK-O1 (250 mm*50 mm, 10 µm); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 35%-35%, 3.3 min; 30 min) to give (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (6.38 mg, 20.8% yield, 97.8% purity) as an off-white solid. (2S,3R)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide was also produced as an off-white solid (7.49 mg, 24.4% yield, 97.8% purity).

[0194]

[0195] Example 2

[0196] Synthesis of (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (INF015)

[0197]

[0198] a) To a solution of methyl 2-chloroquinoline-3-carboxylate (25.0 g, 112 mmol) in DMF (250 mL) was added [4-(tert-butoxycarbonylamino)phenyl]boronic acid (32.0 g, 135 mmol). Then Na2CO3 (35.8 g, 338 mmol) in H2O (100 mL) was added followed by Pd(PPh3)4 (13.0 g, 11.2 mmol). The mixture was stirred at 50°C for 5 hours under N2. Then Pd(dppf)Cl2 (8.25 g, 11.2 mmol) was added. The mixture was stirred at 50°C for 5 hours. LCMS showed that a small amount of starting material remained but a new major peak was formed (R t= 0.975 min, MS+1 = 379.0). The reaction mixture was diluted with H2O (1.20 L) and extracted with EtOAc 600 mL (300 mL × 2). The combined organic layer was washed with brine 600 mL (300 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2:1). Methyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)quinoline-3-carboxylate (30.0 g, 77.6 mmol, 68.8% yield) was obtained as a yellow solid, which was confirmed by LCMS: R t = 0.973 min, MS+1 = 379.1.

[0199] b) A mixture of methyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)quinoline-3-carboxylate (24.0 g, 63.4 mmol) and LiOH•H2O (7.98 g, 190 mmol) in THF (240 mL) and H2O (100 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 15°C under N2 atmosphere for 3 hours. TLC (petroleum ether / ethyl acetate = 1:1) showed that the starting material (R f = 0.5) is completely consumed and forms a new point (R f = 0.05). The reaction mixture was adjusted to pH = 3 ~ 4 with HCl (1 M), the solid was filtered and concentrated under reduced pressure to give 2-(4-((tert-butoxycarbonyl)amino)phenyl)quinoline-3-carboxylic acid (15.7 g, 43.2 mmol, 68.1 % yield) as a white solid, which was confirmed by LCMS: R t = 0.857 min,MS+1 = 365.0.

[0200] c) To a mixture of 2-(4-((tert-butyloxycarbonyl)amino)phenyl)quinoline-3-carboxylic acid (4.50 g, 12.4 mmol), 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)aniline (5.66 g, 18.5 mmol, 2.13 mL) and DIEA (3.99 g, 30.9 mmol, 5.38 mL) in DMF (40.0 mL) was added HATU (6.10 g, 16.1 mmol). The reaction mixture was stirred at 20-30 °C for 15 h. LCMS indicated that the reaction was complete with the formation of the desired product (MS (R t= 1.036 min, MS+1 = 652.2)). The reaction mixture was poured into water (200 mL) and an off-white solid precipitated. The mixture was filtered. The filter cake was triturated with petroleum ether: EtOAc = 4: 1 (50.0 mL) to produce tert-butyl (4-(3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)quinolin-2-yl)phenyl)carbamate (6.50 g, 9.97 mmol, 80.7% yield) as an off-white solid, which was confirmed by the following: LCMS: R t = 1.036 min, MS+1 = 652.2 and

[0201] .

[0202] d) To a mixture of tert-butyl (4-(3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)quinolin-2-yl)phenyl)carbamate (6.50 g, 9.97 mmol) in THF (60 mL) and MeOH (30.0 mL) was added NaBH3CN (2.51 g, 39.9 mmol) at 15°C. The mixture was adjusted to pH = 5-6 with HCl / dioxane (4 M). The mixture was stirred at 15-30°C for 1 hour. TLC (petroleum ether: EtOAc = 3: 1) indicated that the reaction was complete and two spots (R f = 0.7 and 0.6). The reaction mixture was adjusted to pH = 8~9 with saturated NaHCO3 and then concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (200 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with petroleum ether: EtOAc = 6: 1 (70 mL) to give the desired cis compound (4.20 g, 5.89 mmol, 59.1% yield) as an off-white solid.

