Aryl, heteroaryl and heterocyclic compounds for the treatment of complement mediated diseases

文档序号：1347058 发布日期：2020-07-24 浏览：17次中文

阅读说明：本技术 用于治疗补体介导疾病的芳基、杂芳基和杂环化合物 (Aryl, heteroaryl and heterocyclic compounds for the treatment of complement mediated diseases ) 是由 V·R·加德哈查恩达王秋萍 G·派斯桥本彰宏陈大为王祥柱 A·阿加瓦尔 M·德于 2015-02-25 设计创作，主要内容包括：本发明提供了式I的化合物或其药学可接受的盐或组合物、使用方法及制备包含式I或其药学可接受的盐或组合物的补体因子D抑制剂的方法,其中A基团上的R12或R13为芳基、杂芳基或杂环基(R32)。本文描述的抑制剂靶向因子D,并在替代补体途径中在早期和必要点处抑制或调节补体级联,并降低因子D调节经典和凝集素补体途径的能力。本文描述的因子D的抑制剂能够降低补体的过度活化,所述过度活化与某些自身免疫、炎性和神经变性疾病以及缺血-再灌注损伤和癌症相关。(The invention provides compounds of formula I, or pharmaceutically acceptable salts or compositions thereof, methods of use, and methods of making complement factor D inhibitors comprising formula I, or pharmaceutically acceptable salts or compositions thereof, wherein R on the A group 12 Or R 13 Is aryl, heteroaryl or heterocyclyl (R) 32 ). The inhibitors described herein target factor D and inhibit or modulate the complement cascade early and at the necessary point in the alternative complement pathway and reduce the ability of factor D to modulate the classical and lectin complement pathways. Inhibitors of factor D described herein are capable of reducing over-activation of complement, which is associated with certain autoimmune, inflammatory and neurodegenerative diseases as well as ischemia-reperfusion injury and cancer.)

1. Use of a compound according to the formula:

wherein:

R³²is a pyrimidine optionally substituted with one or more substituents independently selected from halogen, C₁-C₆Alkyl, cyano and C₁-C₆An alkoxy group; and

R³³independently selected from halogen and C₁-C₆An alkyl group.

2. The use according to claim 1, wherein R³²Is 1 selected from halogen and C₁-C₆Alkyl, cyano and C₁-C₆Substituent of alkoxy.

3. The use according to claim 1, wherein C₁-C₆Alkyl is methyl.

4. Use according to claim 1, whereinComprises the following steps:

5. the use according to claim 1, wherein R³²Is that

6. The use according to claim 1, wherein R³³Is bromine.

7. The use according to claim 1, wherein R³²Is a pyrimidine substituted with a methyl group.

8. The use of claim 1, wherein the compound is a compound having the structure:

or a pharmaceutically acceptable salt thereof.

9. The use of any one of claims 1-8, wherein the disease is a disease mediated by complement factor D.

10. The use of any one of claims 1-8, wherein the disease is age-related macular degeneration (AMD).

11. The use according to any one of claims 1-8, wherein the disease is Paroxysmal Nocturnal Hemoglobinuria (PNH).

12. The use according to any one of claims 1-8, wherein the disease is multiple sclerosis, arthritis or COPD.

13. The use according to any one of claims 1-8, wherein the disease is an ophthalmic disease.

14. The use according to any one of claims 1-8, wherein the disease is a respiratory disease.

15. The use according to any one of claims 1-8, wherein the disease is a cardiovascular disease.

16. The use according to any one of claims 1-8, wherein the disease is atypical or typical hemolytic uremic syndrome.

17. The use according to any one of claims 1 to 8, wherein the disease is rheumatoid arthritis.

18. The use according to any one of claims 1 to 8, wherein the disease is C3 glomerulonephritis.

19. The use according to any one of claims 1-8, wherein the disease is MPGNII.

20. The use according to any one of claims 1-8, wherein the medicament is for administration in combination with an effective amount of a further active agent.

Background

The complement system is part of the innate immune system, which is not adapted to changes in the life of the host, but is recruited and used by the adaptive immune system (recurait). For example, it aids or complements the ability of antibodies and phagocytic cells to eliminate pathogens. This complex regulatory pathway allows a rapid response to pathogenic organisms while protecting the host cell from damage. Over thirty proteins and protein fragments make up the complement system. These proteins act by opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (disrupting the membrane of foreign cells), and agglutination (clustering and binding pathogens together).

ComplementThe system has three approaches: classical, alternative and lectin. Complement factor D plays an early and central role in the activation of alternative pathways of the complement cascade. Activation of the alternative complement pathway results from spontaneous hydrolysis of thioester linkages within C3 to yield C3 (H)₂O), C3 (H)₂O) associates with factor B to form C3 (H)₂O) B complex. The role of complement factor D is to cleave C3 (H)₂O) factor B within the B complex to form Ba and Bb. Bb fragment remains with C3 (H)₂O) to form the alternative pathway C3 convertase C3 (H)₂O) Bb. In addition, C3B produced by any C3 convertase also associates with factor B to form C3bB, and factor D cleaves to produce the late alternative pathway C3 convertase C3 bBb. This latter form of alternative pathway C3 convertase can provide important downstream amplification within all three defined complement pathways, ultimately leading to recruitment and assembly of other factors in the complement cascade pathway, including the cleavage of C5 into C5a and C5 b. C5b plays a role in the assembly of factors C6, C7, C8 and C9 into a membrane attack complex that can destroy pathogenic cells by lysing the cells.

Complement dysfunction or overactivation has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases as well as ischemia-reperfusion injury and cancer. For example, activation of alternative pathways of the complement cascade contributes to the production of C3a and C5a (both potent anaphylatoxins), and C3a and C5a also play a role in many inflammatory diseases. Thus, in some cases, it is desirable to reduce the response of the complement pathway, including the alternative complement pathway. Some examples of diseases mediated by the complement pathway include age-related macular degeneration (AMD), Paroxysmal Nocturnal Hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis.

Age-related macular degeneration (AMD) is the leading cause of vision loss in industrialized countries. Based on many genetic studies, there is evidence for a link between the complement cascade and macular degeneration. Individuals with mutations in the gene encoding complement factor H have a five-fold increased risk of macular degeneration, as do individuals with mutations in other complement factor genes. Individuals with mutant factor H also have elevated levels of C-reactive protein, which is a marker of inflammation. Without the proper functional factor H, alternative pathways of the complement cascade would be over-activated, leading to cell damage. Inhibition of alternative pathways is therefore desirable.

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a non-malignant hematological disorder characterized by the absence of expansion of hematopoietic stem cells and progeny mature blood cells in some surface proteins. PNH erythrocytes are unable to regulate their surface complement activation, which leads to the chronic activation of complement-mediated vascular anemia, a hallmark of PNH. Currently, there is only one product: the anti-C5 monoclonal antibody eculizumab has been approved in the united states for the treatment of PNH. However, many patients treated with eculizumab remain anemic, and many continue to require blood transfusion. In addition, treatment with eculizumab requires lifelong intravenous injections. Thus, there is an unmet need to develop novel inhibitors of the complement pathway.

Due to its early and important role in the alternative complement pathway and its potential role in signal amplification within the classical and lectin complement pathways, factor D is an attractive target for inhibiting or modulating the complement cascade. Inhibition of factor D effectively interrupts the pathway and impairs the formation of membrane attack complexes.

Although preliminary attempts have been made to develop inhibitors of factor D, no small molecule factor D inhibitors are currently available in clinical trials. Examples of factor D inhibitors or prolyl compounds are described in the following disclosure.

A fused bicyclic compound is described in Biocrystal Pharmaceuticals, U.S. Pat. No. 6653340 entitled "Compounds useful in the composition, coagulut and kallikreinpathways and method for the preparation" as a potent inhibitor of factor D. The development of the factor D inhibitor BCX1470 was interrupted by the lack of specificity and short half-life of the compound.

Novartis PCT patent publication WO2012/093101 entitled "oil compounds or analytes of use for the treatment of a related volumetric production" describes certain factor D inhibitors.

Novartis PCT publication WO2014/002057 entitled "Pyrrolidine derivatives and the third use as a complementary pathway inhibitors" and WO2014/009833 entitled "complementary pathway inhibitors and uses therof" describe other factor D inhibitors having a heterocyclic substituent. Other factor D inhibitors are described in Novartis PCT patent publications WO2014/002051, WO2014/002052, WO2014/002053, WO2014/002054, WO2014/002058, WO2014/002059, and WO 2014/005150.

Bristol-Myers Squibb PCT patent publication WO2004/045518, entitled "Open chain prolyl urea-related modulators of androgen receptors functions," describes Open chain prolylurea and thiourea related compounds useful for treating androgen receptor related disorders such as age-related diseases, e.g., sarcopenia.

Japanese tobacoinc. pct patent publication WO 1999/048492, entitled "Amide derivatives and nociceptin antaronists" describes compounds having a proline nucleus and an aromatic substituent linked to the proline nucleus by an Amide bond that are useful for the treatment of pain.

Ferring b.v. and yamanouchi Pharmaceutical co. L td.pct patent publication WO 1993/020099, entitled "CCK and/or hormone receptors ligands" describes compounds having a proline-like core and a heterocyclic substituent attached to the proline core by an amide bond for use in the treatment of, for example, gastric disease or pain.

Alexion pharmaceuticals PCT patent publication WO 1995/029697, entitled "Methods and compositions for the treatment of glyconephrophilis and other inflammatory disorders," discloses antibodies to C5 involved in the complement pathway for the treatment of glomerulonephritis and inflammatory disorders involving pathological activation of the complement system. anti-C5 antibody eculizumab to Alexion PharmaceuticalIs the only complement-specific antibody currently on the market and is the first and only approved therapeutic agent for Paroxysmal Nocturnal Hemoglobinuria (PNH).

There is a need for compounds that mediate the complement pathway and, for example, act as factor D inhibitors to treat diseases associated with the misregulation of the complement cascade in a host, including humans.

Disclosure of Invention

Wherein R on the A group has been found¹²Or R¹³Compounds of formula I that are aryl, heteroaryl or heterocyclic or pharmaceutically acceptable salts or compositions thereof are excellent inhibitors of complement factor D.

In one embodiment, there is provided a method for the treatment of a disease associated with dysfunction, including increased activity, of the complement pathway comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, as described in more detail below.

In one embodiment, the disease is associated with the alternative complement cascade pathway. In yet another embodiment, the disease is associated with the classical pathway of complement. In yet another embodiment, the disease is associated with the complement lectin pathway. By administering an effective amount in a suitable manner to a host in need thereof, factor D inhibitors provided herein can thus attenuate or inhibit detrimental complement activity in the host.

Particular embodiments of the invention relate to certain disease indications. In one embodiment, there is provided a method for treating Paroxysmal Nocturnal Hemoglobinuria (PNH) comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating age-related macular degeneration (AMD) comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating rheumatoid arthritis comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating multiple sclerosis comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

In other embodiments of the invention, active compounds provided herein can be used to treat or prevent diseases mediated by complement factor D, or by an excessive or detrimental amount of the C3 amplification loop of the complement pathway, in a host. By way of example, the invention includes methods of treating or preventing complement-associated diseases induced by antibody-antigen interactions, components of immune or autoimmune diseases, or by ischemic injury. The invention also provides methods of reducing inflammation or immune responses, including autoimmune responses mediated or affected by factor D therein.

The present invention provides compounds of formula I

And pharmaceutically acceptable salts and compositions thereof, wherein:

Q¹is N (R)¹) Or C (R)¹R^1’)；

Q²Is C (R)²R^2’)、C(R²R^2’)-C(R²R^2’)、S、O、N(R²) Or C (R)²R^2’)O；

Q³Is N (R)³) S or C (R)³R^3’)；

X¹And X²Independently N, CH or CZ, or X¹And X²Together are C ═ C; and

wherein Q¹、Q²、Q³、X¹And X²Selected such that a stable compound is produced.

Non-limiting examples of rings are illustrated below (any of which may additionally be represented by R¹、R^1’、R²、R^2’、R³And R^3’Substituted) which will be described in more detail below.

Wherein q is 0, 1,2 or 3 and r is 1,2 or 3.

R and R' are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or any other substituent herein that will provide the desired properties, each of which may be optionally substituted. In some embodiments, the ring comprises one or more chiral carbon atoms. The invention includes embodiments in which the chiral carbon may be provided as an enantiomer, or a mixture of enantiomers including a racemic mixture. When the ring contains more than one stereocenter, all enantiomers and diastereomers are included as separate species in the present invention.