[0203]

[0204]

[0205] g) To a mixture of 2-fluoro-6-methylbenzoyl chloride (1.05 g, 6.10 mmol, 336 µL) in DCM (5.00 mL) was added a solution of the compound obtained above in step d) (800 mg, 1.22 mmol), DMAP (45 mg, 368 µmol) and DIEA (960 mg, 7.43 mmol, 1.29 mL) in THF (10.0 mL) at 15°C. The reaction mixture was stirred at 15-25°C for 30 hours. LCMS indicated a homogeneous product with the desired product MS (R t = 1.271 min) leaving 13.1% of the raw material (R t = 1.235 min). The reaction mixture was quenched with water (50.0 mL), extracted with DCM (100 mL), the organic phase was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the desired compound (1.80 g, crude) as a black oil, which was used directly in the next step. LCMS: R t = 1.271 min MS+46 = 837.4.

[0206] h) To a mixture of the compound obtained above in step g) (1.80 g, 2.27 mmol) in EtOAc (15.0 mL) was added HCl / dioxane (4 M, 15.0 mL). The reaction mixture was stirred at 15°C for 2 hours. LCMS indicated that the reaction was complete and the desired MS (Rt = 0.860 min) was found. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% TFA) to give the title compound (126 mg, 13.6% yield for 2 steps) as a yellow foam, which was confirmed by LCMS. LCMS: R t =0.860 min, MS+1 = 578.2.

[0207] i, j, k) To a mixture of the compound obtained above in step h) (53 mg, 91.8 µmol) and cyclopentanone (62 mg, 737 µmol, 65.3 µL) in MeOH (1.00 mL) was added AcOH (1 mg, 16.7 µmol, 0.95 µL) (step i)). The reaction mixture was stirred at 15 °C for 1 hour, then NaBH3CN (30 mg, 478 µmol) was added and the mixture was stirred at 15 °C for 0.5 hour (step j)). LCMS indicated the reaction was complete and the desired MS (R t=0.929 min). The reaction mixture was quenched with water (10.0 mL) and extracted with EtOAc (20.0 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (TFA conditions). The collected mobile phase was concentrated in vacuo and the residue was adjusted to pH = 8 with NaHCO3 (solid) and extracted with EtOAc (20.0 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. In step k), the residue was separated by SFC (column: DAICELCHIRALCEL OJ-H (250 mm×30 mm, 5 µm); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 25%-25%, 4.9 min; 60 min) to produce the target compound (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (10 mg, 14.3 µmol, 31.1% yield, as an off-white solid).

[0208]

[0209] (2S,3R)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide was also produced as an off-white solid (10 mg, 15.33 µmol, 33.4% yield).

[0210]

[0211] Example 3

[0212] Synthesis of (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-2-(4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (INF011)

[0213]

[0214] By replacing 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-(trifluoromethyl)aniline in step c of Example 2 above with 4-methyl-3-(trifluoromethyl)aniline (step e), the desired product, tert-butyl (4-(3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)quinolin-2-yl)phenyl)carbamate (5.20 g, 9.97 mmol, 80.7% yield) was produced. The product was then reduced (step f) to produce tert-butyl cis (4-(3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,3,4-tetrahydroquinolin-2-yl)phenyl)carbamate (3.10 g, 5.78 mmol, 58.0% yield) as a white solid.

[0215]

[0216] l) To a solution of 2-fluoro-6-methylbenzoyl chloride (1.32 g, 7.65 mmol) in DCM (30.0 mL) was added tert-butyl cis-(4-(3-((4-methyl-3-(trifluoromethyl)phenyl)carbamoyl)-1,2,3,4-tetrahydroquinolin-2-yl)phenyl)carbamate (1.00 g, 1.90 mmol), DIEA (1.24 g, 9.59 mmol, 1.67 mL) and DMAP (80 mg, 655 µmol) in DCM (30 mL) at 15°C. The reaction mixture was stirred at 15 ~ 30°C for 10 hours. LCMS indicated the desired product MS (R t = 1.132 min) leaving 14% of the raw material (R t = 1.081 min). The reaction was quenched with water (100 mL) and extracted with EtOAc (100 mL×2). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (0.1% TFA) to give the target compound (1.00 g, 1.51 mmol, 79.4 % yield) as a yellow solid. LCMS: R t = 1.132 min, MS+23 = 684.2.

[0217] m) To a solution of the compound obtained in step l) above (1.00 g, 1.51 mmol) in EtOAc (5.00 mL) was added HCl / dioxane (4 M, 5.00 mL). The reaction mixture was stirred at 20 °C for 2 hours. LCMS indicated the reaction was complete and the desired MS (R t= 0.908 min). The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50.0 mL), washed with saturated NaHCO3 (50.0 mL), separated, dried over Na2SO4, filtered and concentrated in vacuo to give the desired product as a yellow foam (803 mg, 1.43 mmol, 94.6 % yield). LCMS: R t = 0.908min, MS+1 = 562.2.

[0218] n, o, p) To a mixture of the compound obtained above in step m) (200 mg, 356 µmol) and tetrahydropyran-4-one (286 mg, 2.86 mmol, 262 µL) in MeOH (2.00 mL) was added AcOH (3 mg, 50.0 µmol, 2.86 µL) (step n)). The reaction mixture was stirred at 15°C for 1 hour. Then NaBH3CN (115 mg, 1.83 mmol) (step o) was added and the mixture was stirred at 15°C for 1 hour. LCMS indicated that the reaction was complete and the desired compound was found MS (R t = 0.985 min). The reaction mixture was quenched with water (50.0 mL) and extracted with EtOAc (50.0 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was separated by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm×30 mm, 5 µm); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 25%-25%, 4.3 min; 60 min) (step p) to give (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-2-(4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (8 mg, 12.1 µmol, 6.78% yield) as a white solid, which was confirmed by LCMS. t = 0.885 min, MS+1 = 646.3.

[0219]

[0220] Also produced was (2S,3R)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-2-(4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (8 mg, 12.0 µmol, 6.76% yield) as a white solid, which was confirmed by LCMS: R t = 0.884 min, MS+1 = 646.2.

[0221]

[0222] Example 4

[0223] Synthesis of (2R,3S)-1-(2-chlorobenzoyl)-2-(4-(cyclopentylamino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (INF014)

[0224]

[0225] q) To a solution of 2-chlorobenzoyl chloride (400 mg, 2.29 mmol, 336 µL) in DCM (7.50 mL) was added a solution of the compound obtained above in Example 2, step d) (300 mg, 457 µmol), DMAP (8 mg, 65.5 µmol) and DIEA (360 mg, 2.79 mmol, 485 µL) in DMF (1.50 mL) at 15°C. The reaction mixture was stirred at 30°C for 10 hours. LCMS indicated a homogeneous product with the desired compound (MS (R t = 1.273 min)) together with 3.5% of the raw material (R t = 1.232 min). The reaction mixture was quenched with water (50.0 mL) and extracted with EtOAc (60.0 mL × 2). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (0.1% TFA) to give the title compound (206 mg, 259 µmol, 56.7% yield) as a yellow foam. LCMS: R t = 1.273 min, MS+23 = 816.3.

[0226]

[0227] r) To a solution of the compound obtained above in step q) (206 mg, 297 µmol) in EtOAc (3.00 mL) was added HCl / dioxane (4 M, 3 mL). The reaction mixture was stirred at 15°C for 2 hours. LCMS indicated that the reaction was complete and the desired compound MS (R t = 0.891 min). The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated NaHCO3 (50.0 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (151 mg, 260 µmol, 87.7% yield) as a yellow foam. LCMS: R t =0.891 min, MS+1 = 580.1.