Z is F, Cl, NH₂、CH₃、CH₂D、CHD₂Or CD₃。

R¹、R^1’、R²、R^2’、R³And R^3’Independently at each occurrence and yielding only stable compounds, is selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy radical, C₂-C₆Alkynyl, C₂-C₆Alkanoyl radical, C₁-C₆Thioalkyl, hydroxy C₁-C₆Alkyl, amino C₁-C₆Alkyl, -C₀-C₄Alkyl radical NR⁹R¹⁰、-C(O)OR⁹、-OC(O)R⁹、-NR⁹C(O)R¹⁰、-C(O)NR⁹R¹⁰、-OC(O)NR⁹R¹⁰、-NR⁹C(O)OR¹⁰、C₁-C₂Haloalkyl and C₁-C₂Haloalkoxy, wherein R⁹And R¹⁰Independently at each occurrence, selected from hydrogen, C₁-C₆Alkyl, (C)₃-C₇Cycloalkyl) C₀-C₄Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl) and-O-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl groups).

In alternative embodiments, R¹And R^1’Or R³And R^3’May together form a 3-to 6-membered carbocyclic spiro ring or a 3-to 6-membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N, O or S; r²And R^2’May together form a 3-to 6-membered carbocyclic spiro ring; or R²And R^2’May together form a 3-to 6-membered heterocyclic spiro ring; each spiro ring of each ring may be unsubstituted or substituted by 1 or more substituents independently selected from halogen (especially F), hydroxy, -cyano, -COOH, C₁-C₄Alkyl (including especially methyl), C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Alkoxy radical, C₂-C₄Alkanoyl, hydroxy C₁-C₄Alkyl, (mono-and di-C)₁-C₄Alkylamino) C₀-C₄Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -O-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

In alternative embodiments, R¹And R²May together form a 3-membered carbocyclic ring; r¹And R²May together form a 4-to 6-membered carbocyclic or aromatic ring or a 4-to 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms independently selected from N, O and S; or R²And R³Together may form a 3-to 6-membered carbocyclic or aromatic ring or a 3-to 6-membered heterocyclic or heteroaromatic ring if bonded to adjacent carbon atoms; each of said rings may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (especially F), hydroxy, -cyano, -COOH, C₁-C₄Alkyl (including especially methyl), C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Alkoxy radical, C₂-C₄Alkanoyl, hydroxy C₁-C₄Alkyl, (mono-and di-C)₁-C₄Alkylamino) C₀-C₄Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -O-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

In alternative embodiments, R¹And R^1’、R²And R^2’Or R³And R^3’Together may form a carbonyl group. In alternative embodiments, R¹And R²Or R²And R³May together form a carbon-carbon double bond.

A is a group selected from:

R⁴is selected from-CHO, -CONH₂、C₂-C₆Alkanoyl, hydrogen, -SO₂NH₂、-C(CH₂)₂F、-CH(CF₃)NH₂、C₁-C₆Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -C (O) C₀-C₂Alkyl radical (C)₃-C₇Cycloalkyl radicals),

Dehydrogenation, -CHO and-CONH₂Each of said R' s⁴Is unsubstituted or substituted by amino, imino, halogen, hydroxy, cyano, cyanoimino, C₁-C₂Alkyl radical, C₁-C₂Alkoxy, -C₀-C₂Alkyl (mono-and di-C)₁-C₄Alkylamino), C₁-C₂Haloalkyl and C₁-C₂One of the haloalkoxy groupsOr a plurality thereof.

R⁵And R⁶Independently selected from-CHO, -C (O) NH₂、-C(O)NH(CH₃)、C₂-C₆Alkanoyl, hydrogen, hydroxy, halogen, cyano, nitro, -COOH, -SO₂NH₂Vinyl group, C₁-C₆Alkyl (including methyl), C₂-C₆Alkenyl radical, C₁-C₆Alkoxy, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -C (O) C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -P (O) (OR)⁹)₂、-OC(O)R⁹、-C(O)OR⁹、-C(O)N(CH₂CH₂R⁹)(R¹⁰)、-NR⁹C(O)R¹⁰Phenyl or 5-to 6-membered heteroaryl.

Each R other than hydrogen, hydroxy, cyano and-COOH⁵And R⁶Is unsubstituted or optionally substituted. For example, R other than hydrogen, hydroxy, cyano and-COOH⁵And R⁶May be substituted with one or more substituents independently selected from halogen, hydroxy, amino, imino, cyano, cyanoimino, C₁-C₂Alkyl radical, C₁-C₄Alkoxy, -C₀-C₂Alkyl (mono-and di-C)₁-C₄Alkylamino), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

R^6’Is hydrogen, halogen, hydroxy, C₁-C₄Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl) or C₁-C₄An alkoxy group; or R⁶And R^6’Together may form an oxo, vinyl or imino group.

R⁷Is hydrogen, C₁-C₆Alkyl or-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl groups).

R⁸And R^8’Independently selected from hydrogen, halogen, hydroxy, C₁-C₆Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₆Alkoxy and (C)₁-C₄Alkylamino) C₀-C₂An alkyl group; or R⁸And R^8’Together form an oxo group; or R⁸And R^8’May form a 3-membered carbocyclic ring together with the carbon to which they are bonded.

R¹⁶Is absent or may comprise one or more substituents independently selected from halogen, hydroxy, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy, -C₀-C₄Alkyl (mono-and di-C)₁-C₆Alkylamino), -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

R¹⁹Is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl, -SO₂C₁-C₆Alkyl, (mono-and di-C)₁-C₆Alkylamino) C₁-C₄Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -C₀-C₄Alkyl radical (C)₃-C₇Heterocycloalkyl) C₀-C₄Alkyl (aryl), C₀-C₄Alkyl (heteroaryl), and wherein R is other than hydrogen¹⁹Is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, amino, -COOH and-C (O) OC₁-C₄An alkyl group.

X¹¹Is N or CR¹¹。

X¹²Is N or CR¹²。

X¹³Is N or CR¹³。

X¹⁴Is N or CR¹⁴。

X¹¹、X¹²、X¹³And X¹⁴Wherein the number of N is not more than 2.

R¹²And R¹³One of them is selected from R³¹And R is¹²And R¹³Is selected from R³². In alternative embodiments, R¹²And R¹³Each independently selected from R³²And (4) partial.

R³¹Selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, -COOH, C₁-C₂Haloalkyl, C₁-C₂Haloalkoxy, C₁-C₆Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkenyloxy, -C (O) OR⁹、C₁-C₆Thioalkyl, -C₀-C₄Alkyl radical NR⁹R¹⁰、-C(O)NR⁹R¹⁰、-SO₂R⁹、-SO₂NR⁹R¹⁰、-OC(O)R⁹and-C (NR)⁹)NR⁹R¹⁰Removing hydrogen, halogen, hydroxy, nitro, cyano, C₁-C₂Haloalkyl and C₁-C₂Each of said R's other than haloalkoxy³¹Is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, nitro, cyano, amino, -COOH, -CONH₂、C₁-C₂Haloalkyl and C₁-C₂Haloalkoxy, and each of said R³¹And is further optionally substituted with a substituent selected from phenyl and a 4-to 7-membered heterocyclic ring containing 1,2 or 3 heteroatoms independently selected from N, O and S; said phenyl or 4-to 7-membered heterocyclic ring being unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy groups, (mono-and di-C)₁-C₆Alkylamino) C₀-C₄Alkyl radical, C₁-C₆Alkyl esters, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group;

R³²is selected from aryl; a saturated or unsaturated heterocyclic ring (e.g., a 5-6 membered ring having 1,2, or 3 heteroatoms independently selected from N, O and S), wherein the heterocyclic ring is bonded to R through a carbon atom in the heterocyclic ring¹²Or R¹³The carbon atom of ring a in position; and heteroaryl (e.g., a 5-6 membered ring having 1,2, or 3 heteroatoms independently selected from N, O and S), wherein the aryl, heterocyclic, or heteroaryl ring can be optionally substituted;

R¹¹、R¹⁴and R¹⁵Independently at each occurrence, selected from hydrogen, halogen, hydroxy, nitro, cyano, -O (PO) (OR)⁹)₂、-(PO)(OR⁹)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₂-C₆Alkenyl (aryl), C₂-C₆Alkenyl (cycloalkyl), C₂-C₆Alkenyl (heterocycle), C₂-C₆Alkenyl (heteroaryl), C₂-C₆Alkynyl, C₂-C₆Alkynyl (aryl), C₂-C₆Alkynyl (cycloalkyl), C₂-C₆Alkynyl (heterocycle), C₂-C₆Alkynyl (heteroaryl), C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy radical, C₁-C₆Thioalkyl, -C₀-C₄Alkyl (mono-and di-C)₁-C₆Alkylamino), -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -C₀-C₄Alkoxy (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

L is a bond or is selected from the following formulas

Wherein R is¹⁷Is hydrogen, C₁-C₆Alkyl or-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), R¹⁸And R^18’Independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is 0, 1,2 or 3.

B is a monocyclic or bicyclic carbocyclic ring; a monocyclic or bicyclic carbocyclic group; a monocyclic, bicyclic or tricyclic heterocyclic group having 1,2,3 or 4 heteroatoms independently selected from N, O and S and having 4 to 7 ring atoms per ring; c₂-C₆An alkenyl group; c₂-C₆An alkynyl group; - (C)₀-C₄Alkyl) (aryl); - (C)₀-C₄Alkyl) (heteroaryl) or- (C)₀-C₄Alkyl) (biphenyl).

Each said B is unsubstituted or substituted with one or more substituents independently selected from R³³And R³⁴And 0 or 1 substituent is selected from R³⁵And R³⁶。

R³³Independently selected from halogen, hydroxy, -COOH, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy, -C₀-C₄Alkyl radical NR⁹R¹⁰、-SO₂R⁹、C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group;

R³⁴independently selected from nitro, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Thioalkyl, -JC₃-C₇Cycloalkyl, -B (OH)₂、-JC(O)NR⁹R²³、-JOSO₂OR²¹、-C(O)(CH₂)_1-4S(O)R²¹、-O(CH₂)_1-4S(O)NR²¹R²²、-JOP(O)(OR²¹)(OR²²)、-JP(O)(OR²¹)(OR²²)、-JOP(O)(OR²¹)R²²、-JP(O)(OR²¹)R²²、-JOP(O)R²¹R²²、-JP(O)R²¹R²²、-JSP(O)(OR²¹)(OR²²)、-JSP(O)(OR²¹)(R²²)、-JSP(O)(R²¹)(R²²)、-JNR⁹P(O)(NHR²¹)(NHR²²)、-JNR⁹P(O)(OR²¹)(NHR²²)、-JNR⁹P(O)(OR²¹)(OR²²)、-JC(S)R²¹、-JNR²¹SO₂R²²、JNR⁹S(O)NR¹⁰R²²、-JNR⁹SO₂NR¹⁰R²²、-JSO₂NR⁹COR²²、-JSO₂NR⁹CONR²¹R²²、-JNR²¹SO₂R²²、-JC(O)NR²¹SO₂R²²、-JC(NH₂)NR²²、-JC(NH₂)NR⁹S(O)₂R²²、-JOC(O)NR²¹R²²、-JNR²¹C(O)OR²²、-JNR²¹OC(O)R²²、-(CH₂)_1-4C(O)NR²¹R²²、-JC(O)R²⁴R²⁵、-JNR⁹C(O)R²¹、-JC(O)R²¹、-JNR⁹C(O)NR¹⁰R²²、-CCR²¹、-(CH₂)_1-4OC(O)R²¹and-JC (O) OR²³(ii) a Each of said R³⁴May be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, nitro, cyano, amino, oxo, -B (OH)₂、-Si(CH₃)₃、-COOH、-CONH₂、-P(O)(OH)₂、C₁-C₆Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₆Alkoxy, -C₀-C₂Alkyl (mono-and di-C)₁-C₄Alkylamino), C₁-C₆Alkyl ester, C₁-C₄Alkylamino radical, C₁-C₄Hydroxyalkyl radical, C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

R³⁵Independently selected from naphthyl, naphthyloxy, indanyl, (4-to 7-membered heterocycloalkyl) C containing 1 or 2 heteroatoms selected from N, O and S₀-C₄Alkyl and a bicyclic heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S and containing 4-to 7-ring atoms in each ring; each of said R³⁵Is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy groups, (mono-and di-C)₁-C₆Alkylamino) C₀-C₄Alkyl radical, C₁-C₆Alkyl esters, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -SO₂R⁹、C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

R³⁶Independently selected from tetrazolyl, (phenyl) C₀-C₂Alkyl, (phenyl) C₁-C₂Alkoxy, phenoxy and 5-or 6-membered heteroaryl containing 1,2 or 3 heteroatoms independently selected from N, O, B and S, each of said R³⁶Is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy groups, (mono-and di-C)₁-C₆Alkylamino) C₀-C₄Alkyl radical, C₁-C₆Alkyl esters, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -SO₂R⁹、-OSi(CH₃)₂C(CH₃)₃、-Si(CH₃)₂C(CH₃)₃、C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

R²¹And R²²Independently at each occurrence, selected from hydrogen, hydroxy, cyano, amino, C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy group, (C)₃-C₇Cycloalkyl) C₀-C₄Alkyl, (phenyl) C₀-C₄Alkyl, -C₁-C₄Alkyl OC (O) OC₁-C₆Alkyl radical, C₁-C₄Alkyl OC (O) C₁-C₆Alkyl, -C₁-C₄Alkyl C (O) OC₁-C₆Alkyl, (4-to 7-membered heterocycloalkyl) C having 1,2 or 3 heteroatoms independently selected from N, O and S₀-C₄Alkyl and (5-or 6-membered unsaturated or aromatic heterocyclic) C having 1,2 or 3 heteroatoms independently selected from N, O and S₀-C₄Alkyl, and each R²¹And R²²May be optionally substituted.

R²³Independently at each occurrence is selected from C₁-C₆Alkyl radical, C₁-C₆Haloalkyl, (aryl) C₀-C₄Alkyl, (C)₃-C₇Cycloalkyl) C₀-C₄Alkyl, (phenyl) C₀-C₄Alkyl, (4-to 7-membered heterocycloalkyl) C having 1,2 or 3 heteroatoms independently selected from N, O and S₀-C₄Alkyl and (5-or 6-membered unsaturated or aromatic heterocyclic) C having 1,2 or 3 heteroatoms independently selected from N, O and S₀-C₄Alkyl, and each R²³May be optionally substituted.

R²⁴And R²⁵Together with the nitrogen to which they are attached form a 4-to 7-membered monocyclic heterocycloalkyl group or a 6-to 10-membered bicyclic heterocyclic group having a fused, spiro or bridged ring, and each R²⁴And R²⁵May be optionally substituted.

J is independently selected for each occurrence from a covalent bond, C₁-C₄Alkylene, -OC₁-C₄Alkylene radical, C₂-C₄Alkenylene and C₂-C₄Alkynylene radical.

Also disclosed are pharmaceutical compositions comprising a compound or salt of formula I and a pharmaceutically acceptable carrier.

Also disclosed are methods of treating or preventing diseases mediated by complement cascade factor D, including but not limited to age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), Paroxysmal Nocturnal Hemoglobinuria (PNH), Multiple Sclerosis (MS), arthritis including Rheumatoid Arthritis (RA), respiratory diseases, or cardiovascular diseases, comprising administering to a host, including a human, in need of such treatment a therapeutically effective amount of a compound or salt of formula I.

In another embodiment, an effective amount of an active factor D inhibiting compound is provided to treat inflammatory or immune diseases mediated or affected by factor D, including autoimmune diseases. In an alternative embodiment, the compounds of formula I may be used to treat diseases mediated by the complement pathway, whether or not it is acted upon by factor D.

The invention comprises at least the following features:

(a) compounds of formula I as described herein, and pharmaceutically acceptable salts and prodrugs thereof (each of which and all subgenera and species thereof are contemplated and specifically described separately);

(b) formula I as described herein, and pharmaceutically acceptable salts and prodrugs thereof, for use in treating or preventing diseases mediated by complement pathways such as cascade factor D, including age-related macular degeneration (AMD), retinal degeneration, Paroxysmal Nocturnal Hemoglobinuria (PNH), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA), and others further described herein;

(c) use of formula I and pharmaceutically acceptable salts and prodrugs thereof in the manufacture of a medicament for the treatment or prevention of diseases mediated by complement cascade factor D, including age-related macular degeneration (AMD), retinal degeneration, Paroxysmal Nocturnal Hemoglobinuria (PNH), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA), and other diseases described further herein;

(d) a method of manufacturing a medicament intended for therapeutic use for the treatment or prevention of diseases mediated by complement cascade factor D, including age-related macular degeneration (AMD), retinal degeneration, Paroxysmal Nocturnal Hemoglobinuria (PNH), Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) and other diseases further described herein, the method characterized by using in manufacture formula I as described herein;

(e) a pharmaceutical formulation comprising a host therapeutically effective amount of formula I or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier or diluent;

(f) formula I as described herein in substantially pure form, including substantially isolated (e.g., at least 90 or 95%) from other chemical entities;

(g) methods of making compounds of formula I and salts, compositions, dosage forms thereof; and

(h) a method of preparing a therapeutic product comprising an effective amount of formula I as described herein.

Detailed Description

1. Term(s) for

Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The compounds of any formula described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each were specifically mentioned. "formula I" includes all subgenera of formula I, such as formula IA and formula IB, and also includes pharmaceutically acceptable salts of the compounds of formula I, unless the context in which the expression is used is clearly contradictory. "formula I" also includes all subgenera of formula I, such as formulas IC-ID and formulas II-XXX, and also includes pharmaceutically acceptable salts of all subgenera of formula I, such as formulas IA-ID and formulas II-XXX, unless the context in which the expression is used contradicts.

The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and/or". Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are inclusive of the stated range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The invention includes the use of a compound of formula I and a compound in which an atom is substituted with at least one desired isotope in an amount greater than the natural abundance of the isotope, i.e. enriched in the isotope. Isotopes are atoms having the same atomic number but different mass numbers, i.e. the same number of protons but different numbers of neutrons.

Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl、¹²⁵I. The present invention includes isotopically modified compounds of formula I. In one embodiment, metabolic studies may be performed (using¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) include the use of isotopically labeled compounds in drug or substrate tissue distribution assays or in the radiotherapy of patients. In particular, it is possible to use, for example,¹⁸f-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and the preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

By way of general example and not limitation, the desired result may be achievedIsotopes of hydrogen such as deuterium (g) are used anywhere in the structure²H) And tritium (f)³H) In that respect Alternatively or additionally, isotopes of carbon such as¹³C and¹⁴C. in one embodiment, isotopic substitution is by replacement of hydrogen at one or more positions on the molecule with deuterium to improve the properties of the drug, e.g., pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. for example, deuterium can be bonded to a carbon at the position of bond rupture during metabolism (α -deuterium kinetic isotope effect) or in close proximity to the site of bond rupture or in the vicinity of the site of bond rupture (β -deuterium kinetic isotope effect).

Isotopic substitution, for example deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is 90, 95, or 99% or more abundant at any location of interest. In one embodiment, deuterium is enriched to 90, 95 or 99% at the desired position. Unless otherwise indicated, the enrichment at any point is higher than natural abundance and sufficient to alter the detectability of the drug in humans.

In one embodiment, the substitution of a deuterium atom for a hydrogen atom occurs within the substituent of the R group on the region of moiety L-B in one embodiment, the substitution of a deuterium atom for a hydrogen atom occurs at a position selected from the group consisting of R¹⁸、R^18’、R³³、R³⁴、R³⁵And/or R³⁶Within the R group of any one of. In one embodiment, the substitution of a deuterium atom for a hydrogen atom occurs within the substituent of the R group within the region of the A-carbonyl moiety. In one embodiment, the substitution of deuterium atoms for hydrogen atoms occurs at R⁴、R⁵、R⁶、R^6’、R⁷、R⁸、R^8’、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁹、R²¹、R²²、R²³、R³¹And R³²To (3). In other embodiments, certain substituents on the proline ring are selectively deuterated. For example, in one embodiment, the substitution of deuterium atoms for hydrogen atoms occurs atR、R^’、R¹、R^1’、R²、R^2’、R³And/or R^3’To (3). In one embodiment, for example when any of the R substituents on the proline ring is methyl or methoxy, the alkyl residue is optionally deuterated, e.g., CD₃Or OCD₃. In certain other embodiments, when two substituents of the proline ring are combined to form a cyclopropyl ring, the unsubstituted methylene carbon is deuterated.

When at least one variable within the R group is hydrogen (e.g.,²h or D) or alkyl (e.g. CD)₃) When so, substitution of the hydrogen atom by the deuterium atom occurs within the R group. For example, when any R group is methyl or ethyl, or contains methyl or ethyl, e.g., by substitution, the alkyl residue is typically deuterated, e.g., CD₃、CH₂CD₃Or CD₂CD₃。

The compounds of the present invention may form solvates with solvents, including water. Thus, in one embodiment, the invention encompasses solvated forms of the active compound. The term "solvate" refers to a molecular complex of a compound of the invention (including salts thereof) with one or more solvent molecules. Examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the invention include those in which the solvent of the crystallization may be isotopically substituted, e.g. D₂O、d₆-acetone, d₆-DMSO. The solvate may be in liquid or solid form.

A dash "-" that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, - (C ═ O) NH₂Through the carbon of the ketone (C ═ O) group.

As used herein, the term "substituted" means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom's normal valency is not exceeded. For example, when the substituent is oxo (i.e., ═ O), then two hydrogens on the atom are replaced. When an oxo group replaces two hydrogens in an aromatic moiety, the corresponding partially unsaturated ring will replace the aromatic ring. For example, a pyridyl group substituted with an oxo group is a pyridone. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.

A stable compound or stable structure refers to a compound that produces a compound that can be isolated and formulated into a dosage form having a shelf life of at least one month.

Any suitable group may be present in the "substituted" or "optionally substituted" position, which forms a stable molecule and facilitates the intended purpose of the invention and includes, but is not limited to, for example, halogen (which may independently be F, Cl, Br, or I); a cyano group; a hydroxyl group; a nitro group; an azide group; alkanoyl (e.g. C)₂-C₆Alkanoyl groups); formamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; alkylthio groups including those having one or more thioether linkages; an alkylsulfinyl group; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups, including groups having one or more N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, and the like, each ring either substituted or unsubstituted aromatic); arylalkyl having, for example, 1 to 3 separate or fused rings and 6 to about 14 or 18 ring carbon atoms, benzyl being an exemplary arylalkyl group; arylalkoxy, e.g., having 1 to 3 separate or fused rings, benzyloxy being an exemplary arylalkoxy group; or a saturated, unsaturated or aromatic heterocyclic group having 1 to 3 separate or fused rings, having one or more N, O or S atoms, such as coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such heterocyclic groups may be further substituted, for example, with hydroxy, alkyl, alkoxy, halogen, and amino. In some embodimentsIn this case, "optionally substituted" includes one or more substituents independently selected from halogen, hydroxy, amino, cyano, -CHO, -COOH, -CONH₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, -C₁-C₆Alkoxy radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkyl esters, (mono-and di-C)₁-C₆Alkylamino) C₀-C₂Alkyl radical, C₁-C₂Haloalkyl, hydroxy C₁-C₆Alkyl, ester, carbamate, urea, sulfonamide, -C₁-C₆Alkyl (heterocyclic), C₁-C₆Alkyl (heteroaryl), -C₁-C₆Alkyl radical (C)₃-C₇Cycloalkyl), O-C₁-C₆Alkyl radical (C)₃-C₇Cycloalkyl), B (OH)₂Phosphoric acid group, phosphonic acid group and C₁-C₂A haloalkoxy group.

An "alkyl" group is a branched or straight chain saturated aliphatic hydrocarbon group. In one embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, alkyl is C₁-C₂、C₁-C₃Or C₁-C₆. As used herein, a specified range refers to each member of the range as an independent species of alkyl group. For example, as used herein, the term C₁-C₆Alkyl refers to a straight or branched alkyl group having 1,2,3, 4,5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, as used herein, the term C₁-C₄Alkyl refers to a straight or branched alkyl group having 1,2,3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When C is present₀-C_nWhen an alkyl group is used herein in combination with another group, e.g. (C)₃-C₇Cycloalkyl) C₀-C₄Alkyl or-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), the indicated groups-in this case cycloalkyl, or by a single covalent bond (C)₀Alkyl) are bonded directly or are linked via an alkyl chain (in this case 1,2,3 or 4 carbon atoms). The alkyl groups may also be attached via other groups, e.g. heteroatoms, e.g. at-O-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl) group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2-dimethylbutane, and 2, 3-dimethylbutane. In one embodiment, the alkyl group is optionally substituted as described above.