[0228]

[0229] s) To a solution of the compound obtained in step r) above (153 mg, 264 µmol) and cyclopentanone (220 mg, 2.62 mmol, 232 µL) in MeOH (2.00 mL) was added AcOH (5 mg, 83.3 µmol, 4.76 µL). The reaction mixture was stirred at 20°C for 1 hour, then NaBH3CN (85 mg, 1.35 mmol) was added and the mixture was stirred at 20°C for 1 hour. LCMS indicated that the reaction was complete and the desired compound was detected. MS (R t = 0.908 min). The reaction mixture was quenched with water (10.0 mL) and extracted with EtOAc (20.0 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (TFA) to give the title compound (73 mg, 107 µmol, 40.4% yield) as a white solid. LCMS: R t = 0.908 min, MS+1 = 648.4. HPLC: R t = 2.035 min. SFC: R t = 0.614 and 1.031 min.

[0230]

[0231] t) The compound obtained in step s) above (73 mg, 112 µmol, 1.00 eq) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm, 10 µm); mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 55%-55%, 3.2 min; 40 min) to produce (2R,3S)-1-(2-chlorobenzoyl)-2-(4-(cyclopentylamino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (7 mg, 10.3 µmol, 18.2% yield) as a white solid, which was confirmed by LCMS: R t = 0.827 min, MS+1 = 648.1.

[0232]

[0233] Also produced was (2S,3R)-1-(2-chlorobenzoyl)-2-(4-(cyclopentylamino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide (7 mg, 10.8 µmol, 19.2% yield) as a white solid, which was confirmed by LCMS: R t = 0.826 min, MS+1 = 648.1.

[0234]

[0235] Example 5

[0236] Synthesis of (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide (INF056)

[0237]

[0238] a) A mixture of 2-chloro-5-(trifluoromethyl)nicotinic acid (15.0 g, 66.5 mmol, 1.00 eq) in SOCl2 (49.2 g, 413 mmol, 30.0 mL, 6.22 eq) was stirred at 90 °C for 1 hour, and then the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (20.0 mL), and then the solution was added to a solution of compound 4-methyl-3-(trifluoromethyl)aniline (11.1 g, 63.2 mmol, 9.07 mL, 0.95 eq) in DIEA (25.8 g, 199 mmol, 34.7 mL, 3.00 eq) and DCM (100 mL). The resulting solution was stirred at 25 °C for 10 hours. LC-MS indicated the desired mass was detected (RT = 1.015 min, M+H + : 383). The reaction mixture was quenched by the addition of NaHCO3 (sat.) (100 mL), and then extracted with EtOAc (250 mL × 2). The combined organic layers were washed with brine (200 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired compound (25.0 g, crude) as a yellow solid.

[0239] b) To a mixture of the compound obtained above (25.0 g, 65.3 mmol, 1.00 eq) and (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (17.0 g, 71.7 mmol, 1.10 eq) in toluene (250 mL) was added a solution of K2CO3 (18.1 g, 131 mmol, 2.01 eq) in H2O (50.0 mL) and Pd(dppf)Cl2 (2.39 g, 3.27 mmol, 0.05 eq) under N2. The mixture was stirred at 80 °C for 1 hour. LC-MS showed one major peak with the desired mass (RT = 1.092 min, M+H + : 540). The reaction mixture was quenched by the addition of H2O (100 mL) and extracted with EtOAc (300 mL× 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (100 mL) at 25°C for 30 minutes to give the desired compound (29.0 g, 53.7 mmol, 82.3% yield) as a yellow solid.