An "alkenyl group" is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a point of stability along the chain. Non-limiting examples are C₂-C₈Alkenyl radical, C₂-C₆Alkenyl and C₂-C₄An alkenyl group. As used herein, a specified range refers to each member of the range as an independent species of alkenyl group, as described above for the alkyl moiety. Examples of alkenyl groups include, but are not limited to, ethenyl and propenyl. In one embodiment, the alkenyl group is optionally substituted as described above.

An "alkynyl" group is a branched or straight aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any point of stability along the chain, e.g., C₂-C₈Alkynyl or C₂-C₆Alkynyl. As used herein, a specified range refers to an alkynyl group as an independent species for each member of the range, as described above for the alkyl moiety. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In one embodiment, the alkynyl group is optionally substituted as described above.

An "alkylene" is a divalent saturated hydrocarbon. Alkylene groups may, for example, be 1 to 8 carbon moieties, 1 to 6Carbon moieties or specified number of carbon atoms, e.g. C₁-C₄Alkylene radical, C₁-C₃Alkylene or C₁-C₂An alkylene group.

An "alkenylene" is a divalent hydrocarbon having at least one carbon-carbon double bond. Alkenylene groups may, for example, be 2 to 8 carbon moieties, 2 to 6 carbon moieties or a specified number of carbon atoms, such as C₂-C₄An alkenylene group.

"alkynylene" is a divalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylene groups may be, for example, 2 to 8 carbon moieties, 2 to 6 carbon moieties, or a specified number of carbon atoms, e.g., C₂-C₄Alkynylene radical.

An "alkoxy" group is an alkyl group as described above covalently bonded through an oxygen bridge (-O-). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, an "alkylthio" or "thioalkyl" group is an alkyl group as described above having the specified number of carbon atoms covalently bonded through a sulfur bridge (-S-). In one embodiment, the alkoxy group is optionally substituted as described above.

An "alkenyloxy" group is the alkenyl group covalently bonded through an oxygen bridge (-O-) to the group it replaces.

An "alkanoyl" group is an alkyl group as described above covalently bonded through a carbonyl (C ═ O) bridge. The carbonyl carbons being included in the carbon number, i.e. C₂Alkanoyl is CH₃(C ═ O) -groups. In one embodiment, the alkanoyl group is optionally substituted as described above.

An "alkyl ester" is an alkyl group as described herein covalently bonded through an ester bond. The ester linkage may be in either direction, for example a group of the formula-O (C ═ O) alkyl or a group of the formula- (C ═ O) oalkyl.

"amides" or "carboxamides" are-C (O) NR^aR^bWherein R is^aAnd R^bEach independently selected from hydrogen, alkyl such as C₁-C₆Alkyl, alkenyl, e.g. C₂-C₆Alkenyl, alkynyl, e.g. C₂-C₆Alkynyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -C₀-C₄Alkyl radical (C)₃-C₇Heterocycloalkyl), -C₀-C₄Alkyl (aryl) and-C₀-C₄Alkyl (heteroaryl); or R^aAnd R^bMay form C together with the nitrogen to which it is bonded₃-C₇A heterocyclic ring. In one embodiment, R^aAnd R^bEach independently is optionally substituted as described above.

A "carbocyclic group," "carbocyclic ring," or "cycloalkyl" is a saturated or partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. Carbocyclic groups typically contain 1 ring of 3 to 7 carbon atoms or 2 fused rings each of 3 to 7 carbon atoms. Cycloalkyl substituents may be pendant from a self-substituted nitrogen or carbon atom, or a substituted carbon atom that may have two substituents may have a cycloalkyl group attached as a spiro group. Examples of carbocycles include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, and cyclopropyl rings. In one embodiment, the carbocycle is optionally substituted as described above. In one embodiment, cycloalkyl is a partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms.

A "carbocycle-oxy group" is a monocyclic carbocyclic or mono-or di-cyclic carbocyclic group as described above linked to the group it is substituted for via an oxygen-O-linker.

"haloalkyl" refers to branched and straight chain alkyl groups substituted with 1 or more halogen atoms up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

"haloalkoxy" refers to a haloalkyl group as described herein attached through an oxygen bridge (oxygen of an alcohol radical).

"hydroxyalkyl" is an alkyl group as previously described substituted with at least one hydroxy substituent.

"aminoalkyl" is an alkyl group as previously described that is substituted with at least one amino substituent.

"halogen" independently refers to any of fluorine, chlorine, bromine, and iodine.

"aryl" refers to an aromatic radical containing only carbon in an aromatic ring or rings. In one embodiment, the aryl group contains 1 to 3 separate or fused rings and has 6 to about 14 or 18 ring atoms, with no heteroatoms as ring members. Where indicated, such aryl groups may also be substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 5-to 7-membered saturated cyclic group optionally containing 1 or 2 heteroatoms independently selected from N, O and S to form, for example, a3, 4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl group is a pendant group. Examples of pendant rings are phenyl groups substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described above.

As used herein, The term "heterocycle" refers to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds within The ring without aromatic) carbocyclic group having 3 to about 12, more typically 3, 5,6, 7 to 10 ring atoms, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, The remaining ring atoms being C, wherein one or more ring atoms are optionally substituted independently with one or more of The above substituents. The heterocycle may be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or a bicyclic ring having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P and S), such as bicyclo [4,5], [5,6] or [6,6] systems, in one embodiment, The only heteroatom is nitrogen, in one embodiment, The only one Heterocyclic group is a morpholinyl, a 2, a-oxopiperidinyl, oxapiperidinyl, thiopiperidinyl, 2, oxapiperidinyl, thiopiperidinyl, oxapinyl, and thiopiperidinyl, wherein The ring groups include The recited in The present examples include The Heterocyclic groups as 3, 7, 2, 7, 2-dihydro-azaspiro, and 7, 2-azaspiro-dihydro-azaspiro-2, or 7-2-azaspiro-2, or 7-azaspiro-2 [ e, or 7-azaspiro-2-azaspiro [ e, or 7-azaspiro-2 [ e, or thiopiperidinyl, 2-azaspiro [ e.

A "heterocycioxy group" is a monocyclic heterocyclic or bicyclic heterocyclic group as previously described that is linked to the group it is substituted with via an oxygen-O-linker.

"heteroaryl" refers to a stable monocyclic aromatic ring containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O and S, with the remaining ring atoms being carbon, or a stable bicyclic or tricyclic ring system containing at least one 5-to 7-membered aromatic ring containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms. In some embodiments, bicyclic heteroaryl groups are 9-to 10-membered heteroaryl groups, i.e., groups containing 9 or 10 ring atoms in which one 5-to 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In one embodiment, the total number of S and O atoms in the heteroaryl group is no more than 2. In another embodiment, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include, but are not limited to, pyridyl (including, e.g., 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, e.g., 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl and furopyridinyl. Heteroaryl groups are optionally independently substituted with one or more substituents described herein. A "heteroaryloxy" group is a heteroaryl group bonded to the group it is substituted for via an oxygen-O-linker.

"heterocycloalkyl" is a saturated cyclic group. It may have, for example, 1,2,3 or 4 heteroatoms independently selected from N, S and O, the remaining ring atoms being carbon. In a typical embodiment, the nitrogen is a heteroatom. Monocyclic heterocycloalkyl groups typically have from 3 to about 8 ring atoms or from 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolinyl.

The term "mono-and/or di-alkylamino" refers to a secondary or tertiary alkylamino group, wherein the alkyl groups are independently selected from alkyl groups as defined herein. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono-and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.

"dosage form" refers to an administration unit of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal agents, sublingual agents, topical agents, gels, mucoids and the like. "dosage form" may also include implants, such as optical implants.

A "pharmaceutical composition" is a composition comprising at least one active agent, such as a compound or salt of formula I, and at least one other substance, such as a carrier. A "pharmaceutical combination" is a combination of at least two active agents that can be combined into a single dosage form or provided together in separate dosage forms as dictated by the use of these active agents together to treat any of the diseases described herein.

"pharmaceutically acceptable salts" include derivatives of the disclosed compounds wherein the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. Salts of the present compounds may be synthesized from the parent compound, which contains an acidic or basic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.) or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are generally carried out in water or in an organic solvent or in a mixture of the two. Generally, nonaqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical where feasible. Salts of the present compounds also include solvates of the compounds and salts of the compounds.

Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include those formed from parent compounds formed, for example, from non-toxic inorganic or organic acidsConventional non-toxic salts and quaternary ammonium salts of the compounds. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, hydroxyethanesulfonic acid, HOOC- (CH)₂)_n-COOH (wherein n is 0 to 4), and the like. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences,17th ed., MackPublishing Company, Easton, Pa., p.1418 (1985).

The term "carrier" as applied to the pharmaceutical compositions/combinations of the present invention refers to a diluent, excipient or vehicle with which the active compound is provided.

"pharmaceutically acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition/combination that is generally safe, non-toxic, and neither biologically nor otherwise unsuitable for administration to a host, and in one embodiment includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used herein, "pharmaceutically acceptable excipient" includes one and more than one such excipient.

A "patient" or "host" or "patient" is a human or non-human animal in need of modulation of the complement factor D pathway. Typically, the host is human. "patient" or "host" or "patient" also refers to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.

As used herein, "prodrug" refers to a compound that is converted to the parent drug when administered to a host in vivo. As used herein, the term "parent drug" refers to any of the presently described chemical compounds that may be used to treat any of the diseases described herein, or to control or ameliorate the underlying cause or symptom of a host, typically a human, associated with any of the physiological or pathological conditions described herein. Prodrugs can be used to achieve any desired effect, including enhancing the properties of the parent drug or improving the parent drug or pharmacokinetic properties. There are prodrug strategies that provide for the selection in the modulation of the conditions of in vivo production of the parent drug, all of which are considered to be included herein. Non-limiting examples of prodrug strategies include covalent attachment of a removable group, or removable portion of a group, such as, but not limited to, acylation, phosphorylation, phosphoramidation, amidation, reduction, oxidation, esterification, alkylation, other carboxyl derivatives, sulfoxide or sulfone derivatives, carbonylation or anhydride, and the like.

By "providing a compound of formula I with at least one other active agent" is meant that the compound of formula I and the other active agent or agents are provided simultaneously in a single dosage form, concomitantly in separate dosage forms, or administered in separate dosage forms separated by an amount of time over a period of time wherein both the compound of formula I and the at least one other active agent are in the bloodstream of a patient. In certain embodiments, the compound of formula I and the additional active agent need not be prescribed to the patient by the same healthcare worker. In certain embodiments, the one or more additional active agents need not be a prescription. Administration of the compound of formula I or the at least one other active agent may be via any suitable route, such as oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories, or topical contact.

A "therapeutically effective amount" of a pharmaceutical composition/combination of the invention refers to an amount effective to provide a therapeutic benefit, such as an improvement in symptoms, when administered to a patient, e.g., an amount effective to reduce the symptoms of macular degeneration. In one embodiment, a therapeutically effective amount is an amount sufficient to prevent or will significantly reduce a detectable level of complement factor D in the blood, serum or tissue of a patient.

Detailed description of the active Compounds

According to the present invention there is provided a compound of formula I:

formula I can be considered to have a central core, L-B substituent and (C ═ O) a substituent¹²Or R¹³Compounds of formula I that are aryl, heteroaryl or heterocyclyl or pharmaceutically acceptable salts or compositions thereof are excellent inhibitors of complement factor D and therefore can be used in effective amounts to treat a host in need of complement factor D modulation.

The following shows variables falling within formula I, e.g., A, B, R¹-R^3’And L, the present invention encompasses all combinations of these definitions, so long as a stable compound is produced.

Formula II-XXX

In one aspect, the invention relates to compounds and salts of formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX and XXX, which are within the scope of formula I. The variables shown in formulas II-XXX have the definitions given for formula I in the summary section or any of the definitions given in this disclosure.

In these embodiments, it is understood that when R is¹Or R³When bound to carbon, e.g. at R²/R^2’There may be two separate connections and these should be considered as including all such variations.

Additionally, the present disclosure includes compounds and salts of formula I and pharmaceutically acceptable compositions thereof, as well as any of its sub-formulae (II-XXX) in which at least one of the following conditions is met in the embodiments described below.

R¹²And R¹³Aryl, heteroaryl and heterocyclic substituents

It has surprisingly been found that R on the group A¹²Or R¹³Compounds of formula I, pharmaceutically acceptable salts or compositions thereof, which are aryl, heteroaryl or heterocyclic, are excellent inhibitors of complement factor D.

R¹²And R¹³One of them is selected from R³¹And R is¹²And R¹³Is selected from R³². In another embodiment, R¹²And R¹³Each of which may be independently selected from R³²。

R³¹Selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, -COOH, -C₁-C₂Haloalkyl, C₁-C₂Haloalkoxy, C₁-C₆Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy radical, C₂-C₆Alkenyloxy, -C (O) OR⁹、C₁-C₆Thioalkyl, -C₀-C₄Alkyl radical NR⁹R¹⁰、-C(O)NR⁹R¹⁰、-SO₂R⁹、-SO₂NR⁹R¹⁰、-OC(O)R⁹and-C (NR)⁹)NR⁹R¹⁰Removing hydrogen, halogen, hydroxy, nitro, cyano, C₁-C₂Haloalkyl and C₁-C₂Each of said R's other than haloalkoxy³¹Is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, nitro, cyano, amino、-COOH、-CONH₂、C₁-C₂Haloalkyl and C₁-C₂Haloalkoxy, and each of said R³¹And is further optionally substituted with a substituent selected from phenyl and a 4-to 7-membered heterocyclic ring containing 1,2 or 3 heteroatoms independently selected from N, O and S; said phenyl or 4-to 7-membered heterocyclic ring being unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy groups, (mono-and di-C)₁-C₆Alkylamino) C₀-C₄Alkyl radical, C₁-C₆Alkyl esters, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group;

R³²Are as non-limiting examples

Non-limiting R¹²/R¹³Detailed description of the preferred embodiments

At one isIn embodiments, R¹²Is R³²。

In one embodiment, R¹³Is R³²。

In one embodiment, R¹²Is R³²It is aryl.

In one embodiment, R¹²Is an optionally substituted aryl group.

In one embodiment, R¹²Is an optionally substituted saturated or unsaturated heterocyclic ring bonded to R through a carbon atom in the heterocyclic ring¹²Position the carbon atom of ring a.

In one embodiment, R¹²Is an optionally substituted heteroaryl group.

In one embodiment, R¹³Is an optionally substituted aryl group.

In one embodiment, R¹³Is an optionally substituted saturated or unsaturated heterocyclic ring bonded to R through a carbon atom in the heterocyclic ring¹³Position the carbon atom of ring a.

In one embodiment, R¹³Is an optionally substituted heteroaryl group.

In one embodiment, R¹²Is R³²(5-or 6-membered unsaturated or aromatic heterocycle) having 1,2 or 3 heteroatoms independently selected from N, O and S, wherein the (5-or 6-membered unsaturated heterocycle) is bonded to CR through a carbon atom¹²Or CR¹³Carbon (c) of (a).

In one embodiment, R¹²Is R³²(4-to 7-membered heterocycloalkyl) having 1,2 or 3 heteroatoms independently selected from N, O and S, wherein said (4-to 7-membered heterocycloalkyl) is bonded to CR through a carbon atom¹²Or CR¹³Carbon (c) of (a).

In one embodiment, R¹³Is R³²It is aryl.

In one embodiment, R¹³Is R³²Which is a (5-or 6-membered unsaturated or aromatic heterocyclic ring) having 1,2 or 3 heteroatoms independently selected from N, O and S, which isWherein said (5-or 6-membered unsaturated heterocyclic ring) is bonded to CR through a carbon atom¹²Or CR¹³Carbon (c) of (a).

In one embodiment, R¹³Is R³²(4-to 7-membered heterocycloalkyl) having 1,2 or 3 heteroatoms independently selected from N, O and S, wherein said (4-to 7-membered heterocycloalkyl) is bonded to CR through a carbon atom¹²Or CR¹³Carbon (c) of (a).

In one embodiment, the present invention provides a compound of formula I wherein:

R¹²and R¹³One of them is H and R¹²And R¹³The other of (A) is R³²Wherein:

R³²selected from aryl, which may be optionally substituted; (5-or 6-membered unsaturated or aromatic heterocycle) having 1,2 or 3 heteroatoms independently selected from N, O and S, wherein the (5-or 6-membered unsaturated heterocycle) is bonded to CR through a carbon atom¹²Or CR¹³Wherein the (5-or 6-membered unsaturated or aromatic heterocyclic ring) may be optionally substituted; and (4-to 7-membered heterocycloalkyl) having 1,2, or 3 heteroatoms independently selected from N, O and S, wherein said (4-to 7-membered heterocycloalkyl) is bonded to CR through a carbon atom¹²Or CR¹³And said (4-to 7-membered heterocycloalkyl) may be optionally substituted.

In another embodiment, the present invention provides a compound of formula I wherein:

R¹、R^1’、R²and R^3’Are all hydrogen;

R²is fluorine and R³Is hydrogen, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl) or-O-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl groups);

R⁵is hydrogen, halogen or C₁-C₂An alkyl group;

R¹¹、R¹³、R¹⁴and R¹⁵If present, is independently selected from hydrogen, halogen, hydroxy, amino, C at each occurrence₁-C₄Alkyl radical, C₁-C₄Alkoxy, -C₀-C₂Alkyl (mono-and di-C)₁-C₂Alkylamino), trifluoromethyl and trifluoromethoxy;

X¹²is CR¹²(ii) a And

R¹²selected from aryl, which may be optionally substituted; (5-or 6-membered unsaturated or aromatic heterocycle) having 1,2 or 3 heteroatoms independently selected from N, O and S, wherein the (5-or 6-membered unsaturated heterocycle) is bonded to CR through a carbon atom¹²Or CR¹³Wherein the (5-or 6-membered unsaturated or aromatic heterocyclic ring) may be optionally substituted; and (4-to 7-membered heterocycloalkyl) having 1,2, or 3 heteroatoms independently selected from N, O and S, wherein said (4-to 7-membered heterocycloalkyl) is bonded to CR through a carbon atom¹²Or CR¹³And said (4-to 7-membered heterocycloalkyl) may be optionally substituted.

In one embodiment, the present invention provides a compound of formula I wherein:

m is 0 or 1;

R²is halogen, R^2’Is hydrogen or halogen, R³Is hydrogen, halogen, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl) or-O-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl groups);

R⁶is-C (O) C₁-C₄Alkyl, -C (O) NH₂、-C(O)CF₃、-C(O)(C₃-C₇Cycloalkyl) or-ethyl (cyanoimino);

R¹²and R¹³One of them is selected from hydrogen, halogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, trifluoromethyl and trifluoromethoxy; r¹²And R¹³The other of (A) is R³²Wherein

R³²Is selected from aryl; a saturated or unsaturated heterocyclic ring (e.g., a 5-6 membered ring having 1,2, or 3 heteroatoms independently selected from N, O and S), wherein the heterocyclic ring is bonded to R through a carbon atom in the heterocyclic ring¹²Or R¹³Position middle ringA carbon atom of A; and heteroaryl (e.g., a 5-6 membered ring having 1,2, or 3 heteroatoms independently selected from N, O and S), wherein the aryl, heterocyclic, or heteroaryl ring can be optionally substituted.

In one embodiment, the present invention provides a compound of formula I, wherein R is¹²And R¹³One of them is hydrogen, hydroxy, halogen, methyl or methoxy; r¹²And R¹³The other of (A) is R³²Wherein

R³²Selected from aryl, heteroaryl or heterocyclic, bonded to the a ring through a heterocyclic carbon atom.

In one embodiment, R³²May be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, nitro, cyano, amino, oxo, -B (OH)₂、-Si(CH₃)₃、-COOH、-CONH₂、-P(O)(OH)₂、C₁-C₆Alkyl radical, C₁-C₆Alkoxy, -C₀-C₂Alkyl (mono-and di-C)₁-C₄Alkylamino), C₁-C₆Alkyl ester, C₁-C₄Alkylamino radical, C₁-C₄Hydroxyalkyl radical, C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

Central core part

The central core portion in formula I is illustrated below:

central core part

Wherein:

Q¹is N (R)¹) Or C (R)¹R^1’)；

Q²Is C (R)²R^2’)、C(R²R^2’)-C(R²R^2’)、S、O、N(R²) Or C (R)²R^2’)O；

Q³Is N (R)³) S or C (R)³R^3’)；

X¹And X²Independently N, CH or CZ, or X¹And X²Together are C ═ C; and

wherein Q¹、Q²、Q³、X¹And X²Selected such that a stable compound is produced.

Wherein q is 0, 1,2 or 3 and r is 1,2 or 3.

R and R' are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl (each of which may be optionally substituted), or any other substituent group that provides the desired properties herein. In some embodiments, the ring comprises one or more chiral carbon atoms. The invention includes embodiments in which the chiral carbon may be provided as an enantiomer or a mixture of enantiomers, including a racemic mixture. When the ring contains more than one stereocenter, all enantiomers and diastereomers are included as separate species in the present invention.

Z is F, Cl, NH₂、CH₃、CH₂D、CHD₂Or CD₃。

Non-limiting Central core embodiments

each of said rings may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (especially F), hydroxy, -cyano, -COOH, C₁-C₄Alkyl (including especially methyl), C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Alkoxy radical,C₂-C₄Alkanoyl, hydroxy C₁-C₄Alkyl, (mono-and di-C)₁-C₄Alkylamino) C₀-C₄Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -O-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

each of said rings may be unsubstituted or substituted with 1 or more substituents independently selected from halogen (especially F), hydroxy, -cyano, -COOH, C₁-C₄Alkyl (including especially methyl), C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₄Alkoxy radical, C₂-C₄Alkanoyl, hydroxy C₁-C₄Alkyl, (mono-and di-C)₁-C₄Alkylamino) C₀-C₄Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -O-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

In one embodiment, the central core moiety is proline.

In one embodiment, the central core moiety is 4-fluoroproline.

In one embodiment, R¹、R^1’、R^2’、R³And R^3’And, if present, are hydrogen; r²Is fluorine.

In a fruitIn the embodiment, R¹、R^1’、R^2’And R^3’And, if present, are hydrogen; r²Is fluorine and R³is-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl) or-O-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl groups).

In one embodiment, R¹And R²Together form a 3-to 6-membered cycloalkyl group, and R^1’、R^2’、R³And R^3’And when present, are all hydrogen.

In one embodiment, R¹、R^1’、R³And R^3’If present, is hydrogen, and R²And R^2’Together form a 5-or 6-membered heterocycloalkyl group having 1 or 2 oxygen atoms.

In one embodiment, R¹Is hydrogen and R²Is fluorine.

In one embodiment, R¹And R²Joined to form a 3-membered ring.

The present invention includes compounds of formula I wherein the central pyrrolidine is substituted with a vinyl group, for example:

in one embodiment, the compound of formula I has the structure:

in one embodiment, the central pyrrolidine is modified by adding a second heteroatom such as N, O, S or Si to the pyrrolidine ring, for example:

another modification within the scope of the present invention is the incorporation of a substituent on the central pyrrolidine ring into R⁷Or R⁸To form a 5-to 6-membered heterocyclic ring, for example:

example compounds having the modifications disclosed above include:

central nucleus L-B substituent

The central core L-B substituent in formula I is shown below:

l is a bond or is selected from the group consisting of:

wherein R is¹⁷Is hydrogen, C₁-C₆Alkyl or-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), R¹⁸And R^18’Independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is 0, 1,2 or 3.