[0240] c) To a mixture of the compound obtained above (6.00 g, 11.1 mmol, 1.00 eq) in EtOH (300 mL) were added PtO2 (300 mg, 1.32 mmol, 1.19e-1 eq) and HCl (2.04 g, 20.1 mmol, 2.00 mL, 36.0% purity, 1.81 eq). The mixture was stirred under H2 (15 Psi) at 25 °C for 12 hours. LC-MS indicated that the desired mass was detected (RT = 0.908 min, M+H + : 546). TLC (petroleum ether: ethyl acetate = 3 / 1) showed the formation of two new spots (R f = 0.5, 0.4). The residue was poured into NaHCO3 (100 mL) (sat.), and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The combined organic phase was washed with brine (50.0 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1) to give the desired compound (3.00 g, 5.50 mmol, 49.4% yield) as a white solid.

[0241] d) To a mixture of the compound obtained above (400 mg, 733 umol, 1.00 eq) in THF (6.00 mL) was added DIPEA (482 mg, 3.73 mmol, 649 uL, 5.09 eq) and 2,6-difluorobenzoyl chloride (518 mg, 2.93 mmol, 370 uL, 4.00 eq) in one portion under N2. The mixture was stirred at 25°C for 2 hours. LC-MS indicated that the desired mass was detected (RT = 1.129 min, M+H + : 686). TLC (petroleum ether / ethyl acetate = 3 / 1) showed the formation of a new spot (R f = 0.43). The reaction mixture was quenched by adding H2O (10.0 mL), and then extracted with EtOAc (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give the desired compound (400 mg, 583 umol, 79.6% yield) as a white solid.

[0242] e) To a mixture of the compound obtained above (200 mg, 291 umol, 1.00 eq) in dioxane (2.00 mL) was added HCl / dioxane (4 M, 5.00 mL, 68.5 eq) in one portion. The mixture was stirred at 25 °C for 1 hour. LC-MS indicated that the desired mass was detected (RT = 0.959 min, M+H + : 586). The reaction mixture was quenched by the addition of NaHCO3(sat.) (100 mL), and then extracted with EtOAc (50.0 mL × 2). The combined organic layers were washed with brine (20.0 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired compound (170 mg, crude) as a yellow solid.

[0243] f) To a mixture of the compound obtained above (170 mg, 290 umol, 1.00 eq) and cyclopentanone (73.0 mg, 867umol, 76.8 uL, 2.99 eq) in MeOH (5.00 mL) was added AcOH (2.00 mg, 33.3 umol, 1.90 uL, 0.012 eq) in one portion. The mixture was stirred at 25°C for 30 minutes, and then NaBH3CN (36.0 mg, 572 umol, 1.97 eq) was added to the reaction mixture. The resulting solution was stirred at 25°C for 11.5 hours. LC-MS indicated that the desired mass was detected (RT = 1.052 min, M+H + : 654). The reaction mixture was quenched by the addition of NaHCO3 (sat.) (10.0 mL), and then extracted with EtOAc (20.0 mL × 2). The combined organic layers were washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: PhenomenexGemini-NX C18 75 * 30 mm * 3 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 52%-82%, 7 min) to produce the desired compound (150 mg, 229 umol, 79.0% yield) as a yellow solid.

[0244] g) The compound obtained above (150 mg, 229 umol, 1.00 eq) was purified by SFC (column: DAICELCHIRALCEL OJ-H (250 mm * 30 mm, 5 um); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 25% - 25%, 3.65 min; 238 min). (2R, 3S, 5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide (8.00 mg, 12.1 umol, 10.5% yield, 99.0% purity) was obtained as an off-white solid.

[0245]

[0246] (2S,3R,5S)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide was also obtained as a yellow solid (8.00 mg, 12.2 umol, 10.6% yield, 100% purity).

[0247]

[0248] The compounds (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide (INF056) and (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-dimethylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide (INF053) were obtained in a similar manner.

[0249] B. Biological Detection

[0250] calcium ++ Flow Detection (Calcium ++ mobilization assay)

[0251] U937 cells (ATCC ®CRL-1593.2) were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum in a standard cell culture incubator. Dibutyryl-cAMP (0.5 mM working concentration) was added to the cell culture one day before the assay. The next day, the cells were spun and resuspended in RPMI 1640 to a concentration of 40,000 cells / 50 µl. 40,000 cells were plated in 1 well of a 96-well poly-D-lysine coated plate for 2 hours to allow cell adhesion. After cell adhesion, cytosolic calcium ++ Indicator (FLIPR Calcium 6 Assay Kit, Molecular Devices) was added to each well and incubated at 37°C for 75 minutes. Test compounds were diluted using a robotic liquid handler. The tip of the robotic liquid handler was replaced after each mixing step. Test compounds were added to the cell culture at various concentrations (0.01 nM to 100 µM) for 15 minutes at 37°C. The cell culture plates were then incubated at room temperature for 30 minutes before being placed in a Flexstation-3 plate reader (Molecular Devices). The Flexstation-3 was programmed to add recombinant C5a protein to the cell culture plates at various concentrations (1 nM to 10 nM) and monitor changes in fluorescence intensity that correlate with cytoplasmic calcium concentration. The assay was also performed in the presence of human or animal blood components such as human or bovine plasma or serum.

[0252] Chemotaxis assay

[0253] U937 cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum in a standard cell culture incubator. Dibutyryl-cAMP (0.5 mM working concentration) was added to the cell culture one day before the assay was performed. The next day, the cells were spun and resuspended in RPMI 1640 to a concentration of 50,000 cells / 20 µl. The cells were incubated with various concentrations of compounds (0.01 nM to 100 µM) for 30 minutes at 37°C. 50,000 cells were added in 20 µl RPMI1640 to one well of the upper chamber of a 96-well chemotaxis plate (chemotaxis plates containing cell filters with 8 micron pores were purchased from Neuroprobe). C5a or other chemokines were added to the lower chamber at the preferred concentration in 29 µl HBSS buffer. Cells that migrated to the lower chamber after 1 to 3 h were stained with Cell Titer Glo (Invitrogen) and analyzed using the FlexStation ® 3. Quantification. The assay is also performed in the presence of human or animal blood components such as human or bovine plasma or serum.

[0254] β-Arrestin Testing

[0255] U2OS (ATCC number HTB-96), an osteosarcoma cell line, was used to generate a genetically engineered cell line that overexpresses two types of fusion proteins in the same cells: (a) The fusion protein TEV-C5aR1, which consists of the tobacco etch virus (TEV) protease fused to wild-type human C5aR1 or human C5aR1 mutants. The C5aR1 mutants carry amino acid mutations that are presumed to mediate the interaction between C5aR1 and the test compounds. (b) The fusion protein Luc-arrestin, which consists of β-arrestin-2, inactive permuted luciferase, and a peptide constituting the TEV protease cleavage site. The peptide is localized between β-arrestin-2 and luciferase.

[0256] The engineered U2OS cell line was used to access the activity of C5aR1 and the extent to which the test compounds could modulate the activity of wild-type or mutant C5aR1. In principle, C5a activates C5aR1 on the cell surface by binding to the C5aR1 portion of TEV-C5aR1 to result in binding between the intracellular portion of TEV-C5aR1 and luc-arrestin inside the cell, which enables TEV to cleave a peptide linking beta-arrestin and luciferase. This cleavage converts the inactive luciferase into an active luciferase, which catalyzes the added luciferase substrate and thus generates a luminescent signal. The intensity of the luminescent signal correlates with the activity of C5aR1.

[0257] Experimentally, engineered U2OS cells were cultured in McCoy's medium supplemented with 10% fetal bovine serum in a standard cell culture incubator. The test compound was added to the cell culture medium and incubated for 30 minutes, and then C5a was added to the cell culture medium and incubated for 1 to 3 hours. The cells were then lysed by a reagent containing a luciferase substrate such as One-glo or Bright-glo (Promega). A luminescence plate reader such as the FlexStation ® 3 (Molecular Devices) Luminescence units (RLU) were recorded.