Each said B is unsubstituted or substituted with one or more substituents independently selected from R³³And R³⁴And 0 or 1 substituent is selected from R³⁵And R³⁶。

R³³Is independently selected fromHalogen, hydroxy, -COOH, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy, -C₀-C₄Alkyl radical NR⁹R¹⁰、-SO₂R⁹、C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group;

R³⁴independently selected from nitro, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Thioalkyl, -JC₃-C₇Cycloalkyl, -B (OH)₂、-JC(O)NR⁹R²³、-JOSO₂OR²¹、-C(O)(CH₂)_1-4S(O)R²¹、-O(CH₂)_1-4S(O)NR²¹R²²、-JOP(O)(OR²¹)(OR²²)、-JP(O)(OR²¹)(OR²²)、-JOP(O)(OR²¹)R²²、-JP(O)(OR²¹)R²²、-JOP(O)R²¹R²²、-JP(O)R²¹R²²、-JSP(O)(OR²¹)(OR²²)、-JSP(O)(OR²¹)(R²²)、-JSP(O)(R²¹)(R²²)、-JNR⁹P(O)(NHR²¹)(NHR²²)、-JNR⁹P(O)(OR²¹)(NHR²²)、-JNR⁹P(O)(OR²¹)(OR²²)、-JC(S)R²¹、-JNR²¹SO₂R²²、-JNR⁹S(O)NR¹⁰R²²、-JNR⁹SO₂NR¹⁰R²²、-JSO₂NR⁹COR²²、-JSO₂NR⁹CONR²¹R²²、-JNR²¹SO₂R²²、-JC(O)NR²¹SO₂R²²、-JC(NH₂)NR²²、-JC(NH₂)NR⁹S(O)₂R²²、-JOC(O)NR²¹R²²、-JNR²¹C(O)OR²²、-JNR²¹OC(O)R²²、-(CH₂)_1-4C(O)NR²¹R²²、-JC(O)R²⁴R²⁵、-JNR⁹C(O)R²¹、-JC(O)R²¹、-JNR⁹C(O)NR¹⁰R²²、-CCR²¹、-(CH₂)_1-4OC(O)R²¹and-JC (O) OR²³(ii) a Each of said R³⁴May be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxy, nitro, cyano, amino, oxo, -B (OH)₂、-Si(CH₃)₃、-COOH、-CONH₂、-P(O)(OH)₂、C₁-C₆Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₆Alkoxy, -C₀-C₂Alkyl (mono-and di-C)₁-C₄Alkylamino), C₁-C₆Alkyl ester, C₁-C₄Alkylamino radical, C₁-C₄Hydroxyalkyl radical, C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group;

R³⁵independently selected from naphthyl, naphthyloxy, indanyl, (4-to 7-membered heterocycloalkyl) C containing 1 or 2 heteroatoms selected from N, O and S₀-C₄Alkyl and a bicyclic heterocycle containing 1,2 or 3 heteroatoms independently selected from N, O and S and containing 4-to 7-ring atoms in each ring; each of said R³⁵Is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy groups, (mono-and di-C)₁-C₆Alkylamino) C₀-C₄Alkyl radical, C₁-C₆Alkyl esters, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -SO₂R⁹、C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group; and

R³⁶independently selected from tetrazolyl, (phenyl) C₀-C₂Alkyl, (phenyl) C₁-C₂Alkoxy, phenoxyAnd 5-or 6-membered heteroaryl containing 1,2 or 3 heteroatoms independently selected from N, O, B and S, each of said R³⁶Is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy groups, (mono-and di-C)₁-C₆Alkylamino) C₀-C₄Alkyl radical, C₁-C₆Alkyl esters, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -SO₂R⁹、-OSi(CH₃)₂C(CH₃)₃、-Si(CH₃)₂C(CH₃)₃、C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

J is independently selected for each occurrence from a covalent bond, C₁-C₄Alkylene, -OC₁-C₄Alkylene radical, C₂-C₄Alkenylene and C₂-C₄Alkynylene radical.

In one embodiment, -L-B-is

Wherein

R²⁶And R²⁷Independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy radical, C₁-C₆Thioalkyl, -C₀-C₄Alkyl (mono-and di-C)₁-C₆Alkylamino), -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -C₀-C₄Alkoxy (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl, C₁-C₂Haloalkoxy and C₁-C₂A haloalkylthio group.

Non-limiting L-B embodiment

In another embodiment, -L-B-is

Wherein

R¹⁸And R^18’Independently selected from hydrogen, halogen, hydroxymethyl and methyl; m is 0 or 1; and is

R²⁶、R²⁷And R²⁸Independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy radical, C₁-C₆Thioalkyl, (mono-and di-C)₁-C₆Alkylamino) C₀-C₄Alkyl, (C)₃-C₇Cycloalkyl) C₀-C₄Alkyl, (aryl) C₀-C₄Alkyl-, (heteroaryl) C₀-C₄alkyl-and-C₀-C₄Alkoxy (C)₃-C₇Cycloalkyl groups); each of said R except hydrogen, halogen, hydroxy, nitro, cyano²⁶、R²⁷And R²⁸Is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, amino, C₁-C₂Alkoxy radical, C₁-C₂Haloalkyl, (C)₃-C₇Cycloalkyl) C₀-C₄Alkyl-and C₁-C₂A haloalkoxy group; and

R²⁹is hydrogen, C₁-C₂Alkyl radical, C₁C₂Haloalkyl or-Si (CH)₃)₂C(CH₃)₃。

In one embodiment, m is 0.

In one embodiment, the present invention also includes compounds and salts of formula I wherein B is 2-fluoro-3-chlorophenyl. In another embodiment, another carbocyclic, aryl, heterocyclic or heteroaryl group is used such as 2-bromo-pyridin-6-yl, 1- (2,2, 2-trifluoroethyl) -1H-pyrazol-3-yl, 2, 2-dichlorocyclopropylmethyl or 2-fluoro-3-trimethylsilylphenyl.

In another embodiment, B is phenyl, pyridinyl, or indanyl, each of which is unsubstituted or substituted with one or more substituents independently selected from hydrogen, halogen, hydroxy, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy radical, C₁-C₆Thioalkyl, (mono-and di-C)₁-C₆Alkylamino) C₀-C₄Alkyl, (C)₃-C₇Cycloalkyl) C₀-C₄Alkyl, -C₀-C₄Alkoxy (C)₃-C₇Cycloalkyl), (phenyl) C₀-C₂Alkyl, (pyridyl) C₀-C₂An alkyl group; each of said substituents, except hydrogen, halogen, hydroxy, nitro, cyano, is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, amino, C₁-C₂Alkyl radical, C₁-C₂Alkoxy, -OSi (CH)₃)₂C(CH₃)₃、-Si(CH₃)₂C(CH₃)₃、C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

In another embodiment, B is phenyl or pyridyl substituted with 1,2 or 3 substituents selected from the group consisting of chloro, bromo, hydroxy, -SCF₃、C₁-C₂Alkyl radical, C₁-C₂Alkoxy, trifluoromethyl, phenyl and trifluoromethoxy, except for chlorine, bromine, hydroxy, -SCF₃Each of said substituents may be optionally substituted.

In certain embodiments, B is a 2-fluoro-3-chlorophenyl or 2-fluoro-3-trifluoromethoxyphenyl group.

In one embodiment, B is pyridineOptionally substituted by halogen, C₁-C₂Alkoxy and trifluoromethyl.

In one embodiment, B is phenyl substituted with 1,2 or 3 substituents independently selected from halogen, C₁-C₂Alkyl radical, C₁-C₂Alkoxy, trifluoromethyl and optionally substituted phenyl.

In one embodiment, R²³Independently at each occurrence selected from (C)₃-C₇Cycloalkyl) C₀-C₄Alkyl, (phenyl) C₀-C₄Alkyl, (4-to 7-membered heterocycloalkyl) C having 1,2 or 3 heteroatoms independently selected from N, O and S₀-C₄Alkyl and (5-or 6-membered unsaturated or aromatic heterocyclic) C having 1,2 or 3 heteroatoms independently selected from N, O and S₀-C₄An alkyl group.

In one embodiment, B is selected from

Wherein R is²⁷Is hydrogen, methyl or trifluoromethyl; r²⁸Is hydrogen or halogen; r²⁹Is hydrogen, methyl, trifluoromethyl or-Si (CH)₃)₂C(CH₃)₃。

Central nucleus (C ═ O) A substituent

The central core (C ═ O) a substituent in formula I is illustrated below:

a is a group selected from:

R^6’Is hydrogen, halogen, hydroxy, C₁-C₄Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl) or C₁-C₄An alkoxy group; or R⁶And R^6’Together may form an oxo, vinyl or imino group.

R⁷Is hydrogen, C₁-C₆Alkyl or-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl groups).

R¹⁹Is hydrogen, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl, -SO₂C₁-C₆Alkyl (mono-and di-C)₁-C₆Alkylamino) C₁-C₄Alkyl, -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -C₀-C₄Alkyl radical (C)₃-C₇Heterocycloalkyl), -C₀-C₄Alkyl (aryl), C₀-C₄Alkyl (heteroaryl), and wherein R is other than hydrogen¹⁹Is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, amino, -COOH and-C (O) OC₁-C₄An alkyl group.

X¹¹Is N or CR¹¹。

X¹²Is N or CR¹²。

X¹³Is N or CR¹³。

X¹⁴Is N or CR¹⁴。

X¹¹、X¹²、X¹³And X¹⁴No more than 2 of which are N.

R¹¹、R¹⁴And R¹⁵Independently at each occurrence, selected from hydrogen, halogen, hydroxyNitro, cyano, -O (PO) (OR)⁹)₂、-(PO)(OR⁹)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₂-C₆Alkenyl (aryl), C₂-C₆Alkenyl (cycloalkyl), C₂-C₆Alkenyl (heterocycle), C₂-C₆Alkenyl (heteroaryl), C₂-C₆Alkynyl, C₂-C₆Alkynyl (aryl), C₂-C₆Alkynyl (cycloalkyl), C₂-C₆Alkynyl (heterocycle), C₂-C₆Alkynyl (heteroaryl), C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy radical, C₁-C₆Thioalkyl, -C₀-C₄Alkyl (mono-and di-C)₁-C₆Alkylamino), -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -C₀-C₄Alkoxy (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

In one embodiment, R⁵And R⁶Independently selected from-CHO, -C (O) NH₂、-C(O)NH(CH₃)、C₂-C₆Alkanoyl and hydrogen.

In one embodiment, each R other than hydrogen, hydroxy, cyano and-COOH⁵And R⁶Is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, amino, imino, cyano, cyanoimino, C₁-C₂Alkyl radical, C₁-C₄Alkoxy, -C₀-C₂Alkyl (mono-and di-C)₁-C₄Alkylamino), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

In one embodiment, R⁸And R^8’Independently hydrogen or methyl.

In one embodiment, R⁸And R^8’Is hydrogen.

In one embodiment, R⁷Is hydrogen or methyl.

In one embodiment, R⁷Is hydrogen.

Embodiments of formulae IA, IB, IC and ID

To further illustrate the present invention, various embodiments of formulas IA, IB, IC and ID are provided. These embodiments are presented by way of example to illustrate some variations of the compounds presented within the invention and may be applied to any of formulas I-XXX.

In one aspect, the invention includes compounds and salts of formula IA:

wherein

R⁶、R¹³And B may have any of the definitions given herein for this variable.

In another aspect, the invention includes compounds and salts of formula IB, IC and ID.

In formulas IA, IB, IC and ID, the variables may include any of the definitions given herein to produce stable compounds. In certain embodiments, the following conditions apply to formulas IB and IC.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹Is H, R²Is F, R⁶Is alkanoyl, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹And R²Joined to form a 3-membered ring, R⁶Is alkanoyl, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, wherein m ═ 0,R¹is H, R²Is F, R⁶Is an amide, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹And R²Joined to form a 3-membered ring, R⁶Is an amide, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹Is H, R²Is F, R⁶Is alkanoyl, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹And R²Joined to form a 3-membered ring, R⁶Is alkanoyl, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹Is H, R²Is F, R⁶Is an amide, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹And R²Joined to form a 3-membered ring, R⁶Is an amide, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹Is H, R²Is F, R⁶Is alkanoyl, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is phenyl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹Is H, R²Is F, R⁶Is an amide, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is phenyl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹Is H, R²Is F, R⁶Is alkanoyl, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is phenyl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 0, R¹Is H, R²Is F, R⁶Is an amide, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is phenyl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹Is H, R²Is F, R⁶Is alkanoyl, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹And R²Joined to form a 3-membered ring, R⁶Is alkanoyl, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹Is H, R²Is F, R⁶Is an amide, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹And R²Joined to form a 3-membered ring, R⁶Is an amide, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹Is H, R²Is F, R⁶Is alkanoyl, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹And R²Joined to form a 3-membered ring, R⁶Is alkanoyl, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹Is H, R²Is F, R⁶Is an amide, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹And R²Bonding to form 3-memberedRing, R⁶Is an amide, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹Is H, R²Is F, R⁶Is alkanoyl, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is phenyl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹Is H, R²Is F, R⁶Is an amide, R¹²Is R³²，R³²Is heteroaryl, R¹³Is H, and B is phenyl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹Is H, R²Is F, R⁶Is alkanoyl, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is phenyl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹Is H, R²Is F, R⁶Is an amide，R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is phenyl.

In some embodiments, structures are provided that include formula IB and IC, where m ═ 1, R¹And R²Joined to form a 3-membered ring, R⁶Is an amide, R¹²Is H, R¹³Is R³²，R³²Is heteroaryl and B is phenyl.

Embodiments of formula VII

To further illustrate the present invention, various embodiments of formula VII are provided. In one aspect, the invention includes compounds and salts of formula VII:

wherein:

R¹、R²、R^2’and R³Independently selected from hydrogen, halogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, -C₀-C₂Alkyl radical NR⁹R¹⁰、-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -O-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group;

R⁸and R^8’Independently selected from hydrogen, halogen and methyl;

R⁵is hydrogen, hydroxy, -COOH, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₂-C₆alkanoyl-C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -C (O) C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl or C₁-C₂A haloalkoxy group;

R⁶is-C (O) CH₃、-C(O)NH₂、-C(O)CF₃-c (o) (cyclopropyl) or-ethyl (cyanoimino); and is

R¹¹And R¹⁴Independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkanoyl radical, C₁-C₆Alkoxy radical, C₁-C₆Thioalkyl, -C₀-C₄Alkyl (mono-and di-C)₁-C₆Alkylamino), -C₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), -OC₀-C₄Alkyl radical (C)₃-C₇Cycloalkyl), C₁-C₂Haloalkyl and C₁-C₂A haloalkoxy group.

Prodrugs of formula I are also within the scope of the invention.

Pharmaceutical preparation

The compounds disclosed herein may be administered as pure chemicals, but may also be administered as pharmaceutical compositions comprising an effective amount of a selected compound of formula I as described herein for a host in need of treatment. Accordingly, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier. The pharmaceutical composition may contain a compound or salt of formula I as the only active agent, or in an alternative embodiment, formula I and at least one additional active agent. In certain embodiments, the pharmaceutical composition is in a dosage form containing from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of a compound of formula I and optionally from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of an additional active agent in a unit dosage form. Examples are dosage forms having at least 25, 50, 100, 200, 250, 300, 400, 500, 600, 700 or 750mg of active compound or a salt thereof. The pharmaceutical composition may further comprise a compound of formula I and an additional active agent in a molar ratio. For example, the pharmaceutical composition may contain the additional anti-inflammatory agent in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or from about 1.5:1 to about 4: 1.

The compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implants (including ocular implants), transdermally, via buccal delivery, rectally, as ophthalmic solutions, by injection (including ocular injections), intravenously, intraarterially, intracranially, or by other means, in unit dose formulations containing conventional pharmaceutically acceptable carriers. The pharmaceutical composition may be formulated in any pharmaceutically acceptable form, for example as an aerosol, cream, gel, pill, capsule, tablet, syrup, transdermal patch or ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into unit doses of appropriate size, containing appropriate amounts of the active ingredient, e.g., an amount effective to achieve the desired purpose.

Carriers include excipients and diluents and must be of sufficiently high purity and low toxicity to render them suitable for administration to the patient being treated. The carrier may be inert or it may have its own pharmaceutical benefits. The amount of carrier employed with the compound should be sufficient to provide a practical amount of material for administering each unit dose of the compound.

Classes of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one category, for example vegetable oils may be used as lubricants in some formulations and as diluents in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially interfere with the activity of the compounds of the present invention.

The pharmaceutical compositions/combinations may be formulated for oral administration. These compositions may contain any amount of the active compound of formula I that achieves the desired result, for example between 0.1 and 99 weight percent (wt%) of the compound of formula I, typically at least about 5 wt% of the compound of formula I. Some embodiments comprise from about 25% to about 50% or from about 5% to about 75% by weight of the compound of formula I.

The complement factor D inhibitors of the invention can be administered, for example, systemically or locally. Systemic administration includes, for example, oral, transdermal, subdermal, intraperitoneal, subcutaneous, nasal, sublingual, or rectal. Topical application for ocular administration includes: topical, intravitreal, periocular, transscleral, retrobulbar, paracleral, sub-fascial (tenon) or via intraocular devices. The inhibitor may be delivered via a sustained delivery device implanted intravitreally or transsclerally, or by other known local ocular delivery means.

Methods of treatment

The complement-mediated diseases that can be treated or prevented by the compounds and compositions of the invention include, but are not limited to, inflammatory effects of sepsis, Systemic Inflammatory Response Syndrome (SIRS), ischemia/reperfusion injury (I/R injury), psoriasis, myasthenia gravis, systemic lupus erythematosus (S L E), paroxysmal sleep hemoglobinuria (PNH), hereditary angioedema, multiple sclerosis, trauma, burn, capillary leak syndrome, obesity, diabetes, alzheimer' S senile dementia, stroke, schizophrenia, epilepsy, macular degeneration related, glaucoma, diabetic retinopathy, asthma, anaphylaxis, acute respiratory syndrome (arkis syndrome), hemolytic respiratory syndrome (acute respiratory syndrome), hemolytic syndrome (acute respiratory syndrome), inflammatory bowel disease (paphia syndrome), inflammatory bowel disease, inflammatory syndrome, inflammatory bowel disease, acute glomerulonephritis, inflammatory syndrome, acute glomerulonephritis, inflammatory bowel disease, inflammatory syndrome, inflammatory bowel disease, acute respiratory distress syndrome, inflammatory bowel disease, inflammatory diseases, inflammatory bowel disease, inflammatory diseases, inflammatory bowel disease, rheumatoid arthritis, rheumatoid.

In some embodiments, complement-mediated diseases include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), respiratory diseases, cardiovascular diseases. In other embodiments, the compounds of the invention are suitable for use in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.

In one embodiment, there is provided a method of treating Paroxysmal Nocturnal Hemoglobinuria (PNH) comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating age-related macular degeneration (AMD) comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating rheumatoid arthritis comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating multiple sclerosis comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating myasthenia gravis comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating atypical hemolytic uremic syndrome (aHUS) comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating C3 glomerulonephritis comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating an abdominal aortic aneurysm comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, there is provided a method of treating neuromyelitis optica (NMO) comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides methods of treating or preventing inflammatory or complement-associated diseases by administering to a host in need thereof an effective amount of a compound of formula I of the present invention. In some embodiments, the invention provides methods of treating or preventing an inflammatory disease, more typically an immune disease, an autoimmune disease, or a complement factor D-associated disease, by providing to a patient having a factor D-mediated inflammatory disease an effective amount of a compound of formula I or a pharmaceutically acceptable salt. The compound or salt of formula I may be provided as the sole active agent or may be provided together with one or more additional active agents.

In one embodiment, there is provided a method of treating a disease associated with dysfunction in the complement cascade comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one embodiment, there is provided a method of inhibiting activation of the alternative complement pathway in a patient comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one embodiment, there is provided a method of modulating factor D activity in a patient comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

As used in this disclosure, "preventing" refers to reducing the likelihood of the appearance of symptoms in a patient to whom a compound is administered prophylactically as compared to the likelihood of the appearance of symptoms in a patient to whom a compound is not administered or reducing the severity of symptoms in a patient to whom a compound is administered prophylactically as compared to the severity of symptoms experienced by a patient suffering from a disease or disorder but to whom a compound is not administered. In an alternative embodiment, an effective amount of a compound of formula I is used to prevent or prevent complement factor D-related diseases.

An effective amount of a pharmaceutical composition/combination of the invention can be sufficient to (a) inhibit the development of a complement pathway-mediated disease including an inflammatory disease, an immune (including autoimmune) disease, or a complement factor D-related disease; (b) causing regression of an inflammatory disease, an immune (including autoimmune) disease, or a complement factor D-related disease; or (c) an amount that results in a cure for an inflammatory disease, an immune (including autoimmune) disease, or a complement factor D-related disease.

An effective amount of a compound or pharmaceutical composition described herein will also provide a sufficient amount of the active agent when administered to a patient to provide a clinically beneficial effect. Such an amount can be determined experimentally, for example by determining the blood concentration of the agent or by theoretically calculating the bioavailability.

Combination therapy

In one embodiment, the compound or salt of formula I may be provided in combination or alternation with at least one additional complement system inhibitor or a second active compound having a different biological mechanism of action. In one embodiment, the compound or salt of formula I may be provided in combination with a complement C5 inhibitor or a C5 invertase inhibitor. In another embodiment, the compound or salt of formula I may be provided in combination with eculizumab. In one embodiment, the compound or salt of formula I may be provided in combination with an additional inhibitor of factor D.

In one embodiment, the compound or salt of formula I may be provided with a compound that inhibits an enzyme that metabolizes a protease inhibitor. In one embodiment, the compound or salt of formula I may be provided with ritonavir.

In non-limiting embodiments, the compound or salt of formula I can be provided with a protease inhibitor, a soluble complement regulator, a therapeutic antibody (monoclonal or polyclonal), a complement component inhibitor, a receptor agonist, or an siRNA.

Within these classes, non-limiting examples of active agents are:

protease inhibitors: plasma-derived C1-INH concentrates, e.g.(Sanquin)、(CS L Behring, L ev Pharma) andand recombinant human CI-inhibitors, e.g.

Soluble complement modulators soluble complement receptor 1(TP10) (Avant immunothereutics); sCRl-s L e^x/TP-20(Avant Immunotherapeutics)；MLN-2222/CAB-2(MilleniumPharmaceuticals)；Mirococept(Inflazyme Pharmaceuticals)；

Therapeutic antibodies: eculizumab/soliris (alexion pharmaceuticals); pexelizumab (Alexion Pharmaceuticals); ofatumumab (Genmab A/S); TNX-234 (Tanox); TNX-558 (Tanox); TA106(Taligen Therapeutics); neutrazumab (G2 therapeutics); anti-properdin (novamed therapeutics); HuMax-CD38(Genmab A/S);

complement component inhibitors: Compstatin/POT-4(Potentia Pharmaceuticals); ARC 1905 (Archemix);

receptor agonists PMX-53(Peptech L td.); JPE-137 (Jerni); JSM-7717 (Jerni);

others, recombinant human MB L (rhMB L; Enzon Pharmaceuticals).

In one embodiment, the present invention provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a patient in need thereof an effective amount of a composition comprising a compound of the present invention. In one embodiment, the compositions of the invention are administered in combination with an anti-VEGF agent. Non-limiting examples of anti-VEGF agents include, but are not limited to, Abbericept (R) ((R))Regeneron Pharmaceuticals); ranibizumab (b)Genentech and Novartis); and pegaptanib (OSI Pharmacesicals and Pfizer); bevacizumab (Avastin; Genentech/Roche); anecortave acetate, squalamine lactate, and corticosteroids including, but not limited to, triamcinolone acetonide.

In another embodiment, the compound of formula I may be used in combination with a second agent to treat an ocular disease.

Examples of the types of therapeutic agents that may be used in combination for ocular applications include anti-inflammatory agents, antimicrobial agents, anti-angiogenic agents, immunosuppressive agents, antibodies, steroids, ocular hypotensive agents, and combinations thereof. Examples of therapeutic agents include amikacin, anecortave acetate, anthracenedione, anthracyclines, azoles, amphotericin B, bevacizumab, camptothecin, cefuroxime sodium, chloramphenicol, chlorhexidine bichlorophenformin, chlorhexidine gluconate, clotrimazole cephalosporin, glucocorticoids, dexamethasone (desamethazone), econazole, ceftazidime, epidophyllotoxin, fluconazole, flucytosine, fluorouracil, fluoroquinolones, gatifloxacin, glycopeptides, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides, miconazole nitrate, moxifloxacin, natamycin, neomycin, nystatin, ofloxacin, polyhexamethylene biguanide, prednisolone acetate, piperazinone sodium, platinidine analogs, polymyxin B, propane isethionate, Pyrimidine nucleosides, ranibizumab, squalamine lactate, sulfonamides, triamcinolone acetonide, triazoles, vancomycin, anti-Vascular Endothelial Growth Factor (VEGF) agents, VEGF antibodies, VEGF antibody fragments, vinca alkaloids, timolol, betaxolol, travoprost, latanoprost, bimatoprost, brimonidine, dorzolamide, acetazolamide, pilocarpine, ciprofloxacin, azithromycin, gentamycin, tobramycin, cefazolin, voriconazole, ganciclovir, cidofovir foscarnet sodium, diclofenac, nepafenac, ketorolac, ibuprofen, indomethacin, fluoromethalone, rimexolone, renolone, anecortave, cyclosporine, methotrexate, tacrolimus, and combinations thereof. Examples of ocular diseases that can be treated according to the compositions and methods disclosed herein include ameba keratitis, fungal keratitis, bacterial keratitis, viral keratitis, discoid keratitis (onchocercecalkeratitis), bacterial keratoconjunctivitis, viral keratoconjunctivitis, corneal dystrophic diseases, Fuchs endothelial dystrophy, Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune dry eye disease, environmental dry eye disease, corneal neovascular disease, prevention and treatment of rejection following corneal transplantation, autoimmune uveitis, infectious uveitis, anterior uveitis, posterior uveitis (including toxoplasmosis), panuveitis, inflammatory diseases of the vitreous or retina, prevention and treatment of endophthalmitis, macular edema, macular degeneration, age-related macular degeneration, proliferative and non-proliferative diabetic retinopathy, hypertensive retinopathy, uveitis, uveal retinopathy, uveitis, uveal degeneration of the cornea, ocular inflammation, and ocular inflammation, Retinal autoimmune diseases, primary and metastatic intraocular melanoma, other intraocular metastatic tumors, open angle glaucoma, closed angle glaucoma, pigmentary glaucoma and combinations thereof.