[0258] C5a-induced CD11b expression in whole blood assays

[0259] Fresh peripheral blood samples were obtained from consenting human volunteers. 100 µl of whole blood was incubated with various concentrations of the test compound (0.01 nM to 10 µM) for 20 min at 37°C and then incubated with C5a at a preferred concentration of 1 nM to 30 nM for 20 min at 37°C. Samples were prepared for immunostaining and then FACS (fluorescence activated cell sorting) analysis of CD11b expression by leukocytes. Samples were incubated with anti-CD11b antibody (BioLegend) on ice for 30 min in the dark. 1 ml of Red Cell Lysis Buffer (Miltenyi) was added to 100 µl of blood samples and incubated for 10 min at room temperature. Samples were washed with FACS staining buffer and resuspended in FACS buffer. Samples were analyzed for cell surface CD11b expression by FACS (BeckmanCoulter).

[0260] Animal Neutropenia Detection

[0261] Animals (mice, rats, or gerbils) were acclimated for at least 3 days before use in experiments. Test compounds (1 to 30 mg / kg) were administered orally or intravenously. One to three hours later, animals were anesthetized using standard procedures, such as intraperitoneal administration of ketamine and xylazine. Animals were cannulated for intravenous administration of C5a and blood collection. C5a was constituted in saline and injected intravenously at doses ranging from 30 µg / kg to 120 µg / kg. Blood samples were collected several times over 30 minutes after C5a administration. Blood samples were collected using heparin tubes. White cell differences, such as the abundance of neutrophils, in the collected blood samples were analyzed by an automated blood cell analyzer (Siemens).

[0262] C. result

[0263] The half-maximal inhibitory concentration, IC, is determined in biological assays such as calcium flux assays. 50 Using calcium flux assays, the following IC 50 The percentage inhibition of C5a-induced calcium flux was plotted against various concentrations of the compound.

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274] INF004: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0275] INF011: (2R,3S)-1-(2-Fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-2-(4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0276] INF014: (2R,3S)-1-(2-chlorobenzoyl)-2-(4-(cyclopentylamino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0277] INF015: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0278] INF022: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-6-fluoro-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0279] INF023: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-6-methyl-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0280] INF024: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-6-methoxy-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0281] INF025: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-6,7-difluoro-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0282] INF030: (2R,3S)-1-(2-Fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-2-(4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0283] INF033: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-hydroxy-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0284] INF034: (2R,3S)-1-(2-Fluoro-6-methylbenzoyl)-2-(4-(3-hydroxy-3-methylbutyl)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0285] INF035: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(3-(hydroxymethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0286] INF038: (2R,3S)-1-(2-Fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-2-phenyl-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0287] INF039: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-6-fluoro-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0288] INF040: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1-(2-methylbenzoyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0289] INF041: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluorobenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0290] INF045: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-5-fluoro-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0291] INF046: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-7-fluoro-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0292] INF047: (2R,3S)-6-Chloro-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0293] INF048: (2R,3S)-1-(2-Fluoro-6-methylbenzoyl)-2-(4-(3-hydroxy-3-methylbutyl)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0294] INF049: (2R,3S)-1-(2-Fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-2-(4-(isopropylamino)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0295] INF050: (2R,3S)-2-(4-(cyclobutylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0296] INF051: (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-2-(4-((2-hydroxy-2-methylpropyl)amino)phenyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0297] INF052: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0298] INF053: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-dimethylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0299] INF055: (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0300] INF056: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0301] INF058: (2R,3S)-1-(2-fluoro-6-methylbenzoyl)-2-(4-(2-hydroxy-2-methylpropoxy)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

[0302] INF067: (2R,3S,5R)-2-(4-((cyclopentyl-1-d)amino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0303] INF068: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-hydroxy-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0304] INF069: (2R,3S,5R)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-N-(4-(hydroxymethyl)-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0305] INF070: (2R,3S,5R)-1-(2,6-difluorobenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-2-(4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0306] INF071: (2R,3S,5R)-N-(3-chloro-4-methylphenyl)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0307] INF072: (2R,3S,5R)-N-(3-chloro-4-hydroxyphenyl)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0308] INF075: (2R,3S,5R)-1-(2-chloro-6-fluorobenzoyl)-2-(4-(cyclopentylamino)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0309] INF077: (2R,3S,5R)-N-(4-chloro-3-(trifluoromethyl)phenyl)-2-(4-(cyclopentylamino)phenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide

[0310] INF080: (2R,3S,5R)-2-(4-(Cyclopentylamino)phenyl)-N-(3,4-dichlorophenyl)-1-(2,6-difluorobenzoyl)-5-(trifluoromethyl)piperidine-3-carboxamide.

[0311] References

[0312] 1. Merle, NS et al., Complement System Part I - Molecular Mechanisms of Activation and Regulation. Front Immunol, 2015. 6: p. 262.

[0313] 2. Schatz-Jakobsen, J.A., et al., Structural and functional Characterization of human and murine C5a anaphylatoxins . Acta Crystallogr DBiol Crystallogr, 2014. 70(Pt 6): p. 1704-17.

[0314] 3. Klos, A et al., International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacol Rev, 2013. 65(1): p. 500-43.

[0315] 4. Ricklin, D et al., The renaissance of therapeutic complements . NatRev Nephrol, 2018. 14(1): p. 26-47.

[0316] 5. Tesar, V. and Z. Hruskova, Avacopan in the treatment of ANCA- associated vasculitis . Expert Opin Investig Drugs, 2018. 27(5): p. 491-496.

[0317] 6. Li, G et al., Neuroprotective effects of argatroban and C5a receptor antagonist (PMX53) following intracerebral haemorrhage. Clin Exp Immunol ,2014. 175(2): p. 285-95.

[0318] 7. Nunez-Cruz, S et al., Genetic and pharmacologic inhibition of complement impairs endothelial cell function and ablate ovarian cancer neovascularization . Neoplasia, 2012. 14(11): p. 994-1004.

[0319] 8. Riedemann, NC et al., Controlling the anaphylatoxin C5a in diseases requires a specifically targeted inhibition . Clin Immunol, 2017. 180: p. 25-32.

Claims

1. Compounds having the general formula (II) or formula (XI) and pharmaceutically acceptable salts and rotamers thereof; in C 1 is phenyl; and wherein the phenyl group is optionally substituted by 1 to 3 R 1 Substituent substitution; C 2 is phenyl; and wherein the phenyl group is optionally substituted by 1 to 3 R 2 Substituent substitution; C 3 is phenyl, and wherein the phenyl is optionally substituted by 1 to 3 R 3 Substituent substitution; Each R 1 Independently selected from -R c and -OH; each R c Independently selected from C 1-8 Alkyl and C 1-8 haloalkyl, wherein R c The aliphatic portion is optionally further substituted with 1 hydroxyl group; Each R 2 independently selected from halogen and C 1-8 alkyl; Each R 3 Independently selected from -R i 、-NR g R h 、-OR g and-NHR j , where each R g and R h are independently selected from hydrogen or C 1-8 Alkyl; each R i Selected from C 1-8 alkyl, and each R j Selected from C 3-6 Cycloalkyl and tetrahydropyranyl, and wherein R g , R h and R i The aliphatic and / or cyclic portion is optionally further substituted with 1 hydroxyl group; X is hydrogen; m is 0 to 4; and R 4 Selected from halogen, C1-C6 alkyl, trifluoromethyl and C1-C6 alkoxy.

2. The compound according to claim 1, wherein the compound has formula (IIa) 3. The compound according to claim 1 or 2, wherein the compound is selected from 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 3.

5. Use of a compound according to any one of claims 1 to 3 in the preparation of a medicament for the treatment of a disease or condition involving pathogenic activation of the C5a receptor.

6. The use according to claim 5, wherein the disease or condition is selected from - Autoimmune disorders, - Inflammatory conditions, - cardiovascular or cerebrovascular disease, -HIV infection, - Neurodegenerative disorders, and -cancer.

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