The compound of formula I or a combination of formula I and another active agent can be administered into the ocular compartment via injection into the vitreous cavity, subretinal space, subchorionic space, episcleral layer, conjunctiva, sclera, anterior chamber, and cornea and compartments therein (e.g., subendothelial, intrastromal, endothelial).

In an alternative embodiment, a compound of formula I or a combination of formula I and another active agent may be administered into the ocular compartment by binding to a mucosa-penetrating particle to treat a condition located in the vitreous cavity, subretinal space, subchondral space, episcleral, conjunctiva, sclera, or anterior chamber, as well as the cornea and compartments therein (e.g., subendothelial, intrastromal, endothelial). Mucosal penetrating particles are known in the art and are described, for example, in PCT published application WO 2013166436 to Kala Pharmaceuticals, which is incorporated herein by reference in its entirety.

In other embodiments, compositions suitable for topical administration to the eye comprising a compound of formula I are provided. The pharmaceutical composition comprises a plurality of coated particles comprising a core particle comprising a compound of formula I, wherein formula I constitutes at least about 80 wt.% of the core particle, and a coating comprising one or more surface-altering agents, wherein the one or more surface-altering agents comprise at least one of a poloxamer, a poly (vinyl alcohol), or a polysorbate. The one or more surface-altering agents are present on the outer surface of the core particle at a density of at least 0.01 molecules/nm. The one or more surface modifying agents are present in the pharmaceutical composition in an amount between about 0.001% to about 5% by weight. The plurality of coated particles has an average minimum cross-sectional dimension of less than about 1 micron. The pharmaceutical composition further comprises one or more ophthalmically acceptable carriers, additives and/or diluents.

One of ordinary skill in the art will appreciate that particles suitable for use with the methods disclosed herein can exist in a variety of shapes, including but not limited to spheroids, rods, discs, pyramids, cubes, cylinders, nanospirals, nanosprings, nanorings, rod-like particles, arrow-like particles, tear-drop-like particles, tetrapod-like particles, prismatic particles, and a variety of other geometric and non-geometric shapes. In some embodiments, the particles disclosed herein have a spherical shape.

In one embodiment, the present invention provides a method of treating or preventing Paroxysmal Nocturnal Hemoglobinuria (PNH) by administering to a patient in need thereof an effective amount of a composition comprising a compound of the present invention. In one embodiment, the present invention provides a method of treating or preventing Paroxysmal Nocturnal Hemoglobinuria (PNH) by administering to a patient in need thereof an effective amount of a composition comprising a compound of the present invention in combination or alternation with another complement system inhibitor or another active compound having a different biological mechanism of action. In another embodiment, the present invention provides a method of treating or preventing Paroxysmal Nocturnal Hemoglobinuria (PNH) by administering to a patient in need thereof an effective amount of a composition comprising a compound of the present invention in combination or alternation with eculizumab.

In one embodiment, the present invention provides a method of treating or preventing rheumatoid arthritis by administering to a patient in need thereof an effective amount of a composition comprising a compound of the present invention. In one embodiment, the invention provides a method of treating or preventing rheumatoid arthritis by administering to a patient in need thereof an effective amount of a composition comprising a compound of the invention in combination or alternation with an additional complement system inhibitor. In another embodiment, the invention provides a method of treating or preventing rheumatoid arthritis by administering to a patient in need thereof an effective amount of a composition comprising a compound of the invention in combination or alternation with methotrexate.

In certain embodiments, the compound of formula I is administered in combination or alternation with at least one anti-rheumatoid arthritis drug selected from the group consisting of salicylates including Aspirin (Anacin, Ascriptin, Bayer Aspirin, Ecotrin) and salsalate (Mono-Gesic, Salgesic), non-steroidal anti-inflammatory drugs (NSAIDs), non-selective inhibitors of cyclooxygenase (COX-1 and COX-2) enzymes including diclofenac (Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis), naproxen (Alevesyn, Naprosyn), piroxicam (Feldene), etodolac (L odine), indomethacin, oxaprozin (Dadaro), nabumetone (Relan) and Mobilec, selective cyclooxygenase-2 (2) inhibitors including celecoxib (Celrex), cysteine (Paciferol), prednisolone (Deltazar), and sulfadimidine (sulfadoxine), thioredoxin (Deltazar), dexrazine (Altexolone (TM), dexrazine (TM), prednisolone (TM), prednisone (Redoxine), and doxine (enteric), or a), a (enteric, prednisone (enteric), or a (enteric), a (enteric, prednisone (enteric), a) and a (enteric, or enteric, or enteric, or enteric, or enteric, including any of an, including enteric, or enteric, including enteric, or enteric, including enteric, or enteric, or enteric, including enteric, or enteric, or enteric.

In one embodiment, the present invention provides a method of treating or preventing multiple sclerosis by administering to a patient in need thereof an effective amount of a composition comprising a compound of the present invention. In one embodiment, the invention provides a method of treating or preventing multiple sclerosis by administering to a patient in need thereof an effective amount of a composition comprising a compound of the invention in combination or alternation with an additional complement system inhibitor. In another embodiment, the invention provides a method of treating or preventing multiple sclerosis by administering to a patient in need thereof an effective amount of a composition comprising a compound of the invention in combination or alternation with a corticosteroid. Examples of corticosteroids include, but are not limited to, prednisone, dexamethasone, methylprednisolone, and methylprednisolone.

In one embodiment, a compound of formula I is used in combination with at least one anti-multiple sclerosis agent selected from Aubagio (teriflunomide), Avonex (interferon β -1a), Betaseron (interferon β -1b), Copaxone (glatiramer acetate), Extavia (interferon β -1b), Gilenya (fingolimod), L emtrada (alemtuzumab), Novantrone (mitoxantrone), Plegridy (polyethyleneglycol interferon β -1a), Rebif (interferon β -1a), Tecferi (dimethyl fumarate), Tysabri (natalizumab), Solu-Med (methylprednisolone), High-dooral Delosone (prednisone), H.P.Acthar gel (ACTH), and combinations thereof.

In one aspect, the compound or salt of formula I may be provided in combination or alternation with an immunosuppressive or anti-inflammatory agent.

In one embodiment of the invention, the compounds described herein may be administered in combination or alternation with at least one immunosuppressive agent. As a non-limiting example, the immunosuppressive agent can be a calcineurin inhibitor, e.g., a cyclosporin or an ascomycin, such as cyclosporin AFK506 (tacrolimus), pimecrolimus; mTOR inhibitors, e.g. rapamycin or derivatives thereof, such as sirolimusEverolimusTemsirolimus, zotarolimus, bairolimus (biolimus) -7, bairolimus-9, rapar analogs such as ridaforolimus, azathioprine, alemtuzumab 1H, SIP receptor modulators such as fingolimod or analogs thereof, anti-I L-8 antibodies, mycophenolic acid or salts thereof, e.g., sodium salts or prodrugs thereof, such as mycophenolate mofetilOKT3(ORTHOCLONE) A prednisone, Brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tripterygium and leflunomideCT L AI-Ig, anti-CD 25, anti-I L2R, basiliximabDalizumabMizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus,) CT L a41g (acarpol), belazepril, L FA31g, etanercept (by Immunex andsale), adalimumabResist againstInfliximabanti-L FA-1 antibody, natalizumabEnromazumab, gavelomazumab, anti-thymocyte immunoglobulin, cetirizumab, alefacelift, bordeaux, mesalazine, asacol, codeine phosphate, benorilate, fenbufen, naproxen, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

Examples of anti-inflammatory agents include methotrexate, dexamethasone alcohol, dexamethasone sodium phosphate, fluoromethalone acetate, fluoromethalone alcohol, loteprednol, medroxypron, prednisolone acetate, prednisolone sodium phosphate, acebutolone difluoride, rimexolone, hydrocortisone acetate, lodoxylamine tromethamine, aspirin, ibuprofen, suprofen, piroxicam, meloxicam, flurbiprofen, naproxen, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, rofecoxib, glucocorticoids, diclofenac, and any combination thereof.

Process for preparing compounds of formula I

Abbreviations

(Boc)₂Di-tert-butyl O dicarbonate

ACN acetonitrile

AcOEt, EtOAc ethyl acetate

CH₃OH, MeOH methanol

CsF cesium fluoride

CuI cuprous iodide

DCM,CH₂Cl₂Methylene dichloride

DIEA, DIPEA N, N-diisopropylethylamine

DMA N, N-dimethylacetamide

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DPPA diphenylphosphoryl azide

Et₃N, TEA Triethylamine

EtOAc ethyl acetate

EtOH ethanol

HATU 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazole

And [4,5-b ] pyridine 3-oxide hexafluorophosphate salt

HCl hydrochloric acid

ⁱPr₂Net N, N-diisopropylethylamine

K₂CO₃Potassium carbonate

L iOH lithium hydroxide

MTBE methyl tert-butyl ether

Na₂SO₄Sodium sulfate

NaCl sodium chloride

NaH sodium hydride

NaHCO₃Sodium bicarbonate

NEt₃Triethylamine

Pd(OAc)₂Palladium acetate

Pd(dppf)Cl₂[1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (II)

Pd(PPh₃)₂Cl₂Bis (triphenylphosphine) palladium (II) dichloride

Pd(PPh₃)₄Tetrakis (triphenylphosphine) palladium (0)

Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium (0)

PPh₃Triphenylphosphine

RT Room temperature

tBuOK Potassium tert-butoxide

TEA Triethylamine

Tf₂O-Trifluoromethanesulfonic anhydride

TFA trifluoroacetic acid

THF tetrahydrofuran

TMSBr bromotrimethylsilane

t_RResidence time

Zn(CN)₂Zinc cyanide

General procedure

All nonaqueous reactions were carried out under a dry argon or nitrogen atmosphere using anhydrous solvents the progress of the reaction and the purity of the target compound were determined using one of the two liquid chromatography (L C) methods listed below the structures of the starting materials, intermediates and final product were confirmed by standard analytical techniques including NMR spectroscopy and mass spectrometry.

L C method A

Instrument-Waters Acquity Ultra Performance L C

Column of ACQUITY UP L C BEH C182.1 × 50mm,1.7 μm

Column temperature: 40 deg.C

Mobile phase: solvent A: h₂O + 0.05% FA; solvent B: CH (CH)₃CN + 0.05% FA flow Rate 0.8m L/min

Gradient: 0.24min @ 15% B, 3.26min gradient (15-85% B), then 0.5min @ 85% B

Detection UV (PDA), E L S and MS (SQ in EI mode)

L C method B

Shimadzu L C-2010A HT

Column Athena, C18-WP,50 × 4.6.6 mm,5 μm

Column temperature: 40 deg.C

Mobile phase: solvent A: h₂O/CH₃OH/FA is 90/10/0.1; solvent B: h₂O/CH₃OH/FA＝10/90/0.1

Flow rate of 3m L/min

Gradient: 0.4min @ 30% B, 3.4min gradient (30-100% B), then 0.8min @ 100% B

And (3) detection: UV (220/254nm)

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Aryl, heteroaryl and heterocyclic compounds for the treatment of complement mediated diseases

